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This is normal. Tags: DWL-2100AP, LucidLink Jan 28 How to set D-Link DWL-2100AP to client mode and repeater mode? Dlink DWL-2100AP UsernamesDlink DWL-2100AP Passwords adminblank Enter your username and password in the dialog box that pops up. Step 6: Enter a DNS server to assign to your clients. http://infopoool.com/link-dwl/d-link-airplus-xtreme-g-wireless-access-point-driver.html
FAQs Downloads Specifications How do I change my user name and password on my Access Point? MultiRex99 22,127 views 5:29 Configurar Punto de acceso en Modo repetidor.flv - Duration: 4:38. Dlink DWL-2100AP IP Addresses 192.168.0.50 If you did not see your router's ip address in the list above. Working... http://www.dlink.com/uk/en/support/product/dwl-2100ap-xtremeg-108m-wireless-access-point
The key is an alpha-numeric password between 8 and 63 characters long. This feature is not available right now. The default IP address is 192.168.0.50. How do I format my microSD card on my D-Link Omna 180 Cam HD DSH-C310 camera?
FotoMonello dm 14,300 views 0:51 Wireless Bridges for Networking - Duration: 12:53. Do not disconnect the Ethernet cable or power cycle the unit during this process. D-Link DWL-2100AP drivers are tiny programs that enable your Wireless Access Point hardware to communicate with your operating system software. D-link Dwl-2100ap Software Download Note: If you are connecting to a router or a DHCP server, the DHCP server on the access point should be disabled.
SupportSupportDWL-2100AP XtremeG 108M Wireless Access Point Support DWL-2100AP - Revision A Product Status - Phased Out What does this mean? Step 3: Open a web browser and enter in the IP address of the access point (192.168.0.50). cesarchevez1520 37,408 views 8:30 Extend your WiFi range with WiFi repeater setup - Duration: 6:41. find this Loading...
Working... D Link Dwl 2100ap Manual About Press Copyright Creators Advertise Developers +YouTube Terms Privacy Policy & Safety Send feedback Test new features Loading... Learn more Ok Home Solutions Business Solutions Service Provider Solutions Where To BuyPartnersPressAbout D-Link UK D-Link Sign In > Tech Alerts FAQs D-Link Services Warranty Need help? To disable it, select disabled using the drop-down list.
Step 1: Connect the DWL-2100AP to your PC using an Ethernet cable. have a peek at this web-site D-Link around the web Contact UsPrivacyTerms of useSitemap © 2012-2017 D-Link (Europe) Ltd. D'link Dwl-2100ap Default Ip Step 3: Next to Super Mode, select the mode you would like to use from the drop-down menu. Dwl-2100ap Firmware Note: If you are configuring your access point from a wireless adapter, you will lose connectivity as soon as you click Apply.
No thanks Try it free Find out whyClose D-Link AirPlus Xtreme G DWL-2100AP Wireless Access Point Rakuten.com Loading... check over here Rakuten.com 50,859 views 0:57 How to setup Dlink wifi router? - Duration: 7:50. Life of the Rich 2,162,445 views 3:20 setting ap DWL 2100 AP sebagai client - Duration: 3:46. Enter the MAC address of the device you want to repeat (IE 50:23:AB:D4:56:E1). Dwl-2100ap Default Password
How do I reset my access point back to factory default settings? Cancel Unsubscribe Working... The throughput transmission speed limit when using Super G is claimed to be up to 40Mbit/s-60Mbit/s at a 108Mbit/s signaling rate, which is achieved through the bonding of two 54Mbit/s 802.11g http://infopoool.com/link-dwl/d-link-dwl-2100ap-driver.html Login to the Dlink DWL-2100AP Router The Dlink DWL-2100AP has a web interface for configuration.
Working... D Link Dwl 2100ap Reset Click OK. To launch the LucidLink Management Console when Windows starts click the check box next to Automatically open the LucidLink Management Console whenever Windows starts.
Access Point, Bridge PtP, Bridge PtMP y AP Cliente, · Seguridad Avanzada, WPA y 802.1x, · Antena desmontable con conector RSMA, · DHCP Server · Fácil Instalación, · Alto Rendimiento, y Step 7: Select a lease time from the drop-down list. Johnny P 75,382 views 1:13 Install and Secure a Wireless Access Point (WAP) Part 2 of 2 - Duration: 9:47. Dwl-2100ap Price FotoMonello dm 14,300 views 0:51 AP Dlink2100 modorepetidor.mp4 - Duration: 13:50.
Sign in 12 5 Don't like this video? Press Enter Step 2: The default username is admin (all lower case) and the default password is blank (nothing). What do the different LED status lights mean on the D-Link DCH-S150 DCH-S160? http://infopoool.com/link-dwl/d-link-dwl-2100ap-drivers.html How to Reset the Dlink DWL-2100AP Router To Default Settings If you still can not get logged in then you are probably going to have to reset your router to its
Loading... If you are repeating a wireless router, then you must use the LAN or Ethernet MAC address, not the wireless address. Sign in to add this to Watch Later Add to Loading playlists... D-Link Wireless 1 Comment » Super G is Atheros' proprietary frame-bursting, compression and channel bonding technology to improve IEEE 802.11g wireless LAN performance.
She is available on Google+ and you can find more of her articles in the Networking section of our site. Client mode allows any device with an Ethernet connection to connect to your wireless network, such as a printer, gaming console (Xbox, PS2), or a computer. Show more Language: English Content location: United States Restricted Mode: Off History Help Loading... The username is admin (all lower case) and the password is blank (nothing).
Kevin Lowery 369,988 views 5:22 Test D-Link air plus 2000 DWL-2000AP+ - Duration: 0:51. What do the modes mean on my AP? WPA utilizes 128-bit encryption keys and dynamic session keys to ensure your wireless network's privacy and enterprise security.Read More about WPA-PSK. Sign in to report inappropriate content.
Step 4: Click on Advanced at the top and then click Mode on the left side. You may want to follow our guide called How To Reset your Router. The username is admin (all lower case) and the password is blank (nothing). Other Dlink DWL-2100AP Guides Change your Dlink DWL-2100AP IP Address Download Manuals for Dlink DWL-2100AP Setup DNS for your Dlink DWL-2100AP Dlink DWL-2100AP WiFi Instructions Dlink DWL-2100AP Reset Router to Default
Step 4: By default, DHCP Server is set to Disabled. Geekyranjit 1,419,111 views 6:41 D-Link AirPlus G DWL-G700AP Wireless Access Point - Duration: 0:57.
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{pictures are from this post, in case you're wondering why they look oh-so familiar.}Sam,
Ah, where to begin? How about the way you're always there, willing to have a convo via text about some really strange, personal things? Or...how about all those times we laughed at Clark until our faces turned red and you were on the verge of crying? Good times.
Love you like a sis,
your cousin SA (who really doesn't look anything like you :)

subset: commoncrawl


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Napoleon Bonaparte (French: Napoléon Bonaparte, Italian: Napoleone Bonaparte [napoleɔ̃ bɔnɑpaʁt]; 15 August 1769 – 5 May 1821) was a French military and political leader who rose to prominence during the latter stages of the French Revolution and its associated wars in Europe. (Source)
He has become a major influence and source to those whom study strategy and guerilla tactics.
He is regarded as one of the most admirable and proficient military
commanders of all time. That is why it doesn't hurt to learn a thing or
two from the ambitious General.
Here are 22 inspirational quotes by none other than Napoleon Bonaparte (Source)
1. Friends must always be treated as if one day they might be enemies.
2. The stupid speak of the past, the wise of the present, and fools of the future.
3. We walk faster when we walk alone.
4. If you want a thing done well, do it yourself.
5. Impossible is a word to be found only in the dictionary of fools.
6. Six hours sleep for a man, seven for a woman and eight for a fool.
7. In our time none has the conception of what is great. It is up to me to show them.
8. Death is nothing, but to live defeated and inglorious is to die daily.
9. The surest way to remain poor is to be an honest man.
10. If you wish to be success in the world, promise everything, deliver nothing.
11. If I had not been born Napoleon, I would have liked to have been born Alexander.
12. God is on the side with the best artillery.
13. I would kiss a man's arse if I needed him.
14. If the art of war were nothing but the art of avoiding risks, glory would become the prey of mediocre
15. To extraordinary circumstances we must apply extraordinary remedies.
16. Great men are never cruel without necessity.
17. He who fears being conquered is sure of defeat.
18. Take time to deliberate, but when the time for action has arrived, stop thinking and go.
19. Nothing is more difficult, and therefore more precious, than to be able to decide.
20. Victory belongs to the most persevering.
21. You must not fight too often with one enemy, or you will teach him all your art of war.
22. Soldiers generally win battles; generals get credit for them.
Young entrepreneur, assiduous economist, and media innovator Hugo D. Aviles uses his site to share in detail his ideas, challenges and failures along the way. As he provides easy to digest advice, as well as, compelling inspirational stories to reinforce the importance of why working hard and smart is essential.
Wednesday, December 19, 2012
Tuesday, December 18, 2012
Take on a part time hustle or apprenticeship...
For those who are dead set in starting a company from the ground up or jumping into the world of Entrepreneurship. I can't help but to stress the fact that you have to crawl first, before you take the first step, or even sprint. If you take a look at the average corporate 40 hr work week, which usually consists of 9am -5pm, Monday to Friday, there is still ample time for you to start working on a part time hustle or apprenticeship.
Figuratively speaking, you can do some serious damage from the hours of 7pm-12am. That's another 20 productive working hours that you can use to either master a craft, or build the foundation to your future venture. Multiply that times 50 weeks a year, and you have created 1000hrs of extra revenue generated activity. From a quantitative approach, 1000hrs / 8hr full time work day = 125 work days!
The fact is that you have to learn to capitalize on the energy that your youth admits, while you are young, so you can reap the fruits of your labor in the long term (when you are old). This means that you have to take on as much responsibility and accountability while you are young, in order to augment enough tacit (street) knowledge that you can use towards starting your dream venture.
For those whom are looking for a part time, or either full time grind, the Services Sector and Advertising Industry offers several evolving niches. From social media development to design, the potential for income opportunities are limitless. You just have to step outside of your comfort zone, invest in yourself, and look.
Influenced by the CNN Money article, "Young and restless", an article that addresses the top 20 jobs for young movers and shakers on the come up. I couldn't help but to address the following flourishing career as a Product/Brand Manager.
According to the study; (Source)
Median Pay: $90,100
Most people make: $63,000 (90%)
Top Earners: $108,600 (10%)
"You won't be senior management, but you will have control over developing, managing and marketing an assigned product line. In other words, you get to exercise business savvy and creativity. A sizable salary and launching pad to other high-level marketing jobs are part of the package."
If you need some help researching, feel free to use the global search encyclopedia known as "GOOGLE", or you can check out the following Social Media Job site. http://topsocialmediajobs.com/
Please note that we do not endorse the site in any way, we are just using it as an example. It is a pretty legit job search site though. Just saying..
Visit .......the life and times... www.HugoDAviles.com to reinforce the importance of why working hard and smart is essential. Twitter: @HugoDAviles
Wednesday, December 12, 2012
Inside the mind of one of the greatest boxers of all time, Mike Tyson. [10 Quotes | Video]
1. As long as we persevere and endure, we can get anything we want.
2. Discipline is doing what you hate to do but doing it like you love it.
3. People think I was born this way. They dont know what it took to get this way.
4. When you have something in life that you want to accomplish, greatly, you have to be willing to give up your happiness.
5. Deep in your mind you say, God, I dont want to do this no more, and then you push."
6. No one wants to get up at 4 and run when it's pitch-dark, but it has to be done. The only reason i do it so early is because i believe the other guy isn't doing IT.
7. People wouldn't want to be in my shoes. They really think that wow I can make the money, I can get rich, but if they had to go through some of the things I had to go through they will cry.
8. These guys who have been lily white and clean all their lives, if they went through what I went through, they would commit suicide. They don't have the heart that I have. I've lived places they can't defecate in."
9. I said I'm gonna stick to this boxing shit. I turned my whole life over to boxing. I turned into a complete animal, I turned into a disciplinarian."
10. Sometimes you can't have fun accomplishing your goals. Don't give in.
Visit .......the life and times... www.HugoDAviles.com to reinforce the importance of why working hard and smart is essential. Twitter: @HugoDAviles
Saturday, December 8, 2012
Time is the most valuable asset you don't own. [Mark Cuban Excerpt]
In the game of life, the simple fact is that concentrated practice overtime produces effective results. Understanding the fundamental principle that mastering a craft takes time and patience, is quite the burden to most, as we currently live in an impulse world governed by ADHD, OCD, and my favorite "OPP" and any other letters in the alphabet… The enigma is that we live in a society governed by the media and social pressures that continually stray us away from producing effective results.
As Mark Cuban states in the excerpt below, "When you are good at something, passionate and work even harder to excel and be the best at it, good things happen."
To those whom have the mental discipline to master a craft, I commend you. To those whom are weak and have folded to the pressures of society, please move out of the way of those whom are trying. The world is yours…. Vereour Nusquam
An excerpt from Mark Cuban's Blog "Blog Maverick" … (Source)
I hear it all the time from people. "I'm passionate about it." "I'm not going to quit, It's my passion". Or I hear it as advice to students and others "Follow your passion".
What a bunch of BS. "Follow Your Passion" is easily the worst advice you could ever give or get.
Why ? Because everyone is passionate about something. Usually more than 1 thing. We are born with it. There are always going to be things we love to do. That we dream about doing. That we really really want to do with our lives. Those passions aren't worth a nickel.
Think about all the things you have been passionate about in your life. Think about all those passions that you considered making a career out of or building a company around. How many were/are there ? Why did you bounce from one to another ? Why were you not able to make a career or business out of any of those passions ? Or if you have been able to have some success, what was the key to the success.? Was it the passion or the effort you put in to your job or company ?
If you really want to know where you destiny lies, look at where you apply your time.
Time is the most valuable asset you don't own. You may or may not realize it yet, but how you use or don't use your time is going to be the best indication of where your future is going to take you .
Let me make this as clear as possible
1. When you work hard at something you become good at it.
2. When you become good at doing something, you will enjoy it more.
3. When you enjoy doing something, there is a very good chance you will become passionate or more passionate about it
4. When you are good at something, passionate and work even harder to excel and be the best at it, good things happen.
Don't follow your passions, follow your effort. It will lead you to your passions and to success, however you define it.
Visit .......the life and times... www.HugoDAviles.com to reinforce the importance of why working hard and smart is essential. Twitter: @HugoDAviles
Posted by of Hugo D. Aviles..... at 10:17 AM No comments:
Labels: business motivational quotes, Hugo Aviles, is mark Cuban Cuban, mark Cuban net worth, Mark Cuban wealth, mark Cuban worth, motivation in business, venture capital funds, what is venture capital
Thursday, December 6, 2012
Mark Cuban speaks on his early success & the ability to learn from his failures [Video Interview]
This is a great interview done by "The Financialist" with the "Maverick of Entrepreneurship" Mark Cuban. Mark Cuban speaks on his early success and the ability to learn from his failures. (Source)
No Copyright infringement intended; all material belongs to The Financialist
Visit .......the life and times... www.HugoDAviles.com to reinforce the importance of why working hard and smart is essential. Twitter: @HugoDAviles
Posted by of Hugo D. Aviles..... at 6:43 AM No comments:
Labels: business motivational quotes, Hugo Aviles, is mark Cuban Cuban, mark Cuban net worth, Mark Cuban wealth, mark Cuban worth, motivation in business, venture capital funds, what is venture capital
Wednesday, December 5, 2012
He who fights for honor... [Quote]
Often regarded as one of the greatest military strategists in European history, Hannibal would later be considered one of the greatest generals of antiquity, together with Alexander the Great, Julius Caesar, Scipio, and Pyrrhus of Epirus. (Source)
An excerpt from Hannibal's Ninety-Nine Truths...
He who fights for glory never lives long enough to hear the victory songs.
He who fights for gold is already blinded by the glitter and glare of his own greed, all to soon led astray by all things shiny.
He who fights for sport seldom finds the gods in a sporting mood.
He who fights for love must leave the one he loves the most behind so he can dance with the one
he hates the most.
But he who fights for honor cannot be led astray.
Visit .......the life and times... www.HugoDAviles.com to reinforce the importance of why working hard and smart is essential. Twitter: @HugoDAviles
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List of Possible Research Topics
- The pros and cons of religion
- Satanism (Could it be considered a viable religion?)
- Adoption (Why Not?)
- Body piercing (Is it now part of U.S. culture?)
- Teen angst (Real?)
- Child abuse (1/4 girls 1/6 boys)
- Technology (Downfall of humanity because of it)
- Criminal justice (Are we too easy on inmates?)
- Cults (effects on people)
- Gambling (Good or Bad?)
- Home schooling
- Multiculturalism
- OPRAH (The power she holds)
- Obesity
- Women exploited by Abortion
Potential discipline track: JOURNALISM
Research method I will use: APA
Showalter, Elaine. "Representing Ophelia: Women, Madness, and the Responsibilities of Feminist Criticism." EXPLORING Shakespeare. Online ed. Detroit: Gale, 2003. Student Resource Center - Junior. Gale. Adams City High School. 17 Mar. 2011 <http://find.galegroup.com/srcx/infomark.do? &contentSet=GSRC &type=retrieve &tabID=T001 &prodId=SRC-4 &docId=EJ2115515812 &source=gale &srcprod=SRCJ &userGroupName=adamschs &version=1.0>
Response on "Representing Ophelia"
It's way too long. I'll finish reading it later.


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Foot Accessory Navicular Excision
The bones of the foot occasionally develop abnormally in a child and an extra bone called an accessory navicular is present towards the inside of the foot, in front of the ankle. This bone is present in approximately 10% of the general population but not large enough to cause symptoms in the majority of these individuals. The extra bone lump present in childhood can be quite uncomfortable because it rubs on shoes. In addition, the feet associated with the accessory navicular are invariably flat. If the child is active and involved in various athletic activities, this will aggravate the inflammation of the tendon that attaches to the accessory navicular. This tendon is called the posterior tibial tendon and is responsible for maintaining the strength of the arch of the foot. The flat-footedness associated with the accessory navicular usually brings the child for treatment.
It is commonly believed that the posterior tibial tendon loses its vector of pull to heighten the arch. As the posterior muscle contracts, the tendon is no longer pulling straight up on the navicular but must course around the prominence of bone and first pull medially before pulling upward. In addition, the enlarged bones may irritate and damage the insertional area of the posterior tibial tendon, making it less functional. Therefore, the presence of the accessory navicular bone does contribute to posterior tibial dysfunction.
Adolescence is a common time for the symptoms to first appear. This is a time when bones are maturing and cartilage is developing into bone. Sometimes, however, the symptoms do not occur until adulthood. The signs and symptoms of accessory navicular syndrome include a visible bony prominence on the midfoot (the inner side of the foot, just above the arch) Redness and swelling of the bony prominence. Vague pain or throbbing in the midfoot and arch, usually occurring during or after periods of activity.
Accessory navicular syndrome is diagnosed by asking about symptoms and examining the foot for skin irritation and swelling. Doctors may assess the area for discomfort by pressing on the bony prominence. Foot structure, muscle strength, joint motion and walking patterns may also be evaluated.
Non Surgical Treatment
Most cases of accessory navicular syndrome may be treated conservatively with some sort of immobilization. This should allow the fibrous tissue between the two bones to heal. If a patient is extremely flat footed (pronated) then I lean more towards an orthotic than a boot as my main goal is to keep the patient's foot from flattening out too much and thus reduce the strain on the two bones. Supplementation with ice, oral anti-inflammatory medication. If the patient is athletic sometimes we Can you have an operation to make you taller? keep them active with an orthotic, but other times they have to give up their sport for a period of time to allow the condition to heal.
Surgical Treatment
In my experience, the Modified Kidner procedure is one of the most reliable operations for reducing arch pain associated with an accessory navicular bone (a.k.a. os tibial externum). You can also use this procedure to treat a prominence at the inner aspect of the arch, which has been caused by an enlarged navicular bone. The most common patients to visit our office with these problems are between the ages of 8 and 15 and are involved in activities like ice skating, ballet and soccer.
برچسب: How do you get Achilles tendonitis?، What causes pain in the back of the heel?، How we can increase our height?،
ادامه مطلب
+ نوشته شده: ۲۲ مرداد ۱۳۹۶ساعت: ۰۷:۴۷:۲۱ توسط:Mercedes Plunkett موضوع:


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Hi there, It's that guy who posted that weird sounding violin sonata .
I thank every one who took their precious 5 minutes and 31 seconds and listen to that song ... I tried very hard to make it sound at least a little more uh... "ambient" realistic but I can't seem to get that duet effect ... I tried the ambience thing a few million times, can't seem to get the real effect. Think it's the music?
Someone wanna lend the newbie a hand ? lolz


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Discipline is one area where I fail miserably as a parent. I have discussed my concerns with many experienced parents and have read a number of articles to help me grasp the problems I encounter. But somehow, I have always felt inadequate in being able to discipline my 4-year-old.
Root Cause of failure in disciplining my child:
After investing lot of time and speculation, I've arrived at three key issues that have been keeping me from achieving desired results:
- When I was a child, my parents' temper had been the major disciplining force. I used to be too scared of the consequences which would entail severe scolding (only) if I dared to be mischievous or didn't do as I was asked to. This approach when tried, left me feeling miserable and guilty to no bounds and hence I promised myself to not adopt it on my child. Beyond this, I had no inkling on how to inspire my child to adopt a disciplined life.
- The bouts of depression that came along with my divorce, unfortunately, left me confused, broken, frustrated and scared of landing up with the mammoth responsibility of being a single parent. I was in a fragile state of mind, unsure of myself and clueless of how I'll give my child a good life.
- My child and I are temperamentally poles apart. The many challenges parenthood hurled my way infused me the feeling of being a failure parent. I have often caught myself sinking in the ocean of the notion that I am not a good enough parent when it comes to understanding my child.
It took me a lot of homework, introspection and delving into my pent-up emotions to chalk out the above three issues. But ever since I had the clear picture in view, I knew what all I had in hand and what areas I needed to work on.
Modus Operandi:
I had to begin working on my own self to reach an acceptable point of exercising methods of disciplining my child. The journey has been uphill and failures frequent. However, my guiding light has been my determination to evolve as a calmer, clear-headed, smart parent.
I have been guilty of yelling at my child, trying to scare her with negative consequences for bad behavior and failing miserably to implement them. I have written at length about the reasons for the same here and here.
After many hits and misses, I came to realize that for my child the one thing that works well is positive discipline. Positive reinforcement. Praising the good, ignoring the mistakes and encouraging the child to work on their strengths. With anger & frustration keeping me at my wit's end putting it into practice has been very tough for me.
Pari has been a stubborn kid since birth. Her obstinate behavior makes her fight all odds and people irrespective of who they are to do things as she pleases. Locking horns with her were taking me nowhere and were injecting frustration enough to make me go insane day by day.
That's when I decided in my heart to play to her strengths. I had to learn to let go more than my over-cautious self would normally allow. I had to learn to choose my battles wisely. I had to train myself to see the bigger picture of letting her eat instant noodles for dinner before an exam rather than blowing the nutritious food trumpet all the time.
Not wanting to do the homework on an evening is seen as a crime in my family. It took me long to let Pari be and not get dark circles worrying about the homework not done because when I chose to let her be, she surprised me by waking earlier than usual and finishing it before going to school.
Setting clear expectations has helped me big time. Earlier, when I wasn't clear on my expectations from her, I was only adding to her baffled state and my misery. Gradually, I have learnt to picture situations and plan ahead.
I now talk to Pari openly, honestly and as clearly I can make it. I encourage dialogue so that we are clear about where we're coming from and she is coherent of my expectations from her. I tell her before every activity (be it eating, homework, outing, shopping, et al) what all is expected of her and what she can give a miss if she pleases. It's our private talk, but she is briefed beforehand that keeps her carefree and myself relaxed from the anxiety of checking her endlessly.
In the year gone by, I have come a long way in disciplining. Pari still acts stubborn, gets on my nerves with her wrong choices leading to harmful consequences (like catching a cold for eating ice-cream in cold weather). You can see us mother-daughter fight like siblings, not talking to each other for an hour or two, I sometimes lose my patience under work stress but overall, with time we're getting saner.
Though there's a long way to go and I am aware there will never be a point when I'll master the art of disciplining my child. But, life is about constant improvement. I am getting wiser with every mistake I make. I am getting calmer with every knot I've managed to untangle in my mind. I am getting smarter as I am able to understand my child's temperament better with each experience we share.
I am working on setting a positive example by being what I expect her to be. Working hard (read very hard) to control my stress levels and give her positive attention. I'm sure someday I'll be a lot clearer on this topic than I am today.
But most of all, I take a moment out every day to let Pari feel that I love her unconditionally no matter what may happen.
How difficult has disciplining your child been for you?
Which method(s) of disciplining work best for your child?
* This post is part of the April A to Z Challenge 2016. My theme is Parenting.
Please find my other posts here.


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Eltamd UV Clear SPF 46, 48-Gram 1.7 oz.
Product prices and availability are accurate as of the date/time indicated and are subject to change. Any price and availability information displayed on this site at the time of purchase will apply to the purchase of this product
EltaMD UV Clear Broad-Spectrum SPF 46, 1.7 oz
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Product Description
EltaMD UV Clear SPF46 1.7 oz helps calm and protect sensitive skin types prone to breakouts, rosacea and discoloration. It contains niacinamide (vitamin B3), hyaluronic acid and lactic acid, ingredients that promote the appearance of healthy-looking skin. Very lightweight and silky, it may be worn with makeup or alone. Choose from tinted and untinted formulas for use every day.
- Antioxidant protection combats skin-aging free radicals associated with ultraviolet (UV) and infrared radiation (IR).
- Calms and protects acne-prone skin and leaves no residue
- Fragrance-free, oil-free, paraben-free, sensitivity-free and noncomedogenic


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Chip Cummings, Host on the Financial Fitness Show! a nationally-syndicated radio program recently interviewed Sgt. Buschena about "Kick Ass Home Security!"
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So there's been LOTS of heroes asking me to feature their parties on my blog! And I can now confirm, that I'm so totally WILL! I've created a page called 'Party of the Week', where you heroes can send in your most party-tastic and groovin' pics of parties, and I'll pic the best and feature it there, AND on the sidebar! Here's the current party of the week:
AAAND it doesn't just stop there, you can now HOST parties on the SHU Fansite too! Here's the first:
COOL HUH?! So remember, check out my 'Party of the Week' page HERE!!!! What are you waiting for? Have some fun, have a party with some friends and send in your amazing pics!
PARTY ON HEROES~ Lillia


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Artsy Tattoo Video [Video]
Check this chick get a sleeve of non Disney - Alice in Wonderland on her arm ... turn your speakers off though the song that's accompanying it is terrible. Unless you're high on something I guess, then it's probably amazing.
dedicated from kristopher chandroo on Vimeo.


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[Page: S2905] GPO's PDF
Mr. BROWN of Ohio. Madam President, I just met in a room near the Senate floor with doctors and others from three of America's great children's hospitals: Rainbow Children's Hospital in Cleveland, Nationwide Children's Hospital in Columbus, and Cincinnati Children's Hospital. I think Ohio leads the Nation in the number of children's hospitals and, frankly, I think the quality of children's hospitals.
There are so much we need to do--I know the Presiding Officer from North Carolina sits on the Health, Education, Labor, and Pensions Committee and has had an interest in this--where we don't quite focus enough attention on children's health. In the past, when we did research in this country--and we are only now beginning to change this--we used to think about children as just small adults, and if you needed X milligrams in a prescription for a 150-pound adult, for a 30-pound child you gave them one-fifth as much. We now realize that is not the way we should do research or practice medicine. So we have seen a lot of progress, and much of that comes from the activism, if you will, of doctors and nurses and administrators at Nationwide Children's in Columbus, Cincinnati Children's, and Rainbow Children's in Cleveland, affiliated with the University Hospital.
We have been able, through a longtime program--about a dozen years old now--to do something called children's gradual medical education in training pediatricians. We have also seen it find its way into making pharmaceuticals--something called 340B--and getting pharmaceuticals, particularly for orphan drugs and rare diseases, to children's hospitals, which helps many small children in this country.
We are also working on legislation--and Kit Bond, the Republican Senator from Missouri who retired in January, and I worked on this--to really focus on pediatric research and designate a handful of children's hospitals--maybe 15 or 20--around the country, some of the best research hospitals, to get them more focused on children's research because even though we have done better, we are not doing well enough, and this is an opportunity to do that.
So I wanted to share on the floor with my colleagues the importance of this legislation, the importance of that focus on children's hospitals, the importance of training pediatricians, and the importance of children's hospitals overall to our Nation's health, especially as regards the future of our Nation and our children.
Madam President, I yield the floor.


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Fans of the popular Bit.Trip Beat on WiiWare will be pleased to know there's sequel well underway, in the form of Bit.Trip Core.
Bit.Trip Core has you controlling a canon which can fire in one of four directions (up, down, left and right). Here's a trailer:
3,040 news items
Jettwinlock said:
That game looks awesome.
NBA Playgrounds new content teaser
Switch must wait again
The Serious Problem Brewing for Pokemon GO!
A day with Pokemon GO Down Under
Adventure awaits.
Splatoon's Last Ever Splatfest is Coming
And It's Sister vs. Sister
Nintendo President Satoru Iwata Passes Away at 55
Rest In Peace
Nintendo has detailed the return of its World Championship
Do you have what it takes?
Disney Infinity 3.0 Edition Officially Revealed
The Force is strong with this one...
Rumor: Disney Infinity 3.0 Leaked Early
Straight from a Galaxy Far, Far Away...
Mario Kart 8 DLC Pack 2...OH YEAAAAH!
Nintendo should do this more.
oo said:
bagy ... My Baby First Steps
8uyu8 said:
kghkuygiuuuuuuujh ... Tom and Jerry: War of the Whiskers
Rob Jones said:
@mdog86 that might make more sense! Not that bulb boy is big on making sense. ... Bulb Boy review
mdog86 said:
I like to think that that mouse underwater was supposed to be deadmau5 lol ... Bulb Boy review
WeSkiStar said:
HA! Don't use the Miis, they look way out of place when everybody else looks like hand-drawn generic kawaii ppl. If you ... We Ski
Wii's World is not officially affiliated with Nintendo! (but they wish we were).


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The special CBI court on Wednesday issued a notice to Lalu Prasad Yadav's son and former Bihar deputy chief minister Tejashwi Yadav for contempt of court.
It was believed that other RJD leaders were also issued a notice in connection with the contempt of court.
While speaking to the media, lawyer Arvind Singh said in a statement, "The CBI court of Shivapal Singh issued the notices asking why contempt should not be initiated against the four people for their statements issued after Lalu Prasad was convicted".
It was learned that earlier the court has said that the quantum of sentence against Rashtriya Janata Dal (RJD) chief Lalu Prasad and others in connection with fodder scam will be pronounced on Thursday.
Meanwhile, Manoj Jha expressed his shock over the judgment and said, "It is shocking because none of us uttered a single word against the judicial process or the judgment".
The CBI court has summoned them to appear in front of the court on January 23.
Prabhat Kumal legal counsel for Lalu Yadav said that all four has been issued notices as the court found their statements as contemptuous.


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Today driving from Cupar to Newburgh North Fife on well gritted roads approaching Parbroath crossroads. A fantastic landscape rich in history and beauty. On crossing the A92 Kirkcaldy to Dundee road to the right Normans Law becomes dominant. Click to view at other times of the year.
Normans Law with sign indicating self catering cottages for rent. A good choice since they offer hot tubs, perfect for this time of the year.


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Exactly one year ago, I learned that I was diagnosed with Leukemia. We didn't know at the time that it was CML, just that my white count was about 20 times what it was supposed to be. I spent some time today re-reading those e-mails from the first few days, and reliving those days. I'm not sure a professional would say that it's healthy or not to relive the darkest days of your life, but I felt it was important to understand where I was when I started this journey. I've always felt it was important to understand where you have been, before charting a course forward.
What sticks with me, was the incredible support and comfort I received from family, friends, co-workers those first few days and continue to this day. Our familes have stepped up to help in any way they can, and as I write this Cynthia's mother and aunt are staying with her, to help with the kids and anything else she needs, while I'm down in Portland. But the greatest impact to my current situation, is Cynthia giving me the space to get myself in a better place, and there when I needed someone to take over when I wasn't up for it. I think we have definately challanged the wedding vow that talked about in sickness and health.
So I ask myself, why even relive those painful moments in my past, and simply let history be ? In my case, it puts in perspective where I am now, and how much has happened since. The sky hasn't fallen, I'm not feeling ill, and Syracuse basketball is playing better than they have since 2003 when they won the National Championship. The point I am trying to make, is that life has continued, even improved in many ways. The arrival of our 2nd boy Alex has allowed us to rekindle the memories of lack of sleep and being thrown up on constantly. Christian at age 3 is allowing us to rediscover wonders all around us. Many times I wish I could see life as he sees it, I imagine that things are simple, and there is no fear in life (other than the monster in his room at times). But even then we overcome the monster by hiding under his Thomas blanket…We hide together, and we tell the monster to 'go away'.
I'm feeling very educated about CML, since I have spent countless hours diving into as much information as I could gather. It's difficult sometimes, since it's not like I can buy a CML for dummies book at Amazon, or take at course to learn about this. But knowledge has allowed me to take an active role in my treatment, and also be able to communicate with my doctor when needed. I decided that I'm not settling on simply following the prescribed treatment, and being in the trial was due to reaching out and learning about other options. If it wasn't for the trial drug, I would literally be in the midst of a transplant these days since that would be my only option. I have networked with other CML patients, and both found comfort in their stories, and in some case grief when the outcome was not positive. While Tyler is doing good, there are other friends who are worse off, so I don't feel I can rest until we're all out of the woods.
So I ask myself, where am I today ? Well, physically I am sitting down in Portland, part of the Ariad drug trial. I'm feeling great, and I'm anxiously waiting to see if the drug is working as hoped for. Compared to 3 or 6 months ago, I'm actually in a better place in that we now know that the first 2 generations of drugs, wouldn't work since I acquired the T315 mutation. But that is all water under the bridge now. My backup plan (which was like Plan E when we started), is a bone marrow transplant, with my younger sister as a perfect match (10/10). I have to sometimes remind myself that I am only 3-4 weeks away from a transplant at any given time, so that I don't get ahead of myself. One day I imagine I will feel differently, but for now, that is my monster in the room…


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- North America
- United States
- North Carolina
- Grier Field
- Search
Traveling Luck for Grier Field North Carolina, United States
The timezone in Grier Field is America/Iqaluit
Morning Sunrise at 06:14 and Evening Sunset at 20:26. It's light
Rough GPS position Latitude. 35.1322°, Longitude. -80.9383° , Elevation. 192m
Morning Sunrise at 06:14 and Evening Sunset at 20:26. It's light
Rough GPS position Latitude. 35.1322°, Longitude. -80.9383° , Elevation. 192m
Weather near Grier Field Last report from Charlotte, Charlotte / Douglas International Airport, NC 11.4km awayTemperature: 29°C / 84°F
Wind: 5.8km/h Southwest
Cloud: Scattered Towering Cumulus at 3200ft Scattered at 15000ft Broken at 25000ft
Satellite map of Grier Field and it's surroudings...
Geographic features & Photographs around Grier Field in North Carolina, United States
section of populated place a neighborhood or part of a larger town or city.
- Southbourne (subdivision) (0.9km)
- Taragate Farms (subdivision) (1.4km)
- Twelve Oaks (subdivision) (1.9km)
- Olde Whitehall (subdivision) (2.7km)
- Yorkwood (subdivision) (3.1km)
- Windsong Trails (subdivision) (3.8km)
- Lebanon Heights (subdivision) (4.5km)
- Ramblewood (subdivision) (4.6km)
- Colony Acres (subdivision) (4.8km)
- Greycrest (subdivision) (5.5km)
- British Woods (subdivision) (5.5km)
- Ravenwood (subdivision) (5.5km)
Local Feature A Nearby feature worthy of being marked on a map..
- Grier Field (0km)
- Arrowood Southern (1.3km)
- Commerce Industrial Park (2.4km)
- Outlet Marketplace (3.8km)
- Hunters Dairy Farm (4.4km)
- Johnson Horse Farm (historical) (4.4km)
- United States Naval Depot (historical) (4.7km)
- Hart Industrial Park (5.2km)
- Interchange 90 (5.7km)
- Oak Grove Church (historical) (5.8km)
reservoir(s) an artificial pond or lake.
- Johnston Lake (2.3km)
- Johnson Lake (2.4km)
- Moody Lake (3km)
- Number One Settling Basin (4.2km)
- Greenwood Lake (4.3km)
- Spratt Lake (4.6km)
- Maynard Lake (5.5km)
- Creech Pond (5.8km)
school building(s) where instruction in one or more branches of knowledge takes place.
- Robert F Kennedy Middle School (3.4km)
- Olympic High School (4km)
- Lake Wylie Elementary School (4.7km)
- Steele Creek Elementary School (4.8km)
- Charlotte Police and Fire Academy (4.9km)
- Nations Ford Elementary School (5.1km)
- E E Waddell High School (5.8km)
Accommodation around Grier Field
Hilton Garden Inn Charlotte/Ayrsley 1920 Ayrsley Town Blvd, Charlotte
Homewood Charlotte/Ayrsley 1921 Ayrsley Town Blvd, Charlotte
Yorkshire Inn Charlotte 9900 S Tryon St, Charlotte
building(s) a structure built for permanent use, as a house, factory, etc..
- Charlotte Fire Department Station 26 (0.2km)
- Public Library of Charlotte and Mecklenburg County - Steele Creek Branch (0.3km)
- Central Steele Creek Community House (0.4km)
- Charlotte Fire Department Training Academy (4.9km)
- Charlotte Mecklenburg Police Training Academy (4.9km)
- Charlotte Fire Department Station 20 (5.3km)
church a building for public Christian worship.
- Central Steele Creek Church (0.3km)
- Trinity Church (2.4km)
- McClintock Church (5km)
- Mission Church (5.2km)
- Shopton Road Church (5.6km)
stream a body of running water moving to a lower level in a channel on land.
- Coffey Creek (2km)
- Kings Branch (5.8km)
- Walker Branch (5.8km)
populated place a city, town, village, or other agglomeration of buildings where people live and work.
- Steel Creek (historical) (2.7km)
- White Hall (historical) (5.8km)
park an area, often of forested land, maintained as a place of beauty, or for recreation.
airport a place where aircraft regularly land and take off, with runways, navigational aids, and major facilities for the commercial handling of passengers and cargo.
- Carowinds Airport (4.5km)
administrative division an administrative division of a country, undifferentiated as to administrative level.
- Township 3, Steel Creek (5.2km)
tower a high conspicuous structure, typically much higher than its diameter.
- WBT-AM (Charlotte) (5.6km)
canal an artificial watercourse.
- Polk Ditch (5km)
cemetery a burial place or ground.
- Dinkins Cemetery (4km)
dam a barrier constructed across a stream to impound water.
- Johnston Lake Dam (2.3km)
Wikipedia entries close to Grier Field
- Pineville, North Carolina city o city
- Flughafen Charlotte airport airport
- Lake Wylie, South Carolina city o city
- Bank of America Stadium sport landmark
- Tega Cay, South Carolina city o city
- Charlotte Bobcats Arena sport landmark
- Fort Mill, South Carolina city o city
- Riverview, South Carolina city o city
- Charlotte (North Carolina) city c city
- Catawba Nuclear Generating Station building landmark
- Belmont, North Carolina city o city
- Charlotte (Amtrak station) train statio landmark
- India Hook, South Carolina city o city
- Cramerton, North Carolina city o city
- McAdenville, North Carolina city o city
- Mount Holly, North Carolina city o city
Airports close to Grier FieldCharlotte douglas international(CLT), Charlotte, Usa (11.4km)
Hickory rgnl(HKY), Hickory, Usa (99.4km)
Smith reynolds(INT), Winston-salem, Usa (161.5km)
Columbia metropolitan(CAE), Colombia, Usa (169.2km)
Shaw afb(SSC), Sumter, Usa (171.8km)


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I told you yesterday I've spent several weeks being frustrated and angry with God over unmet expectations. In Acts 3 & 4 I saw a story personifying the two options we have to respond to unmet expectations – that of a rejoicing crowd and that of the annoyed Sadducees. I'm a Sadducee most of the time – how can I be a rejoicer instead?
In the story of John & Peter healing the lame man (Acts 3&4) I've most often meditated on the boldness of Peter before the crowd and the Sadducees or the joyous response of the lame man. But overwhelmingly this story is about Jesus. Most of the text is spent reporting Peter's sermons about Jesus. There's a lengthy prayer that's Christ-centered. The author Luke's point was to show off Jesus.
John and Peter were experts on watching God mess up their expectations. They'd spent three years being confused, confounded and annoyed by Jesus. John and his brother had gotten their mom involved in asking for a spot in the earthly kingdom they mistakenly thought Jesus was about to institute. Peter got a verbal backhand by Jesus for trying to make Jesus conform to the common expectations for a victorious Messiah.
But every time their expectations were disappointed, God's plan moved forward. They'd seen over and over again the superiority of God's plan to theirs.
Which is why they preach Jesus to the crowd and the Sadducees. They hadn't planned to preach a sermon nor get thrown in prison that day. But since the opportunity presented itself, they weren't going to waste it arguing with God over their own upset expectations. They knew to look for God's hand instead.
So next time I'm in the middle of being frustrated by the failure of my plan and my unmet expectations – I hope I'm more like Peter and John. I want to bring my focus back to what God is doing. To wait and watch expectantly until I understand what He's got in mind. Because a good sign He's at work is when things aren't going according to my plan!


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SANDOW has sold its Furniture Today Media Group to newly-formed FT Media Holdings, LLC, according to foliomag.com. The company bought the Furniture Today assets from Reed Business Information in 2010.
In addition to the flagship brand and
weekly publication Furniture Today, six other publications — including
Casual Living, Gifts and Decorative Accessories, Home Accents Today,
Home Textiles Today, Kids Today and Playthings — and three annual events
were included in the deal.
For more information, visit foliomag.com.


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Top Ten Toughest Anime Chicksegnomac Anime shows are full of strong and powerful woman who can deliver an ass kicking better than most of the men.
The Top Ten
Defiantly deserves to be #1 she's super strict and is not afraid to show he dominance and will kill anyone that crosses her.
Almost as scary as Izumi Curtis, and that's REALLY saying something. - Absolite
Nobody is afraid of her. They just let her think that so they can run away from her nagging.
PAN can kick her ass. Bulma will probably shoot her in the face with one of her machine guns. Videl and Android 18? Lol they would destroy her.
18 can beat her ass
The only person Goku is scared of.V 1 Comment
She claims to be just a normal house wife but she's so much more than that she's an incredibly powerful Alchemist she even survived at briggs for a whole month she also taught the Elric brothers just don't call her old lady.
Her Dragon Slave attack is extremely powerful enough to destroy an entire city. - egnomac
The Contenders
Yeah! She's tough as hell! !
Shoot! I meant to vote for Saber, but I accidentally clicked on Toph by mistake (although she is a very strong female character as well). Anyways, Saber is definitely one strong King of Knights. Her class being considered the most outstanding, with excellent ratings in all categories, Saber is a force to be reckoned with. Give Arturia Pendragon a higher spot on the list. - ModernSpongeBobSucks
Recommended Lists
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List Stats
4 years, 257 days old
Top Remixes (4)
2. Launch - Dragon Ball
3. Revi - Black Lagoon
2. Chi Chi - Dragon Ball Z
3. Izumi Curtis - FullMetal Alchemist
2. Clare - Claymore
3. Lucy - Elfen Lied
View All 4


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Ken Harris Speaks!!
The first person to die on earth was Abel…the recording is in Genesis 4. But that's not the last time we hear about him. In Hebrews 11, Abel is the lead-off hitter in the list of "Faith Warriors". Hebrews 11:4 states, "…Abel still speaks, even though he is dead."
Ken Harris's faith still speaks and I take liberties to say there are 3 statements he would make. I believe everyone in athletics can learn from him.
- ARRIVE EARLY- Ken kept the score clock at Metrolina for nearly 10 years. In those 10 years, he only missed 2 games. If the game started at 4, which most did, Ken was seated with his green tea, a snack and a towel by 3:15…That's right 45 minutes prior to the game, you'd see Ken. When he met me at my house to fish, he held me accountable as I knew he would be punctual and arrive early.
Arrive early- It shows a great respect for the person who's expecting you.
Arrive early- It demonstrates a personal discipline to prepare.
Arrive early- It tells others, they're important!
For those of us who know the Lord Jesus and know Ken…when we get to Heaven…He's probably going to say one day…what took you so long to get here?
- COMMIT FULLY- Ken took personal ownership of the game clock. He ran the clock on Friday night football and every MS football game when he didn't do Volleyball. In the spring season, he served as an assistant middle school baseball coach…he was truly a 3 sport athlete. He was to have a stint put in his carotid artery early this past spring, however Ken spoke to his cardiologist and asked if he could wait until spring break so he wouldn't miss any baseball games.
Commit Fully- It makes the team stronger.
Commit Fully- It demonstrates sacrifice to others.
Commit Fully- It represents Christ as He committed ALL.
- THANK YOU JESUS, THANK YOU LORD- Every time Ken caught a fish, he treated it as though it was a gift. He would audibly say these words, "Thank you Jesus, Thank you Lord", before dropping his catch back into the lake. Nearly every fishing trip we took, consisted of at least a 45 minute ride. Sometimes we talked, sometimes we just rode. There's a lot to be said early when you're getting to know each other…sometimes silence can be awkward. BUT then you develop that relationship where you don't feel like you have to talk…however if you do, you know the other person's listening. For that I am thankful.
THANK YOU JESUS, THANK YOU LORD- It displays a heart of gratitude to our God.
THANK YOU JESUS, THANK YOU LORD- It reminds us of where our gifts come from.
THANK YOU JESUS, THANK YOU LORD- Ken knows our Heavenly Father and we shall see Ken again.
As for me...I would tell Ken…you fought the good fight, you finished the race, you kept the faith…AND your faith still speaks.
One question for all of us to ponder…"What's your faith saying?"


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$990.00 $693.00
Just because it's fall doesn't mean you can't show a little skin. Crafted from double layers of our lightweight gauzy whisper, this fitted long-sleeve tee features a cold shoulder neckline that adds a sex appeal that is undeniable.93% Cotton, 7% Elastane
Warm iron
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Garnets Sports
Rob Holmes' Big Day
Posted Monday, January 18, 2010 by Jim Powers
Rob Holmes had a Varsity career day on Sunday getting a hat trick - in the 1st period. Rye went on to beat the Whitesboro Warriors 8-2 at the Ice Hutch.
In another glimpse of Rye's future, the Garents' 4th line (Ben Shaffler, CJ Murphy and TJ Carter) played very well against the Warriors.
This page was created in 0.0938 seconds on server 132


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Ozzy Osbourne Waiting for Darkness Lyrics
sponsored linksWaiting for darkness
Doesn't anybody see
Deafened by silence
Doesn't anybody hear.
(I'm waiting darkness)
Playing with fire
But they're screaming
When they're burned
Out of the sunlight
Hasn't anybody learned
I know what they find
Is in their mind
Its what they want to see
Spare me from the light
Here comes the light
And here I'll stay
Waiting for darkness
Promise me rebirth
And then you tear me from the womb
Give me my freedom
And then you lock me in a tomb
I'm waiting for darkness
You gotta believe, you gotta believe its true
I'm waiting for darkness
I just can't concieve why darkness is overdue.
Who knows the answers
Is it friend or is it foe
Don't ask me questions
There are things you shouldn't know
Bark at the Moon Track Listing
1 Bark at the Moon
2 You're No Different
3 Now You See It (Now You Don't)
4 Rock 'n' Roll Rebel
5 Centre of Eternity
6 So Tired
7 Slow Down
8 Waiting for Darkness
Written by: Ozzy Osbourne
Lyrics © BMG RIGHTS MANAGEMENT US, LLC


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Genome-Wide Association Study for Endothelial Growth FactorsCLINICAL PERSPECTIVE
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Background—Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor play important roles in angiogenesis, vascular remodeling, local tumor growth, and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown.
Methods and Results—We performed a genome-wide association study for circulating Ang-2, sTie-2, and hepatocyte growth factor in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. In multivariable-adjusted models, sTie-2 and hepatocyte growth factor concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers (top P=2.40×10−65 [rs2273720] and 3.64×10−19 [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (P=5.05×10−8 in Framingham Heart Study and 8.39×10−5 in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with P=1.84×10−33 in Framingham Heart Study; P=2.53×10−30 in Study of Health in Pomerania) and Ang-2 (rs8176746 with P=2.07×10−8 in Framingham Heart Study; P=0.001 in Study of Health in Pomerania) levels on a genome-wide significant level. The top genetic loci were explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the interindividual variation in biomarker levels.
Conclusions—Genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating hepatocyte growth factor, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.
- angiopoietin-2
- endothelial growth factors
- genetics
- Genome-Wide Association Study
- hepatocyte growth factor
- Tie-2 receptor
Endothelial growth factors play an important role in human physiology. Because of their pivotal effects on angiogenesis and vascular remodeling,1 endothelial growth factors have been implicated in early vascular development,2 the local spread/growth and metastatic potential of various cancers3,4 and the pathogenesis of chronic conditions, including cardiovascular and metabolic diseases.5
Clinical Perspective on p 397
Previous evidence suggests that circulating levels of these endothelial growth factors are heritable. Specifically, 56%, 38%, and 27% of the interindividual variation in soluble Tie-2 (sTie-2), hepatocyte growth factor (HGF), and angiopoietin-2 (Ang-2) concentrations, respectively, were explained by additive genetic factors.6,7 However, the precise genetic underpinnings of circulating Ang-2, Tie-2, and HGF levels are largely unknown. A previous family-based analysis identified significant linkage of sTie-2 levels to a relatively broad locus on chromosome 9, including the Tie-2 gene (logarithm of the odds score, 8.31).7 In the present analyses, we report the results of a genome-wide association study for serum levels of Ang-2, sTie-2, and HGF (discovery sample, n=3571; independent replication sample for Ang-2 and sTie-2, n=3184). Given the moderate to substantial heritability estimates,6,7 we hypothesized that circulating concentrations of all the 3 biomarkers will be associated with common genetic variants.
Discovery Sample (Framingham Heart Study)
The initial genome-wide analyses were performed in participants of the Third Generation cohort of the Framingham Heart Study (FHS).8 At the baseline examination cycle (2002–2005), participants were comprehensively phenotyped, including assessment of standard cardiovascular disease risk factors, a physical examination, and a standardized interview by an FHS physician. The sample sizes available for genome-wide analyses in the discovery sample varied slightly between biomarkers depending on the availability of covariates: HGF, n=3571; Ang-2, n=3574; and sTie-2, n=3574. Written informed consent (including consent to genetic analyses) was provided by all participants and the Institutional Review Board at the Boston University Medical Center approved the study protocol.
Replication Sample (Study of Health in Pomerania)
Replication of single-nucleotide polymorphisms (SNPs) that reached genome-wide significance (P<5×10−8) for association with Ang-2 or sTie-2 levels in the discovery sample (FHS sample) was assessed in participants of the second examination cycle (2002–2006) of the Study of Health in Pomerania (SHIP)-1. SHIP is a community-based sample in Northeast Germany. The study design has been described in detail elsewhere.9 In essence, SHIP represents a random cluster sample, representative of the population of West Pomerania, located in Northeast Germany. The response rate of the SHIP-1 examination cycle was 83.6%.9 The SHIP study was approved by the Ethics Committee of the University of Greifswald. Previous genetic analyses had shown that the SHIP sample is genetically homogeneous and provided no evidence for a genetic drift.10,11 Furthermore, the design effects (because of cluster sampling) on the P values caused by deviation from simple random sampling were negligible. Therefore, the cluster sampling was not taken into account in our genetic analyses.
Biomarker Measurement
In the FHS sample, blood was drawn in the early morning (usually between 7:00 and 9:00 am) after an overnight fast, immediately centrifuged, and stored at −80°C until biomarkers were assayed. Ang-2, sTie-2 and HGF were measured using commercial assays (R&D Inc), as described previously.6,7 The average interassay coefficients of variation for all the 3 biomarkers were low: 5.7% for Ang-2, 3.2% for Tie-2, and 1.6% for HGF.6,7 In SHIP, Ang-2 and Tie-2 were measured likewise using commercially available R&D assays. The minimum detectable concentration was 1.20 pg/mL and 0.001 ng/mL for Ang-2 and for Tie-2, respectively. The interassay coefficients of variation in SHIP were 10.6% and 13.3% for Ang-2, and 5.6% and 6.7% for Tie-2, for low and high biomarker concentrations, respectively.12
Genotyping, Imputation, and Controlling for Population Stratification
FHS participants were genotyped with the Affymetrix Human Mapping 500K Array Set and the 50K Human Gene Focused Panel. The mean call rate was 98%.13 SNPs with a call rate <95% or deviation from Hardy–Weinberg equilibrium (P<10−6) were excluded. As additional quality control measures in FHS and SHIP, the reported sex in the database had to agree with the called sex in the genetic data set, identity by descent estimations were performed to identify and exclude duplicated individuals, and individuals with a high genome-wide heterozygosity rate (beyond 5 SDs of the mean) were removed before analyses.14,15 Genotypes were imputed to the ≈2.5 million SNP of the HapMap CEU panel (release 22; build 36; http://hapmap.ncbi.nlm.nih.gov/) using the Markov Chain Haplotyping (MACH) algorithm.16 Quantile–quantile plots and λ estimates were obtained to assess whether the observed distribution of P values fits the P-value distribution expected under the null hypothesis of no association, except at the extreme tail. Principal component analyses were performed using EIGENSTRAT17 to account for potential population substructures within the FHS data set, but no admixture was observed in the FHS cohort.
SHIP participants were genotyped with the Affymetrix Human SNP Array 6.0 using the Birdseed2 clustering algorithm.11 Pair-wise linkage disequilibrium between SNPs was assessed using the SNP annotation and proxy search (SNAP) tool.18 Details of the exact location of SNPs within or between genes were assessed using the UCSC genome browser (http://genome.ucsc.edu/).
Statistical Analyses
Because of their skewed distributions, all biomarkers were natural logarithmically transformed before performing genetic analyses. Plots of untransformed and transformed concentrations of HGF, Ang-2, and Tie-2 in the FHS sample (Figures IA–IIIA in the Data Supplement) and in the SHIP sample (Figures IB–IIIB in the Data Supplement) are provided in Figures I–III in the Data Supplement. Assuming an additive genetic model with 1 degree of freedom, we related each of the 2.5 million SNPs in the FHS sample to each circulating biomarker (HGF, Ang-2, and sTie-2), using a linear mixed-effects model that accounts for the familial relatedness (R package Genome-Wide Association analyses with Family [GWAF]).19 Specifically, we accounted for familial correlations with a linear mixed-effects model that uses relationship coefficient matrix as within pedigree correlation matrix. The relationship coefficient (which is twice the kinship coefficient) was calculated based on available pedigree information and structure. Multivariable analyses were adjusted for age, sex, and known clinical correlates of each biomarker, as identified in previous analyses in the FHS data set.6–7 These additional covariates were as follows: for Ang-2: smoking, total cholesterol, diastolic and systolic blood pressure, antihypertensive treatment, and diabetes mellitus; for Tie-2: diabetes mellitus, body mass index, estimated glomerular filtration rate, alcohol consumption, and triglycerides; and for HGF: diastolic blood pressure, antihypertensive treatment, high-density lipoprotein cholesterol, triglycerides, smoking, body mass index, and diabetes mellitus. A P<5×10−8 was considered genome-wide significant. A top SNP (rs2442517) of the Ang-2 genome-wide association study with a P=5.05×10−8 was also listed as the P value was close to the genome-wide significance threshold. For each biomarker, we graphically plotted each SNP's P value versus its physical position (Manhattan plot).
The top SNP of each locus associated with Ang-2 and Tie-2 levels in the FHS sample in a genome-wide significant fashion was tested for replication in the SHIP sample, likewise using a linear regression model assuming an additive genetic model and adjusting for the same set of covariates as described above. We did not assess replication of the top SNPs related to HGF concentrations because HGF levels were not available in SHIP.
Pathway Analyses
Pathway analyses were conducted for Ang-2 and sTie-2 combined and separately for HGF using the program Ingenuity Pathway Analysis software package (Ingenuity Systems, Redwood, CA). A SNP score was assigned to each genetic variant. This SNP score was equivalent to the lower P value of the 2 traits (Ang-2 and Tie-2, respectively) examined. For the pathway analysis for HGF, the SNP score was equivalent to the P value for association with HGF. On the basis of the human reference genome (NCBI Build 36, 2006), the location of all SNPs relative to RefSeq genes were obtained from UCSC Genome Browser (http://genome.ucsc.edu/). A gene score was defined as the most significant variant that was located within 110 kb upstream and 40 kb downstream of the gene's most extreme transcript boundaries. If a SNP could be mapped to multiple genes, all these genes received the same gene score (the P value of this SNP) if the respective SNP had the lowest P value in the region. Of the ≈23 000 genes evaluated, 234 genes and 294 genes reached a score <1.0×10−4 for HGF and for Ang-2/sTie-2, respectively. These genes were then used for pathway analyses. Enrichment of each of the canonical pathways for HGF- and Ang-2/sTie-2–related SNPs, respectively, was assessed using Fisher exact test.
Statistical analyses were performed in R.19 The authors had full access to the data and take responsibility for its integrity. M.H.C. performed the statistical analyses for the FHS sample, and A.T. performed the statistical analyses for the SHIP sample. The pathway analyses were performed by H.L. All authors have read and agreed to the article as written.
Clinical and biochemical characteristics of the discovery and the replication sample are provided in Table 1. In the discovery sample, the genomic inflation factor did not indicate systematic inflation for each of the biomarkers (between 1.01 and 1.02; Figure IV in the Data Supplement). The top genome-wide significant (P≤5×10−8) hits for Ang-2, sTie-2, and HGF were listed in Table 2. Figure 1 displays the P values for ≈2.5 million genetic variants associated with HGF, Ang-2, and sTie-2, respectively.
Genetic Loci Associated With Circulating HGF Concentrations
In the FHS sample, 29 SNPs within or close to the HGF gene on chromosome 7 were associated with circulating HGF levels on a genome-wide significant level (P<5×10−8), most of these SNPs were in moderate linkage disequilibrium with the top SNP (rs5745687; Table 2; Figure 2). Overall, 24 of these 29 SNPs were genotyped in the FHS sample, and 5 SNPs were imputed (including rs5745687). A regional plot is shown in Figure 2. The top SNP in the HGF gene explained 2.12% of the variation in circulating HGF levels. Mean HGF levels stratified by rs5745687 genotypes are provided in Figure V in the Data Supplement.
Genetic Loci Associated With Circulating Ang-2 and sTie-2 Concentrations
A total of 5 SNPs in the ABO gene on chromosome 9 were associated with circulating Ang-2 concentrations on a genome-wide significance level (P<5×10−8); 4 of these SNPs were genotyped in the FHS sample. The top SNP was imputed in the FHS and SHIP samples; rs2442517 in the MCPH1 gene on chromosome 8 was close to the genome-wide significance level (P=5.05×10−8). This SNP was genotyped in the FHS sample and imputed in the SHIP sample (Table 2). Regional plots of the MCPH1 locus and the ABO locus are shown in Figure 3A and 3B, respectively. The top SNPs of both loci (rs8176746 and rs2442517) combined explained 1.7% and 0.7% of the interindividual variation in circulating Ang-2 levels in the discovery and in the replication sample, respectively. Ang-2 levels stratified by rs2442517 genotypes (Figure VIA in the Data Supplement) and stratified by rs8176746 genotypes (Figure IVB in the Data Supplement) in the FHS and the SHIP samples are provided in Figure IV in the Data Supplement.
Overall, 17 SNPs within or close to the Tie-2 gene and 56 SNPs within or close to the AB0 gene were associated with sTie-2 levels on a genome-wide significant level (P<5×10−8; Table 2). Regional plots of the Tie-2 and the ABO loci are displayed in Figure 4A and 4B, respectively. The most significant SNPs from each significant locus (rs8176693 and rs2273720) combined explained 11.2% and 8.9% of the interindividual variation in circulating Tie-2 levels in the discovery sample and in the replication sample, respectively. SNP rs2273720 was genotyped in the FHS and SHIP samples, SNP rs8176693 was genotyped in FHS and imputed in the SHIP sample. Tie-2 levels stratified by rs2273720 genotypes (Figure VIIA in the Data Supplement) and stratified by rs8176693 genotypes (Figure VIIB in the Data Supplement) in the FHS and the SHIP samples are provided in Figure VII in the Data Supplement. The top SNPs in the ABO gene that were associated with sTie-2 (rs8176693) and Ang-2 (rs8176746) were in perfect linkage disequilibrium (r2=1), underscoring that Ang-2 and Tie-2 levels were associated with the same genetic locus.
Pathway Analyses
For Ang-2 and sTie-2, no significantly enriched canonical pathway (P<1×10−3) could be identified.
By contrast, several pathways that were over-represented with HGF-related genes could be observed (Table I in the Data Supplement), including the mammalian target of rapamycin (mTOR) pathway and the amyotrophic lateral sclerosis signaling pathway.
Principal Observations
We conducted a genome-wide association study for 3 endothelial growth factors (Ang-2, sTie-2, and HGF) in the FHS and assessed replication of the top SNPs associated with Ang-2 and sTie-2 in the SHIP study, a population-based sample from northeastern Germany. Our main findings were 4-fold. First, all the 3 biomarker levels were associated with common genetic variants within or close to the genes encoding the individual biomarkers. Second, Ang-2 and sTie-2 levels were also associated with genetic variants at the ABO locus. Third, the top genetic loci explained a modest (≈2%; HGF and Ang-2) to moderate (11%; sTie-2) proportion of the interindividual variation in biomarker levels. Fourth, we identified several pathways that were over-represented with HGF-related genes, including the mTOR and the amyotrophic lateral sclerosis signaling pathway.
Genetic Loci Associated With Circulating HGF Concentrations
Previous family-based analyses reported heritability estimates of 38%6 and 48%,20 respectively, for HGF levels. In small clinical samples, few genetic variants in the HGF gene have been tested for association with HGF levels revealing inconsistent results. In 78 control participants from the Cardiovascular Health Study, SNP rs3735520, which is located in the promoter region of the HGF gene, was statistically significantly associated with HGF levels, whereas SNP rs17501108 (likewise located in the promoter) was not.21 However, SNP rs3735520 was not associated with HGF levels in 133 patients with systemic sclerosis,22 although experimental data indicated that this variant was related to transcriptional activity.22 In our data set, both SNP rs3735520 (P=0.12) and SNP rs17501108 (P=0.39) were not associated with HGF concentrations. To date, there has been no genome-wide analysis about the genetic determinants of HGF levels. In our genome-wide approach, only SNPs in the HGF gene reached genome-wide significance for this biomarker. The top SNP (rs5745687) is located in exon 823 and explained ≈ 2.12% of the interindividual variation in HGF levels. According to the pfam database (http://pfam.xfam.org/protein/P14210),24 SNP rs5745687 leads to the replacement of a negatively charged glutamic acid by a positively charged lysine at position 304. This missense mutation is located just before the third kringle domain of the HGF protein. Such kringle domains are important for the interaction with other proteins.24,25 The frequency of the minor allele of rs5745687 is between 0% and 10% in different ethnic subgroups of the 1000 Genomes project26 (Table II in the Data Supplement). We did not assess replication of the top SNPs related to HGF concentrations because HGF levels were not available in SHIP.
Genetic Loci Associated With Circulating Tie-2 and Ang-2 Concentrations
The statistically strongest association signal in our analyses was observed for SNPs in the Tie-2 gene with circulating Tie-2 concentrations. The top SNP of the Tie-2 locus (rs2273720; located in intron 16) explained ≈ 7% of the variability in sTie-2 levels in the FHS sample and ≈ 5% in the SHIP replication sample. These findings are in good agreement with a recent linkage analysis (displaying strong linkage of sTie-2 levels to a locus on chromosome 9, including the Tie-2 gene)7 and suggest that sTie-2 is moderately influenced by genetic variation in the Tie-2 gene. Furthermore, the ABO locus was associated with sTie-2 on a genome-wide scale (please see below for expanded discussion about the ABO locus).
Circulating levels of Ang-2 were associated with rs2442517, an intronic variant in the microcephalin 1 (MCPH1) gene. Interestingly, the Ang-2 gene is nested within the MCPH1 gene (please see regional plot in Figure 3A) and the most probable explanation for this association signal is that Ang-2 levels are in part determined by genetic variation in the Ang-2 gene. However, the correlation between SNP rs2442517 and variants in the Ang-2 gene is only modest (please see linkage disequilibrium structure in Figure 3A), and genetic variants in the Ang-2 gene itself did not reach genome-wide significance for Ang-2 levels. Our data add to smaller genetic-epidemiological studies relating SNPs within the Ang-2 gene to circulating Ang-2 concentrations. SNP rs3739391 (located in the 5′untranslated region; weakly correlated with rs2442517; r2=0.04) was associated with Ang-2 levels in 360 stroke patients, after adjusting for established vascular risk factors. However, in the same sample, 2 other genetic variants (rs2515507 [located in the promoter] and rs3739390 [5′untranslated region]) displayed no association with Ang-2 levels.27 In our data set, none of rs3739391 (P=0.10), rs2515507 (P=0.35), and rs3739390 (P=0.17) displayed statistically significant evidence for association with Ang-2 levels. In another study, SNP rs1868554 (also in weak linkage disequilibrium with rs2442517; r2=0.005) was not associated with plasma Ang-2 levels, but was related to plasma variation in isoforms of Ang-2.28 Interestingly, this variant displayed some evidence of association with Ang-2 levels in our data set (P=6.5×10−6), although the P value does not meet the threshold for genome-wide significance.
In addition to the MCPH1 locus, also the ABO locus was significantly associated with Ang-2 levels in our data set, as detailed in the next paragraph.
Association of the ABO Locus With Circulating Ang-2 and Tie-2 Concentrations
Several SNPs in the AB0 gene were associated with sTie-2 and Ang-2 levels and the top SNPs of the AB0 locus associated with sTie-2 (rs8176693) and Ang-2 (rs8176746) were perfectly correlated (r2=1). Thus, Ang-2 and sTie-2 add to a growing number of biomarkers that are associated with the ABO locus, including von Willebrand factor,29,30 soluble intercellular adhesion molecule-1 (ICAM-1),31,32 E-selectin,33 P-selectin,31 tumor necrosis factors α,34 and Factor VIII.29 This suggests that there might be common mechanisms by which the AB0 gene product modulates circulating biomarker concentrations. The genetic architecture of the ABO locus determines the substrate specificity and activity of a glycosyltransferase, which transfers specific carbohydrates to the H antigen, and thereby determines the ABO blood group (OMIM: 110300).33,35,36
There are several potential explanations for the observed association between the ABO locus and circulating Ang-2 and sTie-2 levels. Given that the Tie-2 receptor contains 4 potential N-glycosylation sites,37 the ABO gene product might modify the Tie-2 receptor, and thereby affect its binding activity, its cleavage from the endothelial cells, or its renal clearance. These mechanisms have been suggested to explain the association of the ABO locus with other biomarkers, including ICAM-1,31,38 P-selectin,31,38 E-selectin,33 and von Willebrand factor.31,38
In a similar fashion, it is possible that glycosylation of the Ang-2 protein affects its binding ability to the endothelial or sTie-2 receptor, and thereby influences circulating Ang-2 serum levels. Such glycosylation (by the ABO gene product) might also modify the Ang-2 clearance rate from the blood stream.31
In addition to the association with circulating biomarkers mentioned above, variation in the ABO gene has been associated with different clinical disease traits, including gastric39 and pancreatic cancer,36 duodenal ulcer,40 as well as myocardial infarction41 and stroke,42 and hematologic traits.43 Many of these disease conditions depend directly or indirectly on angiogenesis and vascular remodeling—processes that are, in part, governed by endothelial growth factors. Thus, the association of these biomarkers with the ABO locus might be a mediating mechanism for the observed associations between genetic variation in the ABO gene and clinical disease events, a premise that is speculative.
Across the 3 biomarkers (HGF, Ang-2, and sTie-2) analyzed, the genome-wide significantly associated genetic variants explained a modest proportion (between 2% and 11%) of the interindividual variation in biomarker levels. This is comparable with other biomarker-related genome-wide analyses, including those for Factor VII, von Willebrand Factor, and ICAM-1, where the identified genome-wide significant loci explained 7.7%, 12.8%, and 8.4%, respectively, of the interindividual biomarker variation.29,32 Additional genetic approaches are warranted to explain parts of the missing heritability,44 including analyses of rare and low-frequency variants or structural genetic variation44 and analyses of all SNPs in the genome.45 Given the reported associations of the analyzed biomarkers with cardiovascular risk factors6,7 and mortality,12 it is of interest, whether these biomarkers and the identified genetic variants (correlated with biomarker levels) improve the prediction of clinically overt cardiovascular events, including myocardial infarction, heart failure, and stroke.
Pathway Analyses
Pathway analyses identified the mTOR signaling pathway as the most significantly enriched canonical pathway for HGF. Our observations are corroborated by experimental studies, indicating that the mTOR pathway is indeed relevant for modulating HGF expression.46,47 Rapamycin (as inhibitor) and Leucin (as stimulator) exert their influence on HGF expression and secretion through the mTOR pathway.46,47 Furthermore, we revealed a statistically significant over-representation of HGF-related genes in the amyotrophic lateral sclerosis signaling pathway. In this context, experimental data support that HGF might improve survival of motor neurons and the clinical course of amyotrophic lateral sclerosis.48–50
Strengths and Limitations
Both the study samples (FHS and SHIP) are large and provide a thorough and comprehensive characterization of their study participants. To the best of our knowledge, this is the first genome-wide analysis for Ang-2, Tie-2, and HGF. Some limitations merit consideration. Our samples consisted of young to middle-aged Europeans and European Americans. The applicability of our observations to other ethnicities or age groups is unclear. Furthermore, each biomarker was measured only once in each individual, possibly leading to some nondifferential misclassification that would bias our results toward the null hypothesis of no association between genetic variants and biomarker levels. We did not evaluate the effect of rare genetic variants (as could be identified by whole-genome sequencing) on biomarker levels.
We identified common genetic variants associated with circulating HGF, Ang-2, and sTie-2 levels. All the 3 biomarkers were related to SNPs located in or close to the genes encoding the respective biomarkers. Furthermore, genetic variants in the ABO gene were associated with Ang-2 and sTie-2 levels. The association findings for Ang-2 and sTie-2 were successfully replicated in an independent sample (SHIP). The genome-wide significantly associated genetic variants explained a modest proportion (between 2% and 11%) of the interindividual variation in biomarker levels. Furthermore, pathway analyses identified the mTOR and other pathways as being over-represented with HGF-related genes. Given the pivotal role of these biomarkers in angiogenesis, vascular remodeling, local cancer growth, and metastatic potential, as well as their potential effect on cardiovascular and metabolic diseases, our findings suggest that genetically determined endothelial growth factor levels might, in part, contribute to the known familial susceptibility of conditions like cancer or cardiovascular disease, a premise that warrants further investigation.
Sources of Funding
This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195; principal investigator, Dr Vasan) and its contract with Affymetrix, Inc for genotyping services (contract No. N02-HL-6-4278), and by grants from the National Heart, Lung, and Blood Institute 2K24HL04334, RO1HL080124, RO1HL077477, and R01HL093328 (Dr Vasan). SHIP is a part of the Community Medicine Research Network, funded by the Federal State of Mecklenburg-West Pomerania and the University Medicine Greifswald. Genome-wide data have been supported by a joint grant from Siemens Healthcare, Erlangen, Germany, and by the Federal State of Mecklenburg, West Pomerania. Furthermore, this work is part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The GANI_MED consortium is funded by the German Federal Ministry of Education and Research and, by the Ministry of Cultural Affairs of the German Federal State of Mecklenburg, West Pomerania (03IS2061A).
Guest Editor for this article was Christopher Semsarian, MBBS, PhD, MPH.
The Data Supplement is available at http://circgenetics.ahajournals.org/lookup/suppl/doi:10.1161/CIRCGENETICS.114.000597/-/DC1.
- Received March 5, 2014.
- Accepted November 12, 2014.
- © 2015 American Heart Association, Inc.
- 1.↵
- 2.↵
- Maisonpierre PC,
- Suri C,
- Jones PF,
- Bartunkova S,
- Wiegand SJ,
- Radziejewski C,
- et al
- 3.↵
- Shim WS,
- Ho IA,
- Wong PE
- 4.↵
- 5.↵
- 6.↵
- Lieb W,
- Safa R,
- Benjamin EJ,
- Xanthakis V,
- Yin X,
- Sullivan LM,
- et al
- 7.↵
- Lieb W,
- Zachariah JP,
- Xanthakis V,
- Safa R,
- Chen MH,
- Sullivan LM,
- et al
- 8.↵
- Splansky GL,
- Corey D,
- Yang Q,
- Atwood LD,
- Cupples LA,
- Benjamin EJ,
- et al
- 9.↵
- Völzke H,
- Alte D,
- Schmidt CO,
- Radke D,
- Lorbeer R,
- Friedrich N,
- et al
- 10.↵
- Stein JL,
- Medland SE,
- Vasquez AA,
- Hibar DP,
- Senstad RE,
- Winkler AM,
- et al
- 11.↵
- 12.↵
- 13.↵
- 14.↵
- Psaty BM,
- O'Donnell CJ,
- Gudnason V,
- Lunetta KL,
- Folsom AR,
- Rotter JI,
- et al
- 15.↵
- 16.↵
- 17.↵
- 18.↵
- Johnson AD,
- Handsaker RE,
- Pulit SL,
- Nizzari MM,
- O'Donnell CJ,
- de Bakker PI
- 19.↵
- Chen MH,
- Yang Q
- 20.↵
- 21.↵
- Burdon KP,
- Macgregor S,
- Bykhovskaya Y,
- Javadiyan S,
- Li X,
- Laurie KJ,
- et al
- 22.↵
- 23.↵
- 24.↵
- Finn RD,
- Bateman A,
- Clements J,
- Coggill P,
- Eberhardt RY,
- Eddy SR,
- et al
- 25.↵
- 26.↵
- 27.↵
- 28.↵
- 29.↵
- Smith NL,
- Chen MH,
- Dehghan A,
- Strachan DP,
- Basu S,
- Soranzo N,
- et al
- 30.↵
- 31.↵
- Barbalic M,
- Dupuis J,
- Dehghan A,
- Bis JC,
- Hoogeveen RC,
- Schnabel RB,
- et al
- 32.↵
- 33.↵
- Paterson AD,
- Lopes-Virella MF,
- Waggott D,
- Boright AP,
- Hosseini SM,
- Carter RE,
- et al
- 34.↵
- 35.↵
- Wolpin BM,
- Kraft P,
- Xu M,
- Steplowski E,
- Olsson ML,
- Arslan AA,
- et al
- 36.↵
- 37.↵
- Macdonald PR,
- Progias P,
- Ciani B,
- Patel S,
- Mayer U,
- Steinmetz MO,
- et al
- 38.↵
- Kiechl S,
- Pare G,
- Barbalic M,
- Qi L,
- Dupuis J,
- Dehghan A,
- et al
- 39.↵
- Aird I,
- Bentall HH,
- Roberts JA
- 40.↵
- 41.↵
- Reilly MP,
- Li M,
- He J,
- Ferguson JF,
- Stylianou IM,
- Mehta NN,
- et al
- 42.↵
- Williams FM,
- Carter AM,
- Hysi PG,
- Surdulescu G,
- Hodgkiss D,
- Soranzo N,
- et al
- 43.↵
- 44.↵
- 45.↵
- 46.↵
- 47.↵
- 48.↵
- 49.↵
- 50.↵
- Sun W,
- Funakoshi H,
- Nakamura T
Endothelial growth factors, including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor (HGF), modulate early vascular development, the local growth and metastatic potential of various cancers and the pathogenesis of cardiovascular and metabolic diseases. These growth factors are heritable traits, but the precise genetic underpinnings of their circulating concentrations are largely unknown. We performed a genome-wide association study for circulating Ang-2, sTie-2, and HGF in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. Circulating Tie-2 and HGF concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers. Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels. Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 and Ang-2 levels. All the top single-nucleotide polymorphisms associated with Ang-2 and sTie-2 could be successfully replicated in Study of Health in Pomerania. The top single-nucleotide polymorphisms explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the interindividual variation in biomarker levels. In conclusion, genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating biomarker concentrations. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies. Ang-2 and sTie-2 add to a growing number of biomarkers associated with genetic variation at the ABO locus.
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- Genome-Wide Association Study for Endothelial Growth FactorsCLINICAL PERSPECTIVEWolfgang Lieb, Ming-Huei Chen, Martin G. Larson, Radwan Safa, Alexander Teumer, Sebastian E. Baumeister, Honghuang Lin, Holly M. Smith, Manja Koch, Roberto Lorbeer, Uwe Völker, Matthias Nauck, Henry Völzke, Henri Wallaschofski, Douglas B. Sawyer and Ramachandran S. VasanCirculation: Genomic and Precision Medicine. 2015;8:389-397, originally published December 31, 2014https://doi.org/10.1161/CIRCGENETICS.114.000597
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- Genome-Wide Association Study for Endothelial Growth FactorsCLINICAL PERSPECTIVEWolfgang Lieb, Ming-Huei Chen, Martin G. Larson, Radwan Safa, Alexander Teumer, Sebastian E. Baumeister, Honghuang Lin, Holly M. Smith, Manja Koch, Roberto Lorbeer, Uwe Völker, Matthias Nauck, Henry Völzke, Henri Wallaschofski, Douglas B. Sawyer and Ramachandran S. VasanCirculation: Genomic and Precision Medicine. 2015;8:389-397, originally published December 31, 2014https://doi.org/10.1161/CIRCGENETICS.114.000597