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12th Congress of the International Society of Nutrigenetics/Nutrigenomics (ISNN)

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Background: Head and neck squamous cell carcinomas (HN-SCC) are caused by the interaction among genetic, epigenetic and environmental factors. This relationship is complex, the use of mi-croRNAs as molecular markers can improve the comprehension of this interaction and help to define preventive strategies. The miR-31 expression has been suggested as a biomarker for HNSCC and could be influenced by diet.
Objective: To determine if the dietary intake of patients with HNSCC is associated with the miR-31 expression.
Methods: A prospective cohort observational study, including 67 patients with HNSCC. The miR-31 expression was determined in salivary rinse by RT-qPCR. The dietary intake was evaluated by food frequency questionnaire. Due to the heterogeneity of the anatomical subgroups of the HNSCC sites, the samples were classified into "oral cavity", "oropharynx", "larynx + hypopharynx". The multiple linear regression adjusted by backward strategy was used to evaluate the association between dietary intake and miR-31 expression.
Results: A hyperexpression (p = 0.04) of the miR-31 was found in oral and oropharynx, compared to larynx + hypopharynx, so the dietary intake analyzes were performed only for oral and oropharyngeal cancer. The meat and processed meat consumption was directly (p = 0.0005) and alcohol ingestion was inversely (p = 0.0027) associated with expression of miR-31 in oral cancer, but not in oropharynx. There was also a direct association between energy, selenium, zinc, calcium and iron consumption, and an inverse association between carbohydrate, cholesterol, saturated fat, trans fat, polyunsaturated fat and dietary fiber consumption with miR-31 expression only in oral cancer.
Conclusion: Dietary factors were associated with the miR-31 expression in saliva from oral cancer patients.
Background: Taste is a fundamental determinant of food selection, and inter-individual variations in taste perception may be important risk factors for poor eating habits and obesity. Characterizing differences in taste perception and their influences on dietary intake may lead to an improved understanding of obesity risk and a potential to develop personalized nutrition recommendations.
Objective: This study explored associations between 93 single nucleotide polymorphisms (SNPs) in sweet, fat, bitter, salt, sour, and umami taste receptors, with psychophysical measures of taste.
Methods: Forty-four families from the Guelph Family Health Study participated, including 60 children and 65 adults. Saliva was collected for genetic analysis and parents completed a three-day food record for their children. Parents underwent a test for suprathreshold sensitivity (ST) and taste preference (PR) for sweet, fat, salt, umami, and sour as well as a phenylthiocarbamide (PTC) taste status test. Children underwent PR tests and a PTC taste status test.
Results: Analysis of SNPs and psychophysical measures of taste yielded 23 significant associations in parents and 11 in children. After adjusting for multiple hypothesis testing, the rs713598 in the TAS2R38 bitter taste receptor gene and rs236514 in the KCNJ2 sour taste receptor gene remained significantly associated with PTC ST and sour PR in parents, respectively. In children, rs173135 in KCNJ2 and rs4790522 in the TRPV1 salt taste receptor gene remained significantly associated with sour and salt taste PRs, respectively. A multiple trait analysis of PR and nutrient composition of diet in the children revealed that rs9701796 in the TAS1R2 sweet taste receptor gene was associated with both sweet PR and percent energy from added sugar in the diet.
Conclusion: These findings provide evidence that for bitter, sour, salt, and sweet taste, certain genetic variants are strongly associated with taste function and may be implicated in eating patterns.
Background: Coffee was suggested to reduce bone mineral density (BMD) and could eventually lead to osteoporotic fracture. However, evidence on the association has been inconsistent. Coffee intake measured by self-reported food frequency questionnaire (FFQ) is subject to bias. Serum metabolomics profiling would act as an objective biomarker to examine the effects of coffee intake on BMD.
Objectives: We aimed to: 1) identify serum metabolites associated with coffee intake; and 2) examine the associations between identified metabolites and BMD.
Methods: 604 healthy free-living adults from the Hong Kong Osteoporosis Study (HKOS) visited in 2001-10 (n = 348) and 2015-16 (n = 256) were included. Coffee consumption was selfreported in a FFQ. Untargeted metabolomics profiling on fasted serum samples were performed using LC-MS platforms. BMD at lumbar spine, femoral neck and total hip was measured by DEXA. Multivariable linear regression and partial Pearson correlation were used to evaluate the association between metabolites and coffee intake. Robust regression was used to analyze coffee-associated metabolites in relation to BMD.
Conclusions: 17 metabolites were significantly associated with coffee intake, including 8 caffeine metabolites. 1-methylxanthine and AMFU were associated with BMD at lumbar spine, while trigonelline was associated with BMD at femoral neck in the Chinese Cohort. These three metabolites could be used as biomarkers to monitor BMD and further study is required to investigate the role of coffee metabolites in bone health. Objective: To evaluate the effect of a hypocaloric diet intervention for weight loss on the DNA methylation profile of women with grade III obesity.

DNA Methylation Analysis of Women with Grade III Obesity before and after Hypocaloric Dietary Intervention
Methodology: This is a longitudinal intervention study, which 11 women (35.7 ± 5.1 years) with grade III obesity were submitted to a hypocaloric dietary intervention (1200 kcal/day) for 6 weeks. Anthropometric data [weight, BMI], body composition [fat free mass (FFM) and fat mass (FM)] and peripheral blood for methylation analysis were collected before and after intervention. Genome-wide methylation analysis was conducted using the Infinium HumanMethylation450 BeadChip. For statistical analysis, Shapiro-Wilk, Wilcoxon and Mann-Whitney test were used (p < 0.05). We applied a threshold for the significant CpG sites based on Δβ with a minimum value of 10% and a p-value less than 0.01.
Conclusion: Hypocaloric dietary intervention for six weeks can reduce weight, BMI and fat mass and is able to change DNA methylation profile of obese women.
Background: The consumption of omega-3 polyunsaturated fatty acids (n-3 PUFA) has been reported to have beneficial health effects, among others, by reducing plasma triglyceride levels. Nonetheless, a concomitant increase in fasting plasma glucose levels is often reported but is highly variable between subjects.
Objectives: To determine the importance of the genetic background in the inter-individual variability of glycemic control following an n-3 PUFA supplementation.
Methods: A total of 210 participants completed a 6-week n-3 PUFA supplementation with 5 g/day of fish oil (providing 1.9 g-2.2 g of eicosapentaenoic acid [EPA] + 1.1 g of docosahexaenoic acid [DHA]). Insulin resistance was estimated by the homeostatic model assessment (HOMA-IR) and subjects were further classified as at-risk-IR (arIR) when they showed increased HOMA-IR after the n-3 PUFA supplementation, as compared to pre-supplementation values. Genome-wide genotyping data was obtained for 138 participants using HumanOmni-5-Quad BeadChips containing 4,301331 single nucleotide polymorphisms (SNPs). A genome-wide association analysis (GWAS) was carried out between arIR and not-at-risk-IR (narIR) participants. A genetic risk score (GRS) was finally constructed by summing the number of risk alleles.
Conclusions: These results suggest that genetic background has a relevant role in the inter-individual variability observed in glycemic control after an n-3 PUFA supplementation. Subjects being at risk of side effects associated with an n-3 PUFA supplementation could be identified using genetic-based precision nutrition approaches. Background: The orphan gene Major Facilitator Superfamily Domain Containing 9 (MFSD9) is phylogenic closely related to MFSD14A and MFSD14B as well as MFSD10. The expression of these genes in the brain is influenced by the protein and energy supply, supporting the hypothesis that they act as nutrient membrane transporters. The human MFSD9 is listed in genomic databases and predicted to encode two putative protein isoforms of a membrane solute carrier protein. Despite emerging information, such as the predicted structure of the mouse isoform, there is a profound lack of information on the MFSD9 gene. Significantly, the curated genomics structure and expression patterns have not been published; however, this is considered essential knowledge to investigate the genes biology.
Objective: To found a basis to investigate the biology and function of this orphan transporter, we characterized the genomic structure, transcripts, splicing and expression patterns of human MFSD9.
Methodology: Genomic sequences, full length transcripts and Expressed Sequence Tags were obtained from the databases of the National Center for Biotechnology Information. Sequences were aligned using Sequencher 4.11, visually curated and annotated. The mRNA expression in human tissues was determined from publicly available RNA-sequencing datasets determined by the Reference Transcriptome Resource (http://nhprtr.org/) and also from UniGene. The TMHMM Server 2.0 (http://www.cbs.dtu.dk/ services/TMHMM/) was used to predict the transmembrane helices in the MFSD9 protein.
Results: The human MFSD9 gene spans 22,264 nucleotides from the transcriptional start site to the poly-A signal, on Chromosome 2q12.1. It contains 6 exons and has two alternatively spliced transcripts, translating into 413 and 474 amino acid proteins. A variety of minor splicing events were found. The canonical protein isoforms are predicted to have 12 transmembrane domains, making it highly likely to encode a membrane transporter. MFSD9 is ubiquitously expressed.
Conclusion: The MFSD9 genomic locus and the originating alternative splice variants are described. This work forms the basis for a better understanding of MFSD9 biology and primes future functional studies. Background: Folic acid participates in one-carbon metabolism, which supplies methyl groups to numerous reactions in the body. Altered delivery of these methyl groups affects gene expression.

Folic Acid-Deficient and Supplemented Diet in Offspring of Rats: Effects on Food Intake, Body Weight and on Methylation and Gene Expression
Objectives: i) to relate the body weight and food intake of offspring of rats submitted to folic acid-deficient and supplemented diet and ii) to analyze the methylation and expression of genes involved in inflammation and energy metabolism.
Methods: Males Wistar rat puppies (n = 12) were weaned at the same diet their mothers into three treatment groups: 1. Control group (2.0 mg of folic acid/kg of food); 2. Deficient group (0.5 mg of folic acid/kg of food); and 3. Supplemented group (8.0 mg of folic acid/kg of food). For three months, the weight and the food intake were measured three times a week in analytical and precision balance. Also, after the treatment, samples of liver and adipose tissue were collected, from which DNA and RNA were extracted using commercial kits.
Results: In general, it was observed that the food intake of the folic acid-deficient group was statistically higher than the control group (p = 0.03). Regarding the body weight, it was observed that in the first weeks the weight of the supplemented group was significantly higher than the control and deficient group (p < 0.001). However, at the end of treatment, it was observed that the weight of the deficient group was significantly (p = 0.03) higher than the control group.
Conclusions: The maternal diet with different concentrations of folic acid, in gestation and lactation and, by the respective offspring fed in the post-weaning, alter the body weight and the food intake of the puppies. The next step of the study will be to analyze the expression and methylation patterns of genes involved in inflammation and energetic metabolism. Background: Genetic and environmental factors that influence vitamin D status might be associated with vitamin D effects on immune and inflammatory responses, a process that has not been fully explored in children with juvenile idiopathic arthritis (JIA).

Vitamin D Pathway -Related Genes Modify the Association between 25(OH)D and Disease Activity in Children with Juvenile Idiopathic Arthritis
Methods: Data from the Biologically-Based Outcome Predictors (BBOP) study, a multi-center cohort study of newly diagnosed Canadian children with JIA (n = 186) were analyzed. At enrollment and 6 month follow-up, blood 25(OH)D, CRP, ESR, Interleukin (IL)-2, IL-4, IL-1ra, IL-10, IL-6, and TNFα were measured. To identify gene polymorphisms of potential relevance to the vitamin D pathway, genome-wide association studies (GWAS) identified significant variables from linear regressions of vitamin D pathway genes (VDR, GC, CYP24A1, and CYP1R1) and gene-gene interactions and gene-environment interactions were analyzed. Vitamin D-related factors (milk intake, season, supplement and steroid use) and clinical data defining remission (no active arthritis, fever, or uveitis, normal ESR and CRP, best possible physicians global assessment score) were collected every 6 months for 2 years. We determined whether 25(OH)D concentrations and related factors can predict disease activity as determined by biochemical measures and remission criteria.
Results: GWAS-identified genes were NOTCH4, c6orf9, HLA-DQA1, LEP, IGFBP4, and GPS1. When genes were not included in the model there was an inverse association of 25(OH)D to disease activity. Genes, when included, modified the association between 25(OH)D and indicators of disease activity; only certain genotypes maintained the inverse association of 25(OH)D and disease activity markers. Drinking milk every day predicted a reduction in indicators of disease activity as measured by CRP, ESR, and IL-6. Background: The human family of ascorbic acid membrane transporters consists of three members: SLC23A1, SLC23A2 and SLC23A3, of which the first two are functionally well characterized sodium dependent ascorbic acid membrane transporter proteins. In contrast, information for SLC23A3 is virtually nonexistent and ambiguous in the current. However, it was suggested that human SLC23A3 does not mediate cellular ascorbic acid uptake when overexpressed in Xenopus laevis oocytes and human embryonal kidney (HEK 293) and cervical carcinoma (HeLa) cells (Bürzle, Suzuki et al. 2013). SLC23A3's genomic structure has not been annotated and its expression patterns have not been described to this date. However, this information is essential for future biological studies, including the evaluation of the nature of genetic variations in this orphan membrane transporter.
Objective: In order to gain insight into the biology and function of this orphan transporter the genomic structure, transcripts, splicing and expression patterns of human SLC23A3 are to be characterized.
Methodology: Genomic sequences, full length transcripts and Expressed Sequence Tags were obtained from the databases of the National Center for Biotechnology Information. Sequences were aligned using Sequencher 4.11, visually curated and annotated.
Results: The human SLC23A3 gene spans 8,636 nucleotides from the transcriptional start site to the poly-A signal, on Chromosome 2q35. It contains 12 exons and has three canonical alternatively spliced transcripts; however, a variety of minor alternative splicing events were identified. Primary expression is detected in the kidney and small intestine. In kidney sections, expression patterns match with the paralogous SLC23A1. Immunocytochemistry reveals plasmalemma membrane location, as well as location in the cell nucleus; however, the epitope of the three protein isoforms are not to be distinct with the utilized antibody. The location and biological roles of the three protein isoforms requires further investigation.
Conclusion: SLC23A3 likely encodes a nutrient/metabolite transporter relevant in intestinal absorption and renal reabsorption. Three protein isoforms exist, of which at least one encodes a membrane protein. Fish contains high quality proteins and essential nutrients including vitamin D (VitD). Its consumption has been inversely associated with the risk of cardiovascular disease (CVD) mortality. Fish peptide (Pep) consumption demonstrated benefits on CVD risk factors while epidemiological studies reported an association between VitD deficiency and CVD.

Short-Term Effects of Fish Peptides and Vitamin D on Gene Expression Levels
Objective: To investigate short-term gene expression changes following a single dose of VitD, Pep, or a combination of both.
Methods: A randomized, crossover, placebo controlled trial was conducted. Eighteen subjects ingested, in random order and at 7-day intervals, 1000 IU of VitD 3 , 3 g of Pep (Bonito Peptide Hydrolysate), a combination of both, or a placebo. Blood samples were collected before and 3-h post-ingestion. Whole-genome expression levels were measured using gene expression arrays. Transcript levels were corrected for age, sex, BMI and estimated blood cell count. Differences in expression levels after vs. before each supplementation were computed using paired t-tests.
Results: Following correction for changes observed with the placebo, VitD treatment differentially affected 16 transcripts (FDR-adjusted P value ≤ 0.05) while Pep and VitD + Pep treatments were found to differentially change 1 and 5 transcripts, respectively. Differential expression of CPT1A gene was observed with VitD, Pep and a combination of both. VitD treatments, with or without Pep, affected the SLC25A20 gene involved in fatty acid oxidation as well as various transcription factors, and genes related to glucose metabolism and inflammation/immunity.
Conclusions: These results suggest that VitD rapidly modulates genes related to CVD risk factors while Pep seems to moderately modulate gene expression levels, or that a longer exposure is needed.
Background: Dietary fatty acids (FA) may vary in their obesogenic effect; the genetic makeup may contribute to fat deposition in response to dietary FA composition. However, little is known about the obesogenic effects of interactions between dietary MU-FAs and genetic factors.
Objective: We evaluated common genetic variants influencing changes in body weight (BW) and body fat mass (BFM) in response to MUFA consumption.
Conclusion: Common variants in LPL, FTO, PPARα, ADIPOQ, APOE, LIPC, and ADRB2 genes modulated BFM changes in response to dietary MUFA in an isocaloric diet. The data suggest that the ability of high mono oils to positively influence body composition is modulated by genetic polymorphisms in genes important in energy conversion pathways. The differential susceptibility hypothesis is a model of gene-environment interaction where individuals display differential responses to positive and negative exposures based on genetic variation. DRD2/ANKK1 Taq1A is a candidate gene for differential susceptibility, but its association with dietary outcomes according to everyday environmental food exposures has not been explored.
Objectives: Evaluate the interaction between DRD2/ANKK1 Taq1A genotype and exposure to neighbourhood in-store marketing strategies of healthful and unhealthful foods on diet quality.
Methods: Data from the CARTaGENE biobank (n = 3,013) were temporally and geospatially linked to neighbourhood data on in-store displays of soft drinks, ice cream, and vegetables. The Canadian-adaptation of the Healthy Eating Index 2010 (HEI-C) was calculated from food frequency questionnaires. Generalized estimating equations adjusted for sociodemographic factors and energy intake were used to evaluate the interaction between the Taq1A variant and standardized food display measures.
Conclusions: Our findings suggest that dietary associations with the retail food environment are partly moderated by genetics. The DRD2/ANKK1 Taq1A polymorphism is associated with response to the obesogenic environment, but further evaluation is needed for evidence of differential susceptibility.

Background:
The retinoid X receptor (RXR) is a member of the steroid/thyroid hormone superfamily of nuclear receptors, which predominantly functions as a transcription factor with roles in development, cell differentiation, metabolism, and cell death. Altered RXR expression and function is reported in many cancers and other diseases. RXR commonly functions as a heterodimer with other nuclear receptors, including the vitamin D receptor (VDR). There is evidence that the frequencies of polymorphisms in the VDR gene varies with skin pigmentation, potentially as an adaptation to reduced vitamin D production in highly pigmented skin. However, the relationship between RXR variants and skin pigmentation remain unexplored.
Objectives: To examine the frequency of common variants in RXRα/β genes by population skin type.
Methods: Population prevalence of RXRα/β variants (MAF <0.35) were examined against Fitzpatrick skin type via collation of genotypic data from ALFRED (Allele Frequency Database) and 1000 Genomes databases (>100 cohorts >6,000 subjects), and categorisation of populations by the Fitzpatrick skin type according to their reported ancestry. Level of significance was adjusted for multiple testing following the Bonferroni method (p <0.0029 for p-trend).
Conclusions: These findings demonstrate novel relationships between skin colour and RXRα/β variants, and suggest regulation of the vitamin D receptor may differ by skin pigmentation, via heterodimer modulation. Such associations are of significance to vitamin related health outcomes that display ethnic differences or seasonality. Background: Vitamin D status has been linked to many common chronic conditions such as cardiovascular disease, diabetes and several cancer forms. However, the role of vitamin D in the etiology of these diseases remains controversial. Vitamin D status is dependent on both environmental exposures and genetic variance, influenced by ultraviolet radiation (UVR) levels; modulated by our degree of skin pigmentation, and also impacted by genetic variation in vitamin D metabolism pathways. Differences in study outcomes may reflect independent and interactive influences of these factors; however, the potential relationship between skin pigmentation and these genetic variants has not yet been explored.

Occurrence of Vitamin D Metabolism Gene Variants Linked to Degree of Skin Pigmentation
Objective: This study aimed to examine for potential association between frequency of common variants in CYP24A1, a key regulatory gene within the vitamin D system, and degree of skin pigmentation.
Methods: Population prevalence of CYP24A1 variants (MAF <0.3) were examined against Fitzpatrick skin phototype of populations via collation of genotypic data from ALFRED (Allele Frequency Database) and 1000 Genomes databases, and categorisation of populations with the common Fitzpatrick phototype of their reported ancestry.
Conclusions: These findings demonstrate novel relationships between skin tone and genetic variance in regulatory genes within the vitamin D system, and may indicate regulation of the vitamin D system may differ by ethnicity. Such associations are of significance to vitamin D-related health outcomes, particularly those that display ethnic differences or seasonality.
Background: Metabolic syndrome (MetS) comprises a cluster of risk factors including central obesity, hypertension, dyslipidemia and impaired glucose homeostasis. Heterogeneous responses to lifestyle interventions that promote improvements in diet quality and exercise may be partially explained by underlying genetic differences. This study aimed to investigate if variants in genes associated with MetS influence the magnitude of improvement in MetS during a lifestyle intervention.
Methods: Data from the Canadian Health Advanced by Nutrition and Graded Exercise (CHANGE) feasibility study (n = 159) was used to investigate the effect of 17 single nucleotide polymorphisms (SNPs) on the response to a 1-year lifestyle intervention. Associations between SNPs and the continuous MetS (cMetS) score, as well as individual MetS components, were examined.
Results: Reductions in cMetS score at 3 months and 1 year were significantly associated with 3 variants: rs662799 (A/G) in APOA5, rs670 (C/T) in APOA1 and rs1501299 (G/T) in ADIPOQ. Individuals carrying a minor allele in rs670 or rs1501299, or who were major allele homozygotes for rs662799 experienced greater reductions in cMetS during the intervention. No associations were consistently identified between the aforementioned SNPs and individual components of MetS. A genetic risk score (GRS) corresponding to these 3 SNPs revealed that individuals carrying no risk alleles experienced significantly greater reductions in cMetS score after 1 year.
Conclusions: These findings suggest that individuals with certain genotypes may benefit more from a lifestyle intervention for MetS and that specific variants could be used as a nutrigenetic tool to further tailor and improve the intervention.
Background: Single nucleotide polymorphisms (SNPs) that moderate how nutrients influence metabolic pathways and the development of diet-related diseases are an important area of research in nutrigenomics. Previous studies have found a degree of correlation between select SNPs and genetic ancestry. Studying multiple diet and lifestyle variants at the population level will enable discovery of global patterns in genetic variation which may help to better inform approaches for personalized nutrition.
Objectives: The present study examined 43 established nutrigenetic SNPs within a global sample of individuals to uncover if populations form distinct 'nutrigenomic SNP profiles' predictive of their genetic ancestry.
Methods: We extracted SNP data for all individuals in the phase 3 1000 genomes project (1KGP) for the 43 SNPs of interest (hg19 build, n = 2504). Individuals from the 1KGP dataset belonged to one of five broad ancestry groups: Admixed American (AMR), African (AFR), East Asian (EAS), European (EUR) and South Asian (SAS). The dataset was first partitioned into an 80:20 training/testing split, and regression models were trained using: 1) all SNPs included as predictor variables of genetic ancestry (no variable selection), 2) only those SNPs that were significantly associated with predicting genetic ancestry in model 1, where p < 0.05 and 3) SNPs selected in GLMnet using LASSO variable selection. All models were then evaluated for their accuracy on the test set (n = 501). Finally, models were applied to a sample obtained from the database of a consumer genetic testing company to assign a predicted ancestry (n = 930).
Results: The GLMnet selection model outperformed the alternative models in accuracy on test data. Adjusted Rand Indices for the three models were: All SNPs = 0.8892, only significant SNPs = 0.8886, GLMnet LASSO variable selection = 0.8912. Predictions on the applied dataset reflected a majority European ancestry class with the following counts: AFR = 0, AMR = 23, EAS = 26, EUR = 839, SAS = 42.
Conclusion: Genetic ancestry can be inferred from nutrigenomic SNP profiles with highest accuracy for AFR and EAS populations. Future work can entail comparison of disease risk allele prevalence between ancestry groups and consequently help to improve risk assessments. The epigenetic mechanism DNA methylation (DNAm) is a process by which dietary nutrients influence gene expression. The leptin protein modulates energy intake, expenditure, and storage. We previously found that changes in DNAm at two functional sites of the leptin core promoter suggested a shortterm adaptive response to dietary fluctuation. Although a differential pattern of DNAm across 7 CpGs of leptin's core promoter appears remarkably similar among diverse populations, functional explanations of pattern variation remain unclear.

Diet and Basal Metabolism Influence DNA Methylation in Siberian Population
Objectives: We examine macronutrient variation and DNAm of these seven CpG cites and their relationship to the reported adaptive response of elevated basal metabolism in Siberian Buryat.
Methods: Basal metabolic rate (BMR), 24 h dietary recall, anthropometrics, and fasting blood draws were collected from 50 Buryat Okrug men and women in 1998. DNA obtained from blood samples was frozen at KU. Our DNA candidate region was subjected to Bisulfate conversion, PCR and Pyrosequencing per Qiagen protocols to produce a methylation frequency at 7 CpG sites in leptin's core promoter. The percentage of methylation at each site was logit transformed to correct for heteroskedasticity and sexstratified partial correlations calculated to determine if basal metabolism and dietary macronutrients were associated with changes in leptin promoter CpG sites. Significance p ≤ 0.05. IRB approved by WWU.
Results: Adjusting for batch, age, serum leptin, and smoking, percent of protein intake was significantly associated with DNAm at the C/EBPαTBS/ r 2 = 0.600 in males and in females (r 2 = 0.388) and TATA/ r 2 = 0.417. BMR was negatively correlated with sites 3/ r 2 = -0.583 and 6/ r 2 = -0.558 in males, each upstream from functional sites. In females, site 1 positively correlated with BMR (r 2 = 0.542) and protein correlated with two sites (site 3/ r 2 = 0.432 and 5/ r 2 = 0.448), both upstream from functional sites.
Conclusion: Significant BMR correlation with upstream sites suggests promoter region contains unidentified energy monitoring signal capacity. Nicoletti 1 , M.A.S. Pinhel 1 , N.Y. Noronha 1 , B.A. de Oliveira 1 ,  A. Jácomo 2 , A.B. Crujeiras 3 , C Background: Methylation patterns are established in early life and can be remodeled in adult cells, being able to alter gene expression profile and may predispose a disease risk. DNA methylation could provide a link between environmental, genetic factors and weight control.

Integrated Analysis of DNA Methylation and Gene Expression Array of Women Who Underwent Bariatric Surgery Reveals New Targets for Obesity Treatment
Objectives: To gain a broader perspective between CpG methylation and functional effects in transcription after bariatric surgery, we performed a concomitant analysis with methylation and expression data.
Methods: The study enrolled 24 normal weight women (control) and 24 obese before and 6 months after gastric bypass. Genome-wide methylation analysis was conducted using the Infinium HumanMethylation450 BeadChip and expression levels were measured using the HumanHT-12 v4 Expression BeadChip. The lists of differentially methylated (Δβ±5%, p < 0.001) and expressed (fold change >2, FDR p < 0.05) probes were analyzed by Venn diagram and classified by gene function.
Results: Pre-surgery versus control women comparison showed six genes that were common in both analyses. Four genes (TPP2, PSMG6, ARL6IP1 and FAM49B) had higher methylation and lower expression level in pre-surgery women. Considering pre and postoperative times, eight genes were common in both arrays, and two genes (ZFP36L1 and USP32) were epigenetically regulated by bariatric surgery. Moreover, these genes are related to MAPK cascade, NIK/NF-kappaB signaling, cellular response to insulin stimulus, proteolysis and others.
Conclusions: Bariatric surgery promotes changes in methylation and gene expression levels of women after six months of significant weight loss. The genes are inserted in adipogenesis, orexigenic, oxidative stress and insulin metabolism pathways and therefore could be considered possible therapeutic targets for obesity. Background: Analysis of gene expression related to energy metabolism and subsequent association with the resting metabolic rate (RMR) may elucidate the understanding of genetic factors that contribute to obesity.

Expression of Genes Related to Energy Metabolism Increase Resting Metabolic Rate Adjusted by Weight in Obese Women
Objectives: The aim of this study was to analyze the expression of genes related to energy metabolism and associate it with the weight-adjusted RMR (kcal/kg) in women with obesity before and after bariatric surgery.
Methods: The sample consisted of 13 women before and after six months of bariatric surgery. The nutritional status was performed using Body Mass Index (BMI). The RMR was determined by the measurement of the oxygen consumed (O 2 ) and carbon dioxide produced (CO 2 ) using the QUARK-RMR equipment. The gene expression analysis was performed in peripheral blood by microarray methodology, BeadChip-Illumina TM and with subsequent validation by the quantitative Real Time PCR method. Data were analyzed by SPSS (p < 0.05).
Results: Differences were observed in weight (115.4 ± 19.5 vs 86.6 ± 13.7 kg, p < 0.01), BMI (42.5 ± 7.0 vs 32.1 ± 5.6 kg/m 2 , p < 0.01) and weight-adjusted RMR (17.7 ± 1.6 vs 19.7 ± 2.0 kcal/kg, p < 0.01) after six months of bariatric surgery. There was an increase in the gene expression of six targets related to energy metabolism after bariatric surgery, genes/fold change respectively, (CTNNB1 The exact mechanism for increasing cardiovascular mortality (CVD) in obese individuals is not fully understood, however, a reduction in heart rate variability (HRV) may be a potential pathway involved in sudden death. In addition, the expression of genes involved in cardiovascular restoration may be altered in these patients. However, both HRV and expression of these genes could be remodeled after bariatric surgery. Therefore, the objective of this study was to evaluate gene expression and HRV of patients before and after bariatric surgery.
Methods: Thirteen women with grade III obesity (Body Mass Index -BMI >40 kg/m 2 ) and 9 eutrophic women (BMI 18 to 24.9 kg/m 2 -Control) were selected. Patients with obesity were evaluated before and after 6 months of bariatric surgery and once in control group. Peripheral blood was collected for RNA extraction and analysis. The Polar RS800CX heart rate monitor was used to capture the RR intervals of the electrocardiogram. We used the Shapiro-Wilk, t-test or Mann-Whitney U tests and genomic software (GenomeStudio ® ) and We consider as significant a p value <0.05. All tests were performed in the SPSS 17.0 program.
Conclusions: Weight loss after bariatric surgery improves HRV and positively modulates genes involved in cardiovascular remodeling, which should be thoroughly investigated as possible biomarkers for CVD. Background: High-throughput sequencing generates large amounts of data. Thus, bioinformatics analyses could help to select the genetic variations that have the higher biological effects. Strategically investigating with such tools, non-synonymous variants in the general population could reveal alterations in the function of the proteins produced. Specifically, variability of vitamin E status partly is explained by genetics. Until this date, 47 variations in 27 genes related to vitamin E metabolism have been reported, however, further work could lead to prediction and uncovering of new variants that modify and contribute to the personalized dietary recommendations. This in-silico analysis must be followed by an intervention study with genotyping and may lead to an accurate variant prioritization involved in vitamin E homeostasis.

In Silico-Study Predicting Damaging Functional and Structural Effects of Nonsynonymous Variants (nsSNVs) in 38 Genes Related to Absorption, Transport, and Metabolism, of Vitamin E
Objective: To analyze all common and rare non-synonymous variants in 38 genes related to absorption, transport, metabolism of vitamin E with the following algorithms: Combined Annotation Dependent Depletion, Annotate Variation, Gene-Aware Variant Interpretation, and Predicting Human Deleterious SNPs and select all nsSNVs that could affect the bioavailability of vitamin E.
Methods: A total of 26 426 non-synonymous variants (nsSN-Vs) were identified in 38 genes checking their allele frequency in the 1000 Genomes, NHLBI-ESP 6500 exomes, and Genome Aggregation Database. Then, we compared scores generated by different deleteriousness-prediction programs. Finally, we evaluated conservation scores of amino acid substitution compared with vertebrates, primates, and mammals which validate their natural selection and functional importance.
Results: After all this evaluation, we selected candidate variations which could have damaging functional and/or structural effects on proteins involved in vitamin E metabolism. We identified 104 candidate variants in 38 genes, most of variants are in ABCA1, IRS1, SEC14L3 and SEC14L4 genes.
Conclusion: Our approach adds 104 valuable non-synonymous variants that may contribute to the heterogeneity of vitamin E status and bioavailability which contribute to personalized nutrition.
Background: Serum branched chain amino acids (BCAA) have been associated with obesity and metabolic syndrome (MS). Although some studies have examined the association between protein intake and plasma BCAA levels, none of them has considered the impact of the protein source.
Objectives: The objective was to explore the associations between protein sources and plasma BCAA levels.
Methods: Data were analysed on 100 men and 99 women aged 18-55 from the INFOGENE Study. Dietary intakes have been estimated using a food frequency questionnaire. Plasma BCAA levels have been quantified using mass spectrometry-based metabolite profiling. Associations between constitutional factors, food intake and plasma BCAA levels were tested using the general linear model (GLM) procedure in SAS. Plasma BCAA levels, protein intake and sources were further compared according to the presence/absence of obesity and MS.
Results: In a model including age, sex, BMI or waist circumference, only age was not associated with plasma BCAA levels. In a model including nutritional factors, BCAA intakes, total calories from protein and total energy intake were not associated to BCAA levels. However, when considering animal versus vegetal protein sources, animal protein was associated with BCAA levels (p = 0.0008). When looking at constituents of the animal protein intake (red meat, organ meat, processed meat, fish, poultry, dairy products, eggs), red meat contributed to BCAA levels (p = 0.04). When subdividing study participants based on overweight/obesity and MS, red meat (p = 0.04) contributed to BCAA levels in overweight/ obese individuals with MS whereas processed meat and eggs (p = 0.02 and p = 0.04) were contributors in non-obese without MS. Finally, in overweight/obese with MS, BCAA levels and intakes of red meat were higher than in non-obese or obese individuals without MS (p = 0.0001 and p = 0.03).
Conclusions: Overall, animal protein intake, especially red meat, was associated with higher plasma BCAA levels. Objective: To identify combinations of SNPs that may associate with the TC response to intakes of dairy products and dietary fatty acids, separately.
Methods: Data of two independent randomized clinical trials, involving 22 candidate SNPs of cholesterol related genes were evaluated. Dataset 1 included 101 participants who consumed 3 servings/d of dairy or energy-matched control products for 4 wk each. Dataset 2 included 68 participants who followed a diet rich in saturated fatty acids (12.4-12.6% E) from either cheese or butter. PLS regression models were used to test the association of SNPs with TC responses to the dietary intakes.
Conclusions: Our preliminary findings suggest a key role that the CYP7A1-rs3808607 and ABCG5-rs6720173 could play in modifying responses of the TC concentrations to dietary interventions. Further analysis is in progress to confirm these findings.
Background: Long-chain omega-3 (n-3) fatty acids (FA) consumption has been proven to reduce triglyceride (TG) levels, yet a large inter-individual variability in the TG response was observed in clinical trials. Our group conducted a genome-wide association study (GWAS) of the plasma TG response to an n-3 FA supplementation and identified three SNPs, rs1216352, rs1216365 and rs931681, in PHF17.
Objective: The aim of the study was to increase the density of markers in PHF17 gene region using imputation to potentially find additional associated SNPs.
Methodology: A total of 141 subjects received 3 g/day of n-3 FA (1.9-2.2 g of EPA and 1.1 g of DHA) supplements for six weeks. TG levels were measured prior to and after the supplementation. Initial GWAS markers in PHF17 that were used to conduct the GWAS (Illumina Infinium Omni5 BeadChip) were used along with the 1000 Genomes project data (release 1000G Phase I v3, updated 26 Aug 2012) as reference to infer genotypes via IM-PUTE2. Differences in allele frequency between responders (reduction in TG levels of >0 mM) and non-responders (increase in TG levels of ≥0 mM) were assessed using PLINK. Significance was set at p < 10 -5 .
Results: Out of 885 initial markers, genotypes of 29255 new SNPs were imputed. After quality control tests, 3028 SNPs were left for the association study. A total of 22 SNPs showed a different allele frequency distribution between responders and non-responders, including the three initial GWAS hits. Several SNPs were in strong linkage disequilibrium.
Conclusion: By increasing the density of markers in a GWAS hit, we identified several novel PHF17 SNPs associated with the plasma TG response to an n-3 FA supplementation.

S. Vimal Karani, et al. (30 authors) & GeNuIne (Gene-Nutrient Interactions) Collaboration
High Sinclair Unit of Human Nutrition, University of Reading, UK *Corresponding Author: v.karani@reading.ac.uk Background: Cardiometabolic disease is a heritable trait that arises from the interactions between multiple genes and dietary factors. Although several studies have examined the gene-diet interactions, the findings have been quite inconsistent. Furthermore, there are no gene-diet interaction studies, to date, in several developing countries, which become a limitation to develop an optimum diet for each ancestral population.
Objectives: To address the above mentioned missing gap in nutrition, GeNuIne (Gene-Nutrient Interactions) Collaboration was initiated through funds from the British Nutrition Foundation to perform gene-diet interactions on cardiometabolic diseases using population-based studies from various ethnic groups with a view towards implementing personalised nutrition.
Methods: The GeNuIne Collaboration was initiated to implement nutrigenetic studies for the first time in developing countries. Two thousand study participants were recruited from the cross-sectional epidemiological study conducted on a representative population of Chennai, India. In addition, pilot studies were carried out in Indonesia, Sri Lanka, Brazil, Turkey and Ghana. Twenty GWAS-identified genetic variants were chosen as candidates. Dietary intake was assessed using validated food frequency questionnaires.
Results: Studies in South Asians have shown that carbohydrate (Pinteraction = 0.04) and dietary fibre (Pinteraction = 0.0008) intakes modified the association of the FTO variant with obesity and individuals carrying rare homozygous alleles of LPL (P = 0.001) and TCF7L2 (P = 0.0001) variants have increased risk of low HDL-C when consuming a high fat diet compared to common homozygotes, respectively. Furthermore, a genetic risk score constructed from 10 cardiometabolic-related variants showed an interaction with carbohydrate energy (%) on insulin levels (P = 0.011) and waist circumference (P = 0.031). Findings from other developing countries confirmed the existence of heterogeneity in gene-diet interactions.
Conclusion: The GeNuIne Collaboration is the first to provide evidence for gene-diet interactions on cardiometabolic traits in South Asians and has identified novel interactions in developing countries, which can possibly be used for implementing personalising diets for each ethnic group.