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Abstract 532: Genetic Variation in CX3CR1 Protects Against Coronary Artery Disease and Myocardial Infarction but Does Not Impair the Acute Inflammatory Response in Humans


 Introduction:
 CX3CR1 is a leukocyte chemokine receptor that binds the chemokine fractalkine (CX3CL1). CX3CR1 is expressed on all bone marrow derived cells and is proposed to function in chronic homeostasis. CX3CR1 supports recruitment of monocytes to the endothelium and promotes atherosclerosis in model systems.
 CX3CR1
 V249I and T280M variants reduce monocyte adhesion but contemporary data is lacking for their association with myocardial infarction (MI) and coronary artery disease (CAD) in humans.
 
 
 Hypothesis:
 Do functional variants in
 CX3CR1,
 V249I and T280M, reduce risk of CAD and MI and if so do they also attenuate the acute response to inflammatory stress?
 
 
 Methods:
 We examined differences by
 CX3CR1
 genotypes in endotoxin-induced cytokines in the Genetics of Evoked responses to Niacin and Endotoxemia (GENE) study (n=268). We then examined the association of these SNPs with CAD and MI in two large datasets, (1) the CARDIoGRAM consortium meta-analysis summary data from 14 studies of CAD comprising 22,233 cases (53,814 with MI) and 64,762 controls of European ancestry, and (2) 9,028 MI cases and 8,379 controls in the Pakistan Risk of Myocardial Infarction Study (PROMIS) as well as additional GWAS datasets for metabolic traits.
 
 
 Results:
 In GENE, there was no significant difference by V249I or T280M genotypes in IL1-RA, IL6, and TNF-alpha cytokine responses to LPS. In CARDIoGRAM, the V249I allele had nominal association with CAD (p=0.037) and MI (p=0.04) with similar trends for T280M allele. In PROMIS, both T280M (p=0.0006) and V249I (p=0.0003) were associated with MI. In comparison, there was no association (p>0.05) of CX3CR1 variants with plasma lipids, type 2 diabetes mellitus, body mass index or glucometabolic traits in GLGC, DIAGRAM, GIANT and MAGIC GWAS consortia meta-analysis data.
 
 
 Conclusion:
 CX3CR1 harbors functional genetic variants that appear to impact the development of atherosclerosis and risk of MI without compromising the acute inflammatory response.
 
 
 
