Association of the Vitamin D Metabolism Gene CYP24A1 With Coronary Artery Calcification

Objective— The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC).Methods and Results— We genotyped single-nucleotide polymorphisms (SNPs) inGC ,CYP27B1, CYP24A1 , andVDR and tested their association with CAC quantity, as measured by electron beam computed tomography. Initial association studies were carried out in a discovery sample comprising 697 Amish subjects, and SNPs nominally associated with CAC quantity (4 SNPs inCYP24A1 ,P =0.008 to 0.00003) were then tested for association with CAC quantity in 2 independent cohorts of subjects of white European ancestry (Genetic Epidemiology Network of Arteriopathy study [n=916] and the Penn Coronary Artery Calcification sample [n=2061]). One of the 4 SNPs, rs2762939, was associated with CAC quantity in both the Genetic Epidemiology Network of Arteriopathy (P =0.007) and Penn Coronary Artery Calcification (P =0.01) studies. In all 3 populations, the rs2762939 C allele was associated with lower CAC quantity. Metaanalysis for the association of this SNP with CAC quantity across all 3 studies yielded aP value of 2.9×10−6 .Conclusion— A common SNP in theCYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity.