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) in GC, CYP27B1, CYP24A1, and VDR 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 in CYP24A1, 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 a P value of 2.9 x 10(-6). Conclusion-A common SNP in the CYP24A1 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. (Arterioscler Thromb Vasc Biol. 2010;30:2648-2654.)