We have identified a common SNP rs27629393 in CYP24A1 that is associated with quantity of coronary artery calcification. The gene product of CYP24A1 is the major enzyme responsible for the catabolism of 1,25 (OH)2D and 25(OH)D. Our data thus suggest that genetic variability in vitamin D homeostasis may contribute to the pathogenesis of coronary artery calcification.
plays a pivotal role in maintaining vitamin D homeostasis. Deletion of Cyp24a1
in mice causes 1,25-(OH)2
D excess and hypercalcemia with severe bone mineralization defects and ectopic vascular calcification (renal calcium deposition) after chronic treatment of 1,25-(OH)2
. On the other hand, transgenic rats that constitutively express Cyp24a1
develop atherosclerotic lesions in the aorta, which greatly progress with high-fat and high-cholesterol feeding18
Although there is much circumstantial evidence, the role of vitamin D in cardiovascular health remains controversial19
. There is some epidemiological evidence in humans supporting a role of vitamin D metabolites in the development of CAC. Watson et al.
measured serum 1,25-(OH)2
D in 153 asymptomatic individuals with high risk of CHD and 13 patients with familial hypercholesterolemia and reported in both groups, an inverse correlation between serum 1,25-(OH)2
D and CAC20
. Doherty TM et al.
reported that serum 1,25-(OH)2
D independently and inversely predicted CAC quantity in a sample of 283 asymptomatic subjects with risk factors for CHD21
. Low 25(OH)D levels were also associated with subsequent development of CAC in the Multi-Ethnic Study of Atherosclerosis (MESA)22
. By contrast, there were no association between serum 25(OH)D levels and coronary calcification in a smaller study of 50 patients undergoing angiography23
. In this Amish population there is no correlation between season-adjusted 25(OH)D levels and prevalent CAC24
. The discordant results observed could be due to limited power to detect associations of small magnitude, differences in patient characteristics between studies, or differences in assays used in these studies.
Although 25(OH)D is the best marker of vitamin D stores, 1,25 (OH)2D is the active metabolite, and 25(OH)D levels might not reflect circulating 1,25 (OH)2D levels. In addition, the unknown local 1,25 (OH)2D production in the vasculature or in macrophages and other cell types involved in plaque formation might be more important than circulating levels for pathogenesis of vascular calcification.
This is the first demonstration of association between CYP24A1
gene variants and vascular calcification in human population studies. CYP24A1
SNPs or haplotypes have also been associated with other diseases in humans, including cancer 25
. In their asthma study, Wjst et al reported that the CYP24A1
haplotype that was moderately associated with asthma was also associated with 1,25 (OH)2
D, 25(OH)D, and IgE26
. A recent genome-wide association analysis based on ~34,000 individuals identified an association between rs6013897, located ~27.5 kb centromeric of CYP24A1, and 25(OH)D levels27
. The SNP is 38.8 kb away from rs2762939, the SNP associated with CAC quantity in the present study, and there is little LD between rs6013897 and rs2762939 (HapMap CEU r2
= 0.04, D’ = 0.27).
Despite the primal role of CYP24A1 to vitamin D metabolism, the mechanism linking rs2762939 to coronary calcification remains unclear. In neither the Amish study nor in an independent sample of 546 premenopausal Caucasian women from Indiana, USA (data not shown) was there any evidence for an association of rs2762939 with 25(OH)D levels. However, while an association of rs2762939 with 25(OH)D levels would have provided a clear potential mechanism linking this SNP to variation in CAC levels, there are several ways through which this SNP could affect CAC without influencing mean 25(OH)D levels. For example, this SNP (or a SNP in high LD with this SNP) could influence the conversion of active 1,25(OH)2D into its inactive metabolite without affecting 25(OH)D levels. One way to test this hypothesis would be to assess the association of rs2762939 with serum 1,25(OH)2D, but unfortunately we do not have these measurements in our study. Another potential mechanism is that this genetic variant may affect 24-hydroxylase expression and vitamin D metabolism locally in the endothelium, and these effects may not be correlated with circulating levels of vitamin D metabolites.
In summary, a common variant in the CYP24A1 gene was associated with CAC quantity in three independent populations. This result suggested a role for vitamin D metabolism in coronary atherosclerosis. Future studies should elucidate the underlying mechanisms and signaling pathways that entwine vitamin D metabolism and vascular health. These studies may lead to novel screening and therapeutic options for the identification and treatment of individuals at increased risk for CVD events.