Is Coronary Artery Calcification at the Intersection of Vitamin D and Coronary Artery Disease? Editorial Is Coronary Artery Calcification at the Intersection of Vitamin D and Coronary Artery Disease? Zari Dastani, J. Brent Richards Cardiovascular disease is the leading cause of deathamong men and women in developed countries.1 Most of this premature mortality occurs in a subgroup of the popula- tion that is prone to accelerated atherogenesis caused by genetic, lifestyle, and environmental factors, along with their interactions. Growing evidence suggests that vitamin D deficiency is associated with coronary artery disease (CAD) development.2 However, mechanistic evidence supporting this association is lacking. Coronary artery calcification (CAC) is strongly associated with risk of vascular disease,3,4 and several studies report an inverse relationship between levels of the active form of vitamin D and atherosclerotic calcification.5 Therefore, it is important to understand if vitamin D metabolism influences degree of CAC; insights into this relationship would provide support for a role of vitamin D in the pathogenesis of CAD. See accompanying article on page 2648 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Shen et al6 present a well-designed candidate gene study to investigate the association of single-nucleotide poly- morphisms (SNPs) in key genes involved in vitamin D metabolism with CAC. The CAC phenotype was quantified as the sum of the calcification scores in both left and right coronary arteries. The researchers selected 5 genes, cyto- chrome P450, family 2, subfamily R (CYP2R1), cytochrome P450, family 27, subfamily B (CYP27B1), cytochrome P450, family 24, subfamily A (CYP24A1), vitamin D receptor (VDR), Viatmin D-binding protein (GC), known to be in- volved in vitamin D homeostasis.6 – 8 In the discovery phase, they conducted the association analysis in samples from Amish families (N�697), with 39 genotyped SNPs from 4 available genes using a chip (HumanCVD BeadChip V2). Although no SNPs in the CYP27B1, VDR, or GC genes were associated with CAC score, 4 SNPs in the CYP24A1 gene were nominally associated with CAC score (P�0.008 to P�0.00003) in the discovery phase. Then, these 4 SNPs were tested for replication in samples from the Genetic Epidemi- ology Network of Arteriopathy (N�916) and the Penn Coronary Artery Calcification (N�2061), 2 independent cohorts of European white ancestry (Figure). In the replica- tion phase, 1 of these 4 SNPs, rs2762939, demonstrated evidence of an association with CAC in both the Genetic Epidemiology Network of Arteriopathy and the Penn Coro- nary Artery Calcification cohorts (P�0.01 and P�0.007, respectively). The subsequent meta-analysis of the data from these 3 populations yielded a probability value of 2.9�10�6 for rs2762939. However, in further analysis, they could not find any association between circulating levels of 25- hydroxy-vitamin D (25[OH]D) levels and this SNP in rela- tively small populations. The results of the study conducted by Shen et al raise the possibility of the role of vitamin D homeostasis in CAC development. The CYP24A1 gene product is central to vitamin D regulation because it degrades the active form of vitamin D, 1,25-dihydroxy-vitamin D (1,25[OH]2D). Despite the fact that previous transgenic studies have revealed the role of the CYP24A1 gene on stability plasma level of 1,25(OH)2D and 25(OH)D,9 the current study did not estab- lish any association between rs2762939 and 25(OH)D levels. In addition, 1,25(OH)2D levels were not available for re- searchers to assess this possible association. It remains possible that the identified SNP may influence 1,25(OH)2D levels and, consequently, CAC, without affecting vitamin D stores, as reflected by 25(OH)D levels. Therefore, it is important that the association between rs2762939, 25(OH)D, 1,25(OH)2D, and other coronary disease outcomes be clari- fied in adequately powered consortia designed to identify the genetic determinants of vitamin D levels or CAD.10 Further- From the Department of Epidemiology and Biostatistics (Z.D. and J.B.R.), Faculty of Medicine, McGill University, Montréal, Quebec, Canada; the Department of Human Genetics (J.B.R.), Faculty of Medi- cine, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Quebec, Canada; and the Department of Medicine (J.B.R.), Faculty of Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Quebec, Canada. Correspondence to J. Brent Richards, MD, MSc, Lady Davis Institute, Jewish General Hospital, Pavillon E-104, 3755 Cote St Catherine, Montréal, QC H3T 1E2, Canada. E-mail brent.richards@mcgill.ca (Arterioscler Thromb Vasc Biol. 2010;30:2329-2330.) © 2010 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.110.216218 Discovery phase Amish samples (N=697)y p 4 SNPs achieved p value <0.01 p ( ) Replica�on phase PennCAC samples (N=2,061)GENOA samples (N=916) One SNP (rs2762939) achieved p value <0.01 Meta-analysis In three cohorts (N = 3,674)Meta-analysis phase Rs2762939, p value =2.9 x 10-6 Figure. The strategy used by Shen and colleagues6 to investigate whether DNA sequence variants in the candidate genes in vitamin D metabolism contribute to Coronary Artery Calcification. 2329 D ow nloaded from http://ahajournals.org by on A pril 5, 2021 more, it will be worthwhile to investigate whether this SNP affects the transcription and protein product levels of the genes involved in the maintenance of 1,25(OH)2D and 25(OH)D levels. This finding raises interesting questions about the direct role of vitamin D in the progression or initiation of athero- sclerosis. Other research has discovered that vitamin D lowers the activity of the inflammatory activator nuclear factor �B, inhibiting foam cell formation and suppressing macrophage cholesterol uptake in patients with type 2 diabetes mellitus.11,12 On the other hand, vitamin D levels are correlated with other CAD risk factors, such as hypertension, hyperlipidemia, and diabetes.13–17 Therefore, the described association may occur directly through vitamin D metabolism or indirectly through other pathways, regardless of their effect on 25(OH)D, by influencing known risk factors for cardiovascular disease (ie, hypertension, diabetes, and inflammation). This study suggests a role for vitamin D homeostasis in CAC and provides an important signpost on the road toward understanding the role of calcium and vitamin D metabolism in risk of CAD. Disclosures None. References 1. Castelli WP. Epidemiology of coronary heart disease: The framingham study. Am J Med. 1984;76:4 –12. 2. Levin A, Li YC. 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