Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study by Ferguson Jane F, Matthews Gregory J, Townsend Raymond R, Raj Dominic S, Kanetsky Peter A, Budoff Matthew, Fischer Michael J, Rosas Sylvia E, Kanthety Radhika, Rahman Mahboob, Master Stephen R, Qasim Atif, Li Mingyao, Mehta Nehal N, Shen Haiqing, Mitchell Braxton D, O'Connell Jeffrey R, Shuldiner Alan R, Ho Weang Kee, Young Robin, Rasheed Asif, Danesh John, He Jiang, Kusek John W, Ojo Akinlolu O, Flack John, Go Alan S, Gadegbeku Crystal A, Wright Jackson T, Saleheen Danish, Feldman Harold I, Rader Daniel J, Foulkes Andrea S, Reilly Muredach P in Journal of the American College of Cardiology (2013). PubMed

Abstract

OBJECTIVES: To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). BACKGROUND: CKD is associated with increased CAC and subsequent coronary heart disease (CHD) but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. METHODS: We performed a candidate gene study (∼2,100 genes; ∼50,000 SNPs) of CAC within the Chronic Renal Insufficiency Cohort (CRIC) Study (n=1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in PennCAC (n=2,560) and Amish Family Calcification Study (AFCS; n=784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the Pakistan Risk of Myocardial Infarction study (PROMIS) (n=14,885). RESULTS: Of 268 SNPs reaching P <5x10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (P <0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported GWAS association with hypertension (e.g., ATP2B1). In PROMIS, four of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1 and ABCA4) had significant associations with MI consistent with their direction of effect on CAC. CONCLUSIONS: We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.

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