Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort).
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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, CRIC Study Principal Investigators
Аннотация
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 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) 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 the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885).
RESULTS: Of 268 SNPs reaching p < 5 × 10(-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 genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 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.