• Jane F Ferguson, Gregory J Matthews, Raymond R Townsend, Dominic S Raj, Peter A Kanetsky, Matthew Budoff, Michael J Fischer, Sylvia E Rosas, Radhika Kanthety, Mahboob Rahman, Stephen R Master, Atif Qasim, Mingyao Li, Nehal N Mehta, Haiqing Shen, Braxton D Mitchell, Jeffrey R O'Connell, Alan R Shuldiner, Weang Kee Ho, Robin Young, Asif Rasheed, John Danesh, Jiang He, John W Kusek, Akinlolu O Ojo, John Flack, Alan S Go, Crystal A Gadegbeku, Jackson T Wright, Danish Saleheen, Harold I Feldman, Daniel J Rader, Andrea S Foulkes, Muredach P Reilly, and CRIC Study Principal Investigators.
• Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
• J. Am. Coll. Cardiol. 2013 Aug 27; 62 (9): 789-98.

ObjectivesThis study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).BackgroundCKD 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.MethodsWe 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).ResultsOf 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.ConclusionsWe 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.Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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