Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort)

Abstract

Objectives: This study sought 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 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.

Keywords: AA; African ancestry; CAC; CHD; CKD; Chronic Renal Insufficiency Cohort Study (CRIC); EA; European ancestry; GWAS; HDL; HTN; LD; LDL; MAF; MI; OR; PC; SNP; candidate genes; chronic kidney disease; chronic kidney disease (CKD); coronary artery calcification; coronary artery calcification (CAC); coronary heart disease; eGFR; estimated glomerular filtration rate; genome-wide association study/studies; high-density lipoprotein cholesterol; hypertension; linkage disequilibrium; low-density lipoprotein; minor allele frequency; myocardial infarction; myocardial infarction (MI); odds ratio; principal component; risk factors; single nucleotide polymorphism; single nucleotide polymorphisms (SNPs).