Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci

Abstract

Acute kidney injury (AKI) is a common, serious complication of cardiac surgery. Since prior studies have supported a genetic basis for postoperative AKI, we conducted a genome-wide association study (GWAS) for AKI following coronary bypass graft (CABG) surgery. The discovery data set consisted of 873 nonemergent CABG surgery patients with cardiopulmonary bypass (PEGASUS), while a replication data set had 380 cardiac surgical patients (CATHGEN). Single-nucleotide polymorphism (SNP) data were based on Illumina Human610-Quad (PEGASUS) and OMNI1-Quad (CATHGEN) BeadChips. We used linear regression with adjustment for a clinical AKI risk score to test SNP associations with the postoperative peak rise relative to preoperative serum creatinine concentration as a quantitative AKI trait. Nine SNPs meeting significance in the discovery set were detected. The rs13317787 in GRM7|LMCD1-AS1 intergenic region (3p21.6) and rs10262995 in BBS9 (7p14.3) were replicated with significance in the CATHGEN data set and exhibited significantly strong overall association following meta-analysis. Additional fine mapping using imputed SNPs across these two regions and meta-analysis found genome-wide significance at the GRM7|LMCD1-AS1 locus and a significantly strong association at BBS9. Thus, through an unbiased GWAS approach, we found two new loci associated with post-CABG AKI providing new insights into the pathogenesis of perioperative AKI.

Figure 1

Regional association plot for (A) chr3p21.6 locus (GRM7|LMCD1-AS1) and (B) BBS9 gene, presenting – log₁₀(p-values) from the discovery (PEGASUS) and replication (CATHGEN) datasets, as well as the meta-analysis. Directly genotyped SNPs are plotted in black; imputed markers are plotted in red.

Figure 2

Comparative graphical representation of genotypic effects of rs13317787 at the chr3p21.6 locus (A&C) and rs10262995 in BBS9 (B&D) on incident post-cardiac surgery acute kidney injury (AKI) – defined using either the KDIGO criteria or peak postoperative serum creatinine increase (%ΔCr). The dashed line represents a 2-fold (100%) increase in serum creatinine from baseline, approximately equivalent to a 50% reduction in glomerular filtration rate.