Smoking is a known risk factor for progression of chronic kidney disease (CKD) but little is known of the role of smoking exposure on genetic effects of variants influencing kidney traits in the general population. We examined the evidence for effect modification of current smoking on the association of single nucleotide polymorphisms (SNP) with estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR), two well established markers of kidney disease, in 23,767 white and 8,110 African American individuals from five studies genotyped using the custom SNP array ITMAT-Broad-CARe (IBC array) in the CARe consortium. We obtained study- and race-specific residuals from linear regression models of natural log-transformed eGFR or UACR regressed on age, sex and study site. We then stratified residuals by current smoking exposure and performed genome wide association analyses using additive genetic models adjusted for 10 principal components, and accounting for family structure using mixed models, if needed. Meta-analyses across smoking-specific strata within each self-reported race were performed using the inverse variance weighted fixed effect models. We assessed smoking interaction using a heterogeneity test (P<0.10) and I
2
metric. Among SNPs reaching the array wide specific significance threshold (2.0x10
-6
) for association with eGFR or UACR, there was significant between smoking-strata heterogeneity for rs7422339 (
CPS1
, P=0.03, I
2
=77.7%) and rs13333226 (
UMOD
, P=0.06, I
2
=71.1%) for eGFR in whites, with larger decreases in eGFR among current smokers compared to past/never smokers. For UACR, rs1801239 (missense variant of
CUBN
, between smoking-strata heterogeneity P=0.09, I
2
=64.8%) T allele showed less protective effect among current smokers than non-smokers in whites only. These loci have been previously identified in genome wide association studies. Our findings, if replicated, suggest possible important interactions of smoking exposure on the genetic effects of known loci associated with kidney traits.
Funding(This research has received full or partial funding support from the American Heart Association, National Center)
Molecular insights into genome-wide association studies of chronic kidney disease-defining traits
