Genome-wide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies

Abstract

Background: The Framingham Heart Study (FHS) recently obtained initial results from the first genome-wide association scan for renal traits. The study of 70,987 single nucleotide polymorphisms (SNPs) in 1,010 FHS participants provides a list of SNPs showing the strongest associations with renal traits which need to be verified in independent study samples.

Methods: Sixteen SNPs were selected for replication based on the most promising associations with chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), and serum cystatin C in FHS. These SNPs were genotyped in 15,747 participants of the Atherosclerosis in Communities (ARIC) Study and evaluated for association using multivariable adjusted regression analyses. Primary outcomes in ARIC were CKD and eGFR. Secondary prospective analyses were conducted for association with kidney disease progression using multivariable adjusted Cox proportional hazards regression. The definition of the outcomes, all covariates, and the use of an additive genetic model was consistent with the original analyses in FHS.

Results: The intronic SNP rs6495446 in the gene MTHFS was significantly associated with CKD among white ARIC participants at visit 4: the odds ratio per each C allele was 1.24 (95% CI 1.09-1.41, p = 0.001). Borderline significant associations of rs6495446 were observed with CKD at study visit 1 (p = 0.024), eGFR at study visits 1 (p = 0.073) and 4 (lower mean eGFR per C allele by 0.6 ml/min/1.73 m2, p = 0.043) and kidney disease progression (hazard ratio 1.13 per each C allele, 95% CI 1.00-1.26, p = 0.041). Another SNP, rs3779748 in EYA1, was significantly associated with CKD at ARIC visit 1 (odds ratio per each T allele 1.22, p = 0.01), but only with eGFR and cystatin C in FHS.

Conclusion: This genome-wide association study provides unbiased information implicating MTHFS as a candidate gene for kidney disease. Our findings highlight the importance of replication to identify common SNPs associated with renal traits.

Figure 1

Selection process of SNPs from the FHS 100 K GWAS screen to be followed up by genotyping in the ARIC cohort. Abbreviations: GWAS: genome-wide association, SNPs: single nucleotide polymorphisms, GEE: generalized estimating equation, FBAT: family-based association test, CKD: chronic kidney disease, eGFR: estimated glomerular filtration rate, cys: cystatin C.

Figure 2

Results from multivariable adjusted association analyses of rs6495446 in MTHFS and both eGFR (panel A) and CKD (panel B) in FHS and ARIC. Risk estimates refer to each additional copy of the C allele. For ARIC, odds ratios of CKD per risk allele and the hazard ratio of kidney disease progression per risk allele are presented on the same scale. Horizontal bars represent 95% confidence intervals. Abbreviations: eGFR: estimated glomerular filtration rate, OR: odds ratio, CKD: chronic kidney disease.