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


CONCLUSIONS
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.
Department of Epidemiology and Welch Center for Prevention, Epidemiology & Clinical Research, Johns Hopkins University, Baltimore, MD, USA. akottgen@jhsph.edu
Anna
A
Kottgen
Wen Hong L
WH
Kao
Shih-Jen
SJ
Hwang
Eric
E
Boerwinkle
Qiong
Q
Yang
Daniel
D
Levy
Emelia J
EJ
Benjamin
Martin G
MG
Larson
Brad C
BC
Astor
Josef
J
Coresh
Caroline S
CS
Fox
D000483:Alleles; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models