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

TitleGenome-wide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies.
Publication TypeJournal Article
Year of Publication2008
AuthorsKöttgen A, Kao W HL, Hwang S-J, Boerwinkle E, Yang Q, Levy D, Benjamin EJ, Larson MG, Astor BC, Coresh J, Fox CS
JournalBMC Med Genet
Volume9
Pagination49
Date Published2008 Jun 03
ISSN1471-2350
KeywordsAlleles, Cardiovascular Diseases, Cohort Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genome, Human, Genotype, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models
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.

DOI10.1186/1471-2350-9-49
Alternate JournalBMC Med Genet
PubMed ID18522750
PubMed Central IDPMC2430944
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
K01 DK067207 / DK / NIDDK NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
K01DK067207 / DK / NIDDK NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States