Dataset Information

Genetic variants in nicotinic acetylcholine receptor genes jointly contribute to kidney function in American Indians: the Strong Heart Family Study.

ABSTRACT: Cigarette smoking negatively affects kidney function. Genetic variants in the nicotinic acetylcholine receptor (nAChR) genes have been associated with nicotine dependence, and are likely to influence renal function and related traits. Whereas each single variant may only exert a small effect, the joint contribution of multiple variants to the risk of disease could be substantial.Using a gene-family approach, we investigated the joint association of 61 tagging SNPs in seven genes encoding the nAChRs with kidney function in 3620 American Indians participating in the Strong Heart Family Study, independent of known risk factors. Kidney function was evaluated by estimated glomerular filtration rate, urinary albumin/creatinine ratio, albuminuria and chronic kidney disease. The joint impact of smoking-related variants was assessed using the weighted truncated product method.Multiple SNPs showed marginal individual effect on renal function variability, and only a few survive multiple comparison correction. In contrast, a gene-family analysis considering the joint impact of all 61 SNPs reveals significant associations of the nAChR gene family with kidney function variables including estimated glomerular filtration rate, urinary albumin/creatinine ratio, and albuminuria (all Ps???0.0001) after adjusting for established risk factors including cigarette smoking.Genetic variants in nAChR genes jointly contribute to renal function or kidney damage in American Indians. The effects of these genetic variants on kidney function or damage are independent of traditional risk factors including cigarette smoking per se.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC4157895 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Genetic variants in nicotinic acetylcholine receptor genes jointly contribute to kidney function in American Indians: the Strong Heart Family Study.

Zhu Yun Y Yang Jingyun J Li Shengxu S Cole Shelley A SA Haack Karin K Umans Jason G JG Franceschini Nora N Howard Barbara V BV Lee Elisa T ET Zhao Jinying J

Journal of hypertension 20140501 5

<h4>Background</h4>Cigarette smoking negatively affects kidney function. Genetic variants in the nicotinic acetylcholine receptor (nAChR) genes have been associated with nicotine dependence, and are likely to influence renal function and related traits. Whereas each single variant may only exert a small effect, the joint contribution of multiple variants to the risk of disease could be substantial.<h4>Methods</h4>Using a gene-family approach, we investigated the joint association of 61 tagging S ...[more]

PMID: 24569419

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Project description:Background: Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations.Methods: The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses.Results: CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10-20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10-7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10-4.Conclusion: In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation.

Project description:In populations with high prevalences of diabetes and obesity, estimating glomerular filtration rate (GFR) by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation may predict cardiovascular disease (CVD) risk better than by using the Modification of Diet in Renal Disease (MDRD) Study equation.Longitudinal cohort study comparing the association of GFR estimated using either the CKD-EPI or MDRD Study equation with incident CVD outcomes.American Indians participating in the Strong Heart Study, a longitudinal population-based cohort with high prevalences of diabetes, CVD, and CKD.Estimated GFR (eGFR) predicted using the CKD-EPI and MDRD Study equations.Fatal and nonfatal cardiovascular events, consisting of coronary heart disease, stroke, and heart failure.The association between eGFR and outcomes was explored in Cox proportional hazards models adjusted for traditional risk factors and albuminuria; the net reclassification index and integrated discrimination improvement were determined for the CKD-EPI versus MDRD Study equations.In 4,549 participants, diabetes was present in 45%; CVD, in 7%; and stages 3-5 CKD, in 10%. During a median of 15 years, there were 1,280 cases of incident CVD, 929 cases of incident coronary heart disease, 305 cases of incident stroke, and 381 cases of incident heart failure. Reduced eGFR (<90 mL/min/1.73 m2) was associated with adverse events in most models. Compared with the MDRD Study equation, the CKD-EPI equation correctly reclassified 17.0% of 2,151 participants without incident CVD to a lower risk (higher eGFR) category and 1.3% (n=28) were reclassified incorrectly to a higher risk (lower eGFR) category.Single measurements of eGFR and albuminuria at study visits.Although eGFR based on either equation had similar associations with incident CVD, coronary heart disease, stroke, and heart failure events, in those not having events, reclassification of participants to eGFR categories was superior using the CKD-EPI equation compared with the MDRD Study equation.

Dataset Information

Genetic variants in nicotinic acetylcholine receptor genes jointly contribute to kidney function in American Indians: the Strong Heart Family Study.

Publications

Genetic variants in nicotinic acetylcholine receptor genes jointly contribute to kidney function in American Indians: the Strong Heart Family Study.

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