Center for Statistical Genetics

Hershey, PA, United States

Center for Statistical Genetics

Hershey, PA, United States
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Kim D.S.,Center for Statistical Genetics | Jackson A.U.,Center for Statistical Genetics | Li Y.K.,Center for Statistical Genetics | Stringham H.M.,Center for Statistical Genetics | And 17 more authors.
Journal of Lipid Research | Year: 2017

A glutamate-to-lysine variant (rs58542926-T) in transmembrane 6 superfamily member 2 (TM6SF2) is associated with increased fatty liver disease and diabetes in conjunction with decreased cardiovascular disease risk. To identify mediators of the effects of TM6SF2, we tested for associations between rs58542926-T and serum lipoprotein/metabolite measures in cross-sectional data from nondia-betic statin-naïve participants. We identifed independent associations between rs58542926-T and apoB-100 particles (P = -0.057 g/l, P = 1.99 × 10) and tyrosine levels (P = 0.0020 mmol/l, P = 1.10 × 10), controlling for potential confounders, in 6,929 Finnish men. The association between rs58542926-T and apoB-100 was confrmed in an independent sample of 2,196 Finnish individuals from the FINRISK study (βreplication = -0.029, Preplication = 0.029). Secondary analyses demonstrated an rs58542926-T dose-dependent decrease in particle concentration, cholesterol, and triglyceride (TG) content for VLDL and LDL particles (P < 0.001 for all). No signifcant associations between rs58542926-T and HDL measures were observed. TM6SF2 SNP rs58542926-T and tyrosine levels were associated with increased incident T2D risk in both METSIM and FINRISK. Decreased liver production/secretion of VLDL, decreased cholesterol and TGs in VLDL/LDL particles in serum, and increased tyrosine levels identify possible mechanisms by which rs58542926-T exerts its effects on increasing risk of fatty liver disease, decreasing cardiovascular disease, and increasing diabetes risk, respectively. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.


Li M.,Johns Hopkins University | Li Y.,Albert Ludwigs University of Freiburg | Weeks O.,Genetics Division | Teumer A.,Institute for Community Medicine | And 156 more authors.
Journal of the American Society of Nephrology : JASN | Year: 2017

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation. Copyright © 2017 by the American Society of Nephrology.

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