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Lipid trait-associated genetic variation is associated with gallstone disease in the diverse Third National Health and Nutrition Examination Survey (NHANES III).

ABSTRACT: Gallstone disease is one of the most common digestive disorders, affecting more than 30 million Americans. Previous twin studies suggest a heritability of 25% for gallstone formation. To date, one genome-wide association study (GWAS) has been performed in a population of European-descent. Several candidate gene studies have been performed in various populations, but most have been inconclusive. Given that gallstones consist of up to 80% cholesterol, we hypothesized that common genetic variants associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) would also be associated with gallstone risk.To test this hypothesis, the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study as part of the Population Architecture using Genomics and Epidemiology (PAGE) study performed tests of association between 49 GWAS-identified lipid trait SNPs and gallstone disease in non-Hispanic whites (446 cases and 1,962 controls), non-Hispanic blacks (179 cases and 1,540 controls), and Mexican Americans (227 cases and 1,478 controls) ascertained for the population-based Third National Health and Nutrition Examination Survey (NHANES III).At a liberal significance threshold of 0.05, five, four, and four SNP(s) were associated with disease risk in non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively. No one SNP was associated with gallstone disease risk in all three racial/ethnic groups. The most significant association was observed for ABCG5 rs6756629 in non-Hispanic whites [odds ratio (OR)?=?1.89; 95% confidence interval (CI)?=?1.44-2.49; p?=?0.0001). ABCG5 rs6756629 is in strong linkage disequilibrium with rs11887534 (D19H), a variant previously associated with gallstone disease risk in populations of European-descent.We replicated a previously associated variant for gallstone disease risk in non-Hispanic whites. Further discovery and fine-mapping efforts in diverse populations are needed to fully describe the genetic architecture of gallstone disease risk in humans.

SUBMITTER: Goodloe R

PROVIDER: S-EPMC3870971 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Lipid trait-associated genetic variation is associated with gallstone disease in the diverse Third National Health and Nutrition Examination Survey (NHANES III).

Goodloe Robert R Brown-Gentry Kristin K Gillani Niloufar B NB Jin Hailing H Mayo Ping P Allen Melissa M McClellan Bob B Boston Jonathan J Sutcliffe Cara C Schnetz-Boutaud Nathalie N Dilks Holli H HH Crawford Dana C DC

BMC medical genetics 20131121

<h4>Background</h4>Gallstone disease is one of the most common digestive disorders, affecting more than 30 million Americans. Previous twin studies suggest a heritability of 25% for gallstone formation. To date, one genome-wide association study (GWAS) has been performed in a population of European-descent. Several candidate gene studies have been performed in various populations, but most have been inconclusive. Given that gallstones consist of up to 80% cholesterol, we hypothesized that common ...[more]

PMID: 24256507

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Project description:Albuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease. While the underlying etiology is unclear, chronic, low-grade inflammation is a suspected key factor. Genetic variants within genes involved in inflammatory processes may, therefore, contribute to the development of albuminuria.We evaluated 60 polymorphisms within 27 inflammatory response genes in participants from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States. Albuminuria was evaluated as logarithm-transformed albumin-to-creatinine ratio (ACR), as ACR ? 30 mg/g, and as ACR above sex-specific thresholds. Multivariable linear regression and haplotype trend analyses were conducted to test for genetic associations in 5321 participants aged 20 years or older. Differences in allele and genotype distributions among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans were tested in additive and codominant genetic models.Variants in several genes were found to be marginally associated (uncorrected P value < 0.05) with log(ACR) in at least one race/ethnic group, but none remained significant in crude or fully-adjusted models when correcting for the false-discovery rate (FDR). In analyses of sex-specific albuminuria, IL1B (rs1143623) among Mexican Americans remained significantly associated with increased odds, while IL1B (rs1143623), CRP (rs1800947) and NOS3 (rs2070744) were significantly associated with ACR ? 30 mg/g in this population (additive models, FDR-P < 0.05). In contrast, no variants were found to be associated with albuminuria among non-Hispanic blacks after adjustment for multiple testing. The only variant among non-Hispanic whites significantly associated with any outcome was TNF rs1800750, which failed the test for Hardy-Weinberg proportions in this population. Haplotypes within MBL2, CRP, ADRB2, IL4R, NOS3, and VDR were significantly associated (FDR-P < 0.05) with log(ACR) or albuminuria in at least one race/ethnic group.Our findings suggest a small role for genetic variation within inflammation-related genes to the susceptibility to albuminuria. Additional studies are needed to further assess whether genetic variation in these, and untested, inflammation genes alter the susceptibility to kidney damage.

Project description:BackgroundThe Chronic Kidney Disease Epidemiology Collaboration equation for estimation of glomerular filtration rate (eGFR(CKD-EPI)) improves GFR estimation compared with the Modification of Diet in Renal Disease Study equation (eGFR(MDRD)) but its association with mortality in a nationally representative population sample in the US has not been studied.MethodsWe examined the association between eGFR and mortality among 16,010 participants of the Third National Health and Nutrition Examination Survey (NHANES III). Primary predictors were eGFR(CKD-EPI) and eGFR(MDRD). Outcomes of interest were all-cause and cardiovascular disease (CVD) mortality. Improvement in risk categorization with eGFR(CKD-EPI) was evaluated using adjusted relative hazard (HR) and Net Reclassification Improvement (NRI).ResultsOverall, 26.9% of the population was reclassified to higher eGFR categories and 2.2% to lower eGFR categories by eGFR(CKD-EPI), reducing the proportion of prevalent CKD classified as stage 3-5 from 45.6% to 28.8%. There were 3,620 deaths (1,540 from CVD) during 215,082 person-years of follow-up (median, 14.3 years). Among those with eGFR(MDRD) 30-59 ml/min/1.73 m(2), 19.4% were reclassified to eGFR(CKD-EPI) 60-89 ml/min/1.73 m(2) and these individuals had a lower risk of all-cause mortality (adjusted HR, 0.53; 95% CI, 0.34-0.84) and CVD mortality (adjusted HR, 0.51; 95% CI, 0.27-0.96) compared with those not reclassified. Among those with eGFR(MDRD) >60 ml/min/1.73 m(2), 0.5% were reclassified to lower eGFR(CKD-EPI) and these individuals had a higher risk of all-cause (adjusted HR, 1.31; 95% CI, 1.01-1.69) and CVD (adjusted HR, 1.42; 95% CI, 1.01-1.99) mortality compared with those not reclassified. Risk prediction improved with eGFR(CKD-EPI); NRI was 0.21 for all-cause mortality (p < 0.001) and 0.22 for CVD mortality (p < 0.001).ConclusionseGFR(CKD-EPI) categories improve mortality risk stratification of individuals in the US population. If eGFR(CKD-EPI) replaces eGFR(MDRD) in the US, it will likely improve risk stratification.

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Lipid trait-associated genetic variation is associated with gallstone disease in the diverse Third National Health and Nutrition Examination Survey (NHANES III).

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Lipid trait-associated genetic variation is associated with gallstone disease in the diverse Third National Health and Nutrition Examination Survey (NHANES III).

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