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Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition, particularly among Hispanic Americans. A genetic variant in PNPLA3 (rs738409) has been identified as a strong predictor of hepatic fat content.To confirm the association of this variant with NAFLD in two minority cohorts, Hispanic Americans and African Americans, in whom liver density was quantified by computed tomography (CT).This analysis was conducted in the Insulin Resistance Atherosclerosis (IRAS) Family Study. Participants were recruited from the general community and included 843 Hispanic American and 371 African American adults aged 18-81 years. A single variant in PNPLA3 (rs738409) was genotyped. Liver density was calculated in Hounsfield Units from abdominal CT scans.Single nucleotide polymorphism (SNP) rs738409 was strongly associated with reduced liver density (i.e. NAFLD) in Hispanic Americans (1.18 × 10??) and in African Americans (P=4.99 × 10??). The association followed an additive genetic model with the G allele conferring risk. The allele was two times more common in Hispanic Americans than in African Americans (40 vs 19%), consistent with the greater prevalence of NAFLD in Hispanic Americans (24 vs 9%). The SNP explained 4.4 and 5.6% of the variance of the adjusted liver density outcome in Hispanic Americans and African Americans, respectively.We confirmed the association of a PNPLA3 variant with NAFLD in Hispanic Americans and African Americans, suggesting that PNPLA3 contributes to the variation in NAFLD across multiple ethnicities. This study adds to the growing evidence that some of the ethnic variation in NAFLD is genetic.

SUBMITTER: Wagenknecht LE

PROVIDER: S-EPMC3703938 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study.

Wagenknecht Lynne E LE Palmer Nicholette D ND Bowden Donald W DW Rotter Jerome I JI Norris Jill M JM Ziegler Julie J Chen Yii-Der I YD Haffner Steven S Scherzinger Ann A Langefeld Carl D CD

Liver international : official journal of the International Association for the Study of the Liver 20110113 3

<h4>Background</h4>Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition, particularly among Hispanic Americans. A genetic variant in PNPLA3 (rs738409) has been identified as a strong predictor of hepatic fat content.<h4>Aims</h4>To confirm the association of this variant with NAFLD in two minority cohorts, Hispanic Americans and African Americans, in whom liver density was quantified by computed tomography (CT).<h4>Methods</h4>This analysis was conducted in the Insulin Resis ...[more]

PMID: 21281435

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Project description:AimsPrior studies have established variation at the PNPLA3 gene to be associated with a risk of developing alcoholic liver disease (ALD). We attempt to replicate this finding and other potential genetic variations previously associated with ALD utilizing a case-control design in a cohort of subjects with alcohol use disorders.Short summaryThis case-control study performed in a US clinical sample of heavy drinkers, replicates the previously reported association between ALD and rs738409 polymorphism in the PNPLA3 gene in heavy drinkers. This association persisted after accounting for the subject's diabetes status.MethodsPatients of European ancestry with a history of ALD were identified (n = 169). Controls consisted of patients without ALD who were from the same cohorts and were ≥ 30 years of age, had lifetime total years drinking ≥20 and lifetime maximum drinks per day ≥12 (n = 259). Patients were genotyped for 40 candidate single nucleotide polymorphisms (SNPs) selected for the purpose of testing their association with ALD. The association of each SNP with ALD was tested using a logistic regression model, assuming log-additive allele effects. Bonferroni correction was applied and multivariable logistic regression models were used to account for relevant covariates.ResultsAge, sex, and body mass index (BMI) distributions were similar between cases and controls. Diabetes was more prevalent in the ALD cases. Three SNPs were associated with ALD at the nominal significance level (rs738409 in PNPLA3, P = 0.00029; rs3741559 in AQP2, P = 0.0185; rs4290029 in NVL, P = 0.0192); only PNPLA3 rs738409 SNP was significant at the Bonferroni-corrected P-value threshold of 0.00125. Association results remained significant after adjustment for diabetes status.ConclusionOur case-control study confirmed that PNPLA3 rs738409 SNP is associated with ALD. This is an important replication in a US clinical sample with control subjects who had long histories of alcohol consumption.

Dataset Information

Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study.

Publications

Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study.

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