Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

By S. Romeo, J. Kozlitina, Chao Xing, A. Pertsemlidis, David Cox, Len A. Pennacchio, Eric Boerwinkle, Jonathan C. Cohen, Helen H. Hobbs. Nature Genetics, 2008

3,244 citations recorded by the source corpus.

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ancestry groups. To identify genetic variants contributing to differences in hepatic fat content, we carried out a genome-wide association scan of nonsynonymous sequence variations (n = 9,229) in a population comprising Hispanic, African American and European American individuals. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels (P = 5.9 × 10−10) and with hepatic inflammation (P = 3.7 × 10−4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was more than twofold higher in PNPLA3 rs738409[G] homozygotes than in noncarriers. Resequencing revealed another allele of PNPLA3 (rs6006460[T], encoding S453I) that was associated with lower hepatic fat content in African Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD.

Subfields: Cardiology and Cardiovascular Medicine, Endocrinology, Diabetes and Metabolism, Epidemiology

View Paper: https://www.semanticscholar.org/paper/7277cd189432336f10df5662972a45b538f388a5

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In Cardiology and Cardiovascular Medicine

1. Gerald I. Shulman
2. V. Samuel
3. Herbert Tilg
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In Endocrinology, Diabetes and Metabolism

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In Epidemiology

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6. S. Friedman
7. M. Parola
8. A. Moschen

Citations in the corpus

• Meta‐analysis of the influence of I148M variant of patatin‐like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease (2011, methodology): “Neither was the trait obesity, as measured by BMI, associated with the variant (Supporting Table 2) in 4,141 subjects included in 10 heterogeneous studies.(1,2,6,15,18,19,21,22) Overall Study Quality.”
• Homozygosity for the patatin‐like phospholipase‐3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease (2010, background): “The 148M variant was more common in Hispanics, who are known to be at increased risk for NASH and cryptogenic cirrhosis.(12) Importantly, the I148M SNP influenced liver fat independently of body mass, dyslipidemia, and insulin resistance.”