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Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.

Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH - Nat. Genet. (2008)

Bottom Line: An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels (P = 5.9 x 10(-10)) and with hepatic inflammation (P = 3.7 x 10(-4)).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.

View Article: PubMed Central - PubMed

Affiliation: Donald W Reynolds Cardiovascular Clinical Research Center, Eugene McDermott Center for Human Growth and Development, Dallas, TX 75390, USA.

ABSTRACT
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 x 10(-10)) and with hepatic inflammation (P = 3.7 x 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.

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Association between a sequence variant in PNPLA3 (I148M) and hepatic triglyceride (TG) content. (a) PNPLA3 is a 481 residue protein that contains a patatin-like domain at the N terminus (residues 10-179, UniProt http://pir.uniprot.org/uniprot/) with consensus sequences for a Ser-Asp catalytic dyad (Gly-X-Ser-X-Gly and Asp-X-Gly/Ala)14. The I148M substitution (rs738409) is located between the consensus sequences for the catalytic dyad and is highly conserved. (b) Median hepatic TG content, body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR) and plasma TG levels in the Dallas Heart Study. Values for hepatic fat content were compared using ANOVA. Age, gender, BMI, diabetes status, ethanol use and global ancestry were included as covariates in the model. (c) Median hepatic fat contents and PNPLA3-I148M genotypes in European-Americans, African-Americans and Hispanics in the Dallas Heart Study. Associations between hepatic fat content and PNPLA3-I148M genotypes were tested using ANOVA with age, local ancestry, gender, diabetes status, ethanol intake and BMI as covariates.
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Figure 2: Association between a sequence variant in PNPLA3 (I148M) and hepatic triglyceride (TG) content. (a) PNPLA3 is a 481 residue protein that contains a patatin-like domain at the N terminus (residues 10-179, UniProt http://pir.uniprot.org/uniprot/) with consensus sequences for a Ser-Asp catalytic dyad (Gly-X-Ser-X-Gly and Asp-X-Gly/Ala)14. The I148M substitution (rs738409) is located between the consensus sequences for the catalytic dyad and is highly conserved. (b) Median hepatic TG content, body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR) and plasma TG levels in the Dallas Heart Study. Values for hepatic fat content were compared using ANOVA. Age, gender, BMI, diabetes status, ethanol use and global ancestry were included as covariates in the model. (c) Median hepatic fat contents and PNPLA3-I148M genotypes in European-Americans, African-Americans and Hispanics in the Dallas Heart Study. Associations between hepatic fat content and PNPLA3-I148M genotypes were tested using ANOVA with age, local ancestry, gender, diabetes status, ethanol intake and BMI as covariates.

Mentions: A single variant in PNPLA3 (rs738409) was strongly associated with hepatic fat content (P=5.9×10−10) (Fig. 1b). The variant is a cytosine to guanine substitution that changes codon 148 from isoleucine to methionine; this residue is highly conserved in vertebrates (Fig. 2a). PNPLA3 encodes a 481 amino acid protein of unknown function that belongs to the patatin-like phospholipase family14. The progenitor of this family, patatin, is a major protein of potato tubers and has nonspecific lipid acyl hydrolase activity15,16. None of the other NS sequence variants tested in the genome-wide scan exceeded the Bonferroni-corrected threshold for significance (P=5.4×10−6) (Fig. 1b).


Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.

Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH - Nat. Genet. (2008)

Association between a sequence variant in PNPLA3 (I148M) and hepatic triglyceride (TG) content. (a) PNPLA3 is a 481 residue protein that contains a patatin-like domain at the N terminus (residues 10-179, UniProt http://pir.uniprot.org/uniprot/) with consensus sequences for a Ser-Asp catalytic dyad (Gly-X-Ser-X-Gly and Asp-X-Gly/Ala)14. The I148M substitution (rs738409) is located between the consensus sequences for the catalytic dyad and is highly conserved. (b) Median hepatic TG content, body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR) and plasma TG levels in the Dallas Heart Study. Values for hepatic fat content were compared using ANOVA. Age, gender, BMI, diabetes status, ethanol use and global ancestry were included as covariates in the model. (c) Median hepatic fat contents and PNPLA3-I148M genotypes in European-Americans, African-Americans and Hispanics in the Dallas Heart Study. Associations between hepatic fat content and PNPLA3-I148M genotypes were tested using ANOVA with age, local ancestry, gender, diabetes status, ethanol intake and BMI as covariates.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2597056&req=5

Figure 2: Association between a sequence variant in PNPLA3 (I148M) and hepatic triglyceride (TG) content. (a) PNPLA3 is a 481 residue protein that contains a patatin-like domain at the N terminus (residues 10-179, UniProt http://pir.uniprot.org/uniprot/) with consensus sequences for a Ser-Asp catalytic dyad (Gly-X-Ser-X-Gly and Asp-X-Gly/Ala)14. The I148M substitution (rs738409) is located between the consensus sequences for the catalytic dyad and is highly conserved. (b) Median hepatic TG content, body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR) and plasma TG levels in the Dallas Heart Study. Values for hepatic fat content were compared using ANOVA. Age, gender, BMI, diabetes status, ethanol use and global ancestry were included as covariates in the model. (c) Median hepatic fat contents and PNPLA3-I148M genotypes in European-Americans, African-Americans and Hispanics in the Dallas Heart Study. Associations between hepatic fat content and PNPLA3-I148M genotypes were tested using ANOVA with age, local ancestry, gender, diabetes status, ethanol intake and BMI as covariates.
Mentions: A single variant in PNPLA3 (rs738409) was strongly associated with hepatic fat content (P=5.9×10−10) (Fig. 1b). The variant is a cytosine to guanine substitution that changes codon 148 from isoleucine to methionine; this residue is highly conserved in vertebrates (Fig. 2a). PNPLA3 encodes a 481 amino acid protein of unknown function that belongs to the patatin-like phospholipase family14. The progenitor of this family, patatin, is a major protein of potato tubers and has nonspecific lipid acyl hydrolase activity15,16. None of the other NS sequence variants tested in the genome-wide scan exceeded the Bonferroni-corrected threshold for significance (P=5.4×10−6) (Fig. 1b).

Bottom Line: An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels (P = 5.9 x 10(-10)) and with hepatic inflammation (P = 3.7 x 10(-4)).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.

View Article: PubMed Central - PubMed

Affiliation: Donald W Reynolds Cardiovascular Clinical Research Center, Eugene McDermott Center for Human Growth and Development, Dallas, TX 75390, USA.

ABSTRACT
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 x 10(-10)) and with hepatic inflammation (P = 3.7 x 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.

Show MeSH
Related in: MedlinePlus