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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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Whole-genome scan of liver triglyceride content measured by proton magnetic resonance imaging in the Dallas Heart Study (n=2,111). (a) Quantile-quantile plot of P-values. (b) Scatter plot of P-values. The dashed line denotes the Bonferroni corrected significance threshold (P=5.4×10−6).
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Figure 1: Whole-genome scan of liver triglyceride content measured by proton magnetic resonance imaging in the Dallas Heart Study (n=2,111). (a) Quantile-quantile plot of P-values. (b) Scatter plot of P-values. The dashed line denotes the Bonferroni corrected significance threshold (P=5.4×10−6).

Mentions: Each variant was tested for association with hepatic fat content in the 1,032 African-American, 696 European-American and 383 Hispanic study participants in the Dallas Heart Study who obtained 1H-MRS of the liver2. To maximize statistical power, the three ethnic groups were pooled and a global ancestry score (calculated using a panel of 2,270 ancestry informative SNPs) was included in the model to control for population stratification (see METHODS). The quantile-quantile plot of P-values showed no systematic deviation from the distribution (Fig. 1a).


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)

Whole-genome scan of liver triglyceride content measured by proton magnetic resonance imaging in the Dallas Heart Study (n=2,111). (a) Quantile-quantile plot of P-values. (b) Scatter plot of P-values. The dashed line denotes the Bonferroni corrected significance threshold (P=5.4×10−6).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2597056&req=5

Figure 1: Whole-genome scan of liver triglyceride content measured by proton magnetic resonance imaging in the Dallas Heart Study (n=2,111). (a) Quantile-quantile plot of P-values. (b) Scatter plot of P-values. The dashed line denotes the Bonferroni corrected significance threshold (P=5.4×10−6).
Mentions: Each variant was tested for association with hepatic fat content in the 1,032 African-American, 696 European-American and 383 Hispanic study participants in the Dallas Heart Study who obtained 1H-MRS of the liver2. To maximize statistical power, the three ethnic groups were pooled and a global ancestry score (calculated using a panel of 2,270 ancestry informative SNPs) was included in the model to control for population stratification (see METHODS). The quantile-quantile plot of P-values showed no systematic deviation from the distribution (Fig. 1a).

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