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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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Identification of a PNPLA3 allele (S453I) associated with lower hepatic fat content in African-Americans in the Dallas Heart Study. (a) Exons and flanking introns of PNPLA3 were sequenced in the 32 European-American and African-American men and women and in the 16 Hispanic men and women with the lowest and highest hepatic triglyceride content determined using proton magnetic resonance imaging2. The NS variations identified in individuals in only the high, only the low and in both the high and low groups are shown. All the variants not found in both groups were present in only a single subject unless otherwise indicated. The rs numbers for polymorphisms and the oligonucleotides used for PCR-sequencing of the coding regions and are provided in Supplementary Tables 3 online and Supplementary Table 4 online. (b) Median hepatic TG content in African-Americans carrying the wild-type or PNPLA3-453I allele. (c) Number of individuals with PNPLA3-453I in the upper and lower deciles of hepatic fat content.
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Figure 3: Identification of a PNPLA3 allele (S453I) associated with lower hepatic fat content in African-Americans in the Dallas Heart Study. (a) Exons and flanking introns of PNPLA3 were sequenced in the 32 European-American and African-American men and women and in the 16 Hispanic men and women with the lowest and highest hepatic triglyceride content determined using proton magnetic resonance imaging2. The NS variations identified in individuals in only the high, only the low and in both the high and low groups are shown. All the variants not found in both groups were present in only a single subject unless otherwise indicated. The rs numbers for polymorphisms and the oligonucleotides used for PCR-sequencing of the coding regions and are provided in Supplementary Tables 3 online and Supplementary Table 4 online. (b) Median hepatic TG content in African-Americans carrying the wild-type or PNPLA3-453I allele. (c) Number of individuals with PNPLA3-453I in the upper and lower deciles of hepatic fat content.

Mentions: To determine if other sequence variations in PNPLA3 contribute to differences in hepatic fat content, we resequenced the coding region of PNPLA3 in the 80 men (32 African-Americans, 32 European-Americans, and 16 Hispanics) and 80 women who had the highest levels of hepatic fat in the Dallas Heart Study, and in a sex- and ethnicity-matched group with the lowest levels2. The number of individuals with NS variants found only in the high group (n=8) was similar to the number found only in the low group (n=9), but the three subjects with likely mutations (Fs-Y21 and IVS7+1) were all in the high group (Fig. 3a), which is consistent with loss-of-function of PNPLA3 causing an increase in hepatic TG content.


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)

Identification of a PNPLA3 allele (S453I) associated with lower hepatic fat content in African-Americans in the Dallas Heart Study. (a) Exons and flanking introns of PNPLA3 were sequenced in the 32 European-American and African-American men and women and in the 16 Hispanic men and women with the lowest and highest hepatic triglyceride content determined using proton magnetic resonance imaging2. The NS variations identified in individuals in only the high, only the low and in both the high and low groups are shown. All the variants not found in both groups were present in only a single subject unless otherwise indicated. The rs numbers for polymorphisms and the oligonucleotides used for PCR-sequencing of the coding regions and are provided in Supplementary Tables 3 online and Supplementary Table 4 online. (b) Median hepatic TG content in African-Americans carrying the wild-type or PNPLA3-453I allele. (c) Number of individuals with PNPLA3-453I in the upper and lower deciles of hepatic fat content.
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Related In: Results  -  Collection

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Figure 3: Identification of a PNPLA3 allele (S453I) associated with lower hepatic fat content in African-Americans in the Dallas Heart Study. (a) Exons and flanking introns of PNPLA3 were sequenced in the 32 European-American and African-American men and women and in the 16 Hispanic men and women with the lowest and highest hepatic triglyceride content determined using proton magnetic resonance imaging2. The NS variations identified in individuals in only the high, only the low and in both the high and low groups are shown. All the variants not found in both groups were present in only a single subject unless otherwise indicated. The rs numbers for polymorphisms and the oligonucleotides used for PCR-sequencing of the coding regions and are provided in Supplementary Tables 3 online and Supplementary Table 4 online. (b) Median hepatic TG content in African-Americans carrying the wild-type or PNPLA3-453I allele. (c) Number of individuals with PNPLA3-453I in the upper and lower deciles of hepatic fat content.
Mentions: To determine if other sequence variations in PNPLA3 contribute to differences in hepatic fat content, we resequenced the coding region of PNPLA3 in the 80 men (32 African-Americans, 32 European-Americans, and 16 Hispanics) and 80 women who had the highest levels of hepatic fat in the Dallas Heart Study, and in a sex- and ethnicity-matched group with the lowest levels2. The number of individuals with NS variants found only in the high group (n=8) was similar to the number found only in the low group (n=9), but the three subjects with likely mutations (Fs-Y21 and IVS7+1) were all in the high group (Fig. 3a), which is consistent with loss-of-function of PNPLA3 causing an increase in hepatic TG content.

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