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Comparative Study
. 2016 Jan;63(1):117-25.
doi: 10.1002/hep.28283. Epub 2015 Nov 16.

Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study

Martina Goffredo  1   2 , Sonia Caprio  1 , Ariel E Feldstein  3 , Ebe D'Adamo  4 , Melissa M Shaw  1 , Bridget Pierpont  1 , Mary Savoye  1 , Hongyu Zhao  5   6 , Allen E Bale  6 , Nicola Santoro  1
Affiliations
Comparative Study

Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study

Martina Goffredo et al. Hepatology. 2016 Jan.

Abstract

We assessed the association between the single-nucleotide polymorphism (SNP) rs58542926 in the transmembrane 6 superfamily member 2 (TM6SF2) gene and fatty liver disease in obese youth. We genotyped the TM6SF2 rs58542926 SNP in a multiethnic cohort of 957 obese children and adolescents (42% Caucasians, 28% African Americans, 30% Hispanics). All underwent an oral glucose tolerance test, a liver panel, and a lipid profile. Of them, 454 children underwent a magnetic resonance imaging study to assess hepatic fat content and 11 underwent liver biopsy to assess the degree of disease severity. The minor allele of the rs58542926 SNP was associated with high hepatic fat content in Caucasians and African Americans (all P < 0.05), with high alanine aminotransferase levels in Hispanics (P < 0.05) and a more favorable lipoprotein profile (lower low-density lipoprotein, small dense low-density lipoprotein, and very small low-density lipoprotein) in Caucasians and Hispanics (all P < 0.05). The liver biopsy showed a higher prevalence of fibrosis (P = 0.04) and a higher nonalcoholic fatty liver disease activity score (P = 0.05) in subjects carrying the minor allele than in those homozygous for the common allele. Moreover, we observed a joint effect among the TM6SF2 rs58542926, the PNPLA3 rs738409, and the GCKR rs1260326 SNPs in determining intrahepatic fat accumulation (P < 0.05).

Conclusion: The rs58542926 SNP in the TM6SF2 gene is associated with pediatric nonalcoholic fatty liver disease but may confer protection against cardiovascular risk.

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Figures

Figure 1
Figure 1. Association of the TM6SF2 rs58542926 with hepatic fat content
Association between TM6SF2 rs58542926 SNP and hepatic fat content (%HFF) in (A) Caucasians, (B) African Americans, and (C) Hispanics. White bars represent the CC and black bars represent CT/TT. P values are adjusted for age, sex, and BMI. Data are shown as mean with SD.
Figure 2
Figure 2. Association between TM6SF2 rs58542926 SNP and liver histology
The TM6SF2 rs58542926 minor allele is associated with liver fibrosis (panel A) and NAFLD Activity score (NAS) (panel B). Data of NAS are shown as mean with SD.
Figure 3
Figure 3. Joint effect of PNPLA3 and GCKR on increased HFF
Association between the genetic risk score calculated adding the risk alleles of rs58542926 in the TM6SF2, the rs738409 in the PNPLA3 and the rs1260326 in the GCKR and the hepatic fat content (%HFF in the overall population (A), in Caucasians (B), in African Americans (C), in Hispanics (D). P values adjusted for age, sex, BMI. Data are shown using the mean % within each group.
Figure 4
Figure 4. Plasma Lipoproteins: effect of rs58542926 TM6SF2 gene variant
Association in Caucasians, African Americans and Hispanics between TM6SF2 rs58542926 SNP and total LDL Particles (panel A-C) and Very Small LDL Particles (panel D-F). White bars indicate the CC and black bars indicate the T allele carriers. P values are adjusted for age, sex, and BMI. Data are shown as mean with SD.
See this image and copyright information in PMC

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