Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study.
The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16-88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7 variants. Carriers of the PNPLA3 and TM6SF2 risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P < 0.05). The PNPLA3 genotype was associated with steatosis grades S2-S3 (P < 0.001) and fibrosis stages F2-F4 (P < 0.001). The TM6SF2 genotype was associated with steatosis (P = 0.003) but not with fibrosis (P > 0.05). The MBOAT7 variant was solely associated with increased fibrosis (P = 0.046). In the multivariate model, variants PNPLA3 (P = 0.004) and TM6SF2 (P = 0.038) were associated with steatosis. Fibrosis stages were affected by the PNPLA3 (P = 0.042) and MBOAT7 (P = 0.021) but not by the TM6SF2 polymorphism (P > 0.05). The PNPLA3, TM6SF2, and MBOAT7 variants are associated with increased liver injury. The TM6SF2 variant seems to modulate predominantly hepatic fat accumulation, whereas the MBOAT7 polymorphism is linked to fibrosis. The PNPLA3 polymorphism confers risk of both increased steatosis and fibrosis.
Department of Medicine II, Saarland University Medical Center, Homburg, Germany.|Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
Marcin
M
Krawczyk
Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany.
Monika
M
Rau
I. Department of Medicine, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany.
Jörn M
JM
Schattenberg
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Heike
H
Bantel
Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany.
Anita
A
Pathil
Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany.
Münevver
M
Demir
Department of Medicine I, Hamburg University Medical Center, Hamburg, Germany.
Johannes
J
Kluwe
Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Tobias
T
Boettler
Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
Frank
F
Lammert
Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany Geier_A2@ukw.de.
Andreas
A
Geier
D000217:Acyltransferases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001706:Biopsy; D005234:Fatty Liver / Q000235:genetics / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D055815:Young Adult; D054512:Phospholipases A2, Calcium-Independent
D000217:Acyltransferases; D008049:Lipase; D008565:Membrane Proteins; C419195:TM6SF2 protein, human; C000616532:MBOAT7 protein, human; C533682:PNPLA3 protein, human; D054512:Phospholipases A2, Calcium-Independent
adiponutrin; fatty liver; fibrosis; steatosis