Case Control Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Oct 27, 2020; 12(10): 792-806
Published online Oct 27, 2020. doi: 10.4254/wjh.v12.i10.792
PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease
Quelson Coelho Lisboa, Mateus Jorge Nardelli, Patrícia de Araújo Pereira, Débora Marques Miranda, Stephanie Nunes Ribeiro, Raissa Soares Neves Costa, Camila Azevedo Versiani, Paula Vieira Teixeira Vidigal, Teresa Cristina de Abreu Ferrari, Claudia Alves Couto
Quelson Coelho Lisboa, Mateus Jorge Nardelli, Patrícia de Araújo Pereira, Débora Marques Miranda, Stephanie Nunes Ribeiro, Raissa Soares Neves Costa, Camila Azevedo Versiani, Paula Vieira Teixeira Vidigal, Teresa Cristina de Abreu Ferrari, Claudia Alves Couto, Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
Author contributions: Lisboa QC, Pereira PA, Miranda DM, Ferrari TCA, and Couto CA planned and designed the study; Lisboa QC, Nardelli MJ, Pereira PA, Miranda DM, Ribeiro SN, Versiani CA, Costa RSN, Ferrari TCA, and Couto CA participated in the acquisition, analysis, and interpretation of the data; Lisboa QC, Nardelli MJ, Ferrari TCA, and Couto CA drafted the manuscript; all authors revised and approved the final draft of the manuscript submitted.
Supported by Fundação de Amparo à Pesquisa do Estado de Minas Gerais, No. APQ-02233-14.
Institutional review board statement: The study was approved by the ethics committee of Hospital das Clínicas da Universidade Federal de Minas Gerais (Belo Horizonte, Brazil).
Informed consent statement: All patients gave informed consent.
Conflict-of-interest statement: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding authors at clalcouto@gmail.com.
STROBE statement: The authors have read the STROBE Statement – checklist of items, and the manuscript was prepared and revised according to the STROBE Statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Claudia Alves Couto, MD, PhD, Associate Professor, Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Avenida Professor Alfredo Balena 190, Belo Horizonte 30130100, Brazil. clalcouto@gmail.com
Received: April 29, 2020
Peer-review started: April 30, 2020
First decision: May 24, 2020
Revised: May 28, 2020
Accepted: September 2, 2020
Article in press: September 2, 2020
Published online: October 27, 2020
Processing time: 177 Days and 0 Hours
Abstract
BACKGROUND

Nonalcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide, with significant morbidity associated with nonalcoholic steatohepatitis (NASH). Genome-wide association studies demonstrated that the variants rs738409 C/G in the PNPLA3 and rs58542926 C/T in the TM6SF2 genes are determinants of inter-individual and ethnicity-related differences in hepatic fat content and NAFLD progression.

AIM

To investigate PNPLA3 and TM6SF2 genotype frequency and their association with NAFLD development and progression in Brazilian patients.

METHODS

This cross-sectional case-control study enrolled 285 individuals from the Gastroenterology and Hepatology clinics at a university hospital in Brazil. The case patients (n = 148) were confirmed to have NAFLD by the identification of hepatic steatosis on ultrasonography and exclusion of other causes of liver disease. According to the clinical protocol, patients underwent liver biopsy when at high risk for NASH and/or advanced fibrosis (n = 65). Steatohepatitis was confirmed in 54 patients. Individuals who did not have biopsy indication or NASH on histology were considered to have simple steatosis (n = 94). The control group (n = 137) was selected among patients that attended the Intestinal Disease clinic and was composed of subjects without abnormalities on abdominal ultrasonography and normal liver biochemical tests. All individuals underwent PNPLA3 and TM6SF2 genotype analysis.

RESULTS

PNPLA3 CC, CG and GG genotype frequencies were 37%, 44% and 19%, respectively, in NAFLD patients and were 58%, 31% and 10% in controls (P < 0.001). In a model adjusted for gender, age, body mass index and type 2 diabetes mellitus, the G allele increased the chance of NAFLD (OR = 1.69, 95%CI: 1.21-2.36, P = 0.002) and NASH (OR = 3.50, 95%CI: 1.84-6.64, P < 0.001). The chance of NASH was even higher with GG homozygosis (OR = 5.53, 95%CI: 2.04-14.92, P = 0.001). No association was found between G allele and the features of metabolic syndrome. In histological assessment, PNPLA3 genotype was not associated with steatosis grade, although GG homozygosis increased the chance of significant NASH activity (OR = 17.11, 95%CI: 1.87-156.25, P = 0.01) and fibrosis (OR = 7.42, 95%CI: 1.55-34.47, P = 0.01) in the same adjusted model. TM6SF2 CC, CT and TT genotype frequencies were 83%, 15% and 0.7%, respectively, in NAFLD patients and were 84%, 16% and 0.7% in controls (P = 0.78). The T allele presence was not associated with NAFLD or NASH, and was not associated with histological features.

CONCLUSION

PNPLA3 may be involved in susceptibility and progression of NAFLD and NASH in the Brazilian population. More advanced histological liver disease was associated with the G allele. The TM6SF2 genetic variants were not associated with NAFLD susceptibility and progressive histological forms in the population studied, but further studies are required to confirm these findings.

Keywords: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Genetic variation; Single nucleotide polymorphism; Genotype; Brazil; Fibrosis

Core Tip: The rs738409 C/G mutation in the PNPLA3 gene may be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) in the Brazilian population. We found an association between this polymorphism and higher susceptibility to NAFLD occurrence, disease progression to nonalcoholic steatohepatitis, more severe histological activity scores and the presence of liver fibrosis. The TM6SF2 gene variants were also evaluated in the Brazilian population, although they were not associated with NAFLD susceptibility and different histological forms.