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
ARTICLE HIGHLIGHTS
Research background

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and encompasses a spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Although highly prevalent, only a minority of NAFLD patients develop significant fibrosis. Thus, NAFLD is considered a complex disorder in which the disease phenotype results from an interaction between environmental exposure and a susceptible polygenic background. Polymorphisms of PNPLA3 and TM6SF2 genes have been associated with greater susceptibility to NAFLD development in previous studies.

Research motivation

There is only one genetic study in Brazilian NAFLD patients, and TM6SF2 polymorphism has not yet been analyzed in this population. As Brazilian NAFLD subjects have been reported as an admixed population presenting diverse genetic ancestry contributions, it is relevant to study the associations between various genotypes and fatty liver disease progression.

Research objectives

We aimed to investigate the association between PNPLA3 and TM6SF2 genotypes and clinical parameters of NAFLD, and analyzed the genotype variations as markers of liver histological features in adult Brazilian NAFLD patients. We also investigated the distribution of these genotype variations among Brazilians.

Research methods

This cross-sectional study enrolled 285 individuals, of which 148 patients had features of NAFLD (case patients) and 137 were non-NAFLD control subjects. NAFLD was diagnosed based on hepatic steatosis by liver ultrasonography and exclusion of other causes of liver disease. Patients who had decompensated cirrhosis or were taking drugs that induce steatosis were excluded. From the total of NAFLD patients, 65 underwent liver biopsy according to the clinical protocol of increased risk for NASH and/or advanced fibrosis. DNA was obtained for genotyping PNPLA3 at rs738409 and TM6SF2 at rs58542926.

Research 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 the 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). Presence of the T allele was not associated with NAFLD or NASH, or with histological features.

Research conclusions

PNPLA3 may be involved in the 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.

Research perspectives

The description of variant genotypes distribution in NAFLD Brazilian patients contributes to a better understanding of the disease clinical characteristics and atypical features in this population. As the TM6SF2 polymorphism is less frequent in the general population, investigations with larger sample are needed. Further studies may investigate additional particular components of fatty liver disease in Brazil. The role of genotyping assessment for risk stratification is still uncertain.