Published online Oct 27, 2020. doi: 10.4254/wjh.v12.i10.792
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
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.
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.
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.
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.
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.
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.
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.