PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease

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 ( ...

The role of PNPLA3 and TM6SF2 polymorphisms on liver fibrosis and metabolic abnormalities in Brazilian patients with chronic hepatitis C

“…Brazilians are an admixed population, and this could justify our results. However, even in Brazil, the PNPLA3 polymorphisms have also been implicated in liver fibrosis in patients with NAFLD [ 22 , 23 , 43 ] and chronic hepatitis C [ 28 , 38 ]. However, data from these HCV studies reveal an unexpectedly high frequency of the PNPLA3 G allele [ 28 , 38 ], and in the report of Magri et al (2020), the PNPLA3 gene was not in Hardy–Weinberg equilibrium, which might preclude firm conclusions [ 38 ].…”

“…The I148M variant of PNPLA3 has shown an association with the progression of liver fibrosis and steatosis, and in the occurrence of hepatocellular carcinoma [ 9 , 19 , 20 ]. The strongest associations with the severity of liver disease were seen in patients with NAFLD, including the Brazilians [ 21 – 23 ]. Studies on chronic hepatitis C corroborate the relationship of this polymorphism with liver disease progression and steatosis [ 19 , 24 , 25 ].…”

Non-Alcoholic Fatty Liver Disease in Long-Term Type 2 Diabetes: Role of rs738409 PNPLA3 and rs499765 FGF21 Polymorphisms and Serum Biomarkers

“…This SNP is responsible for the largest proportion of the genetic predisposition related to NAFLD, and is related to the whole spectrum of the disease [ 11 , 33 ]. In admixed populations, such as in Brazil, this SNP was also related to liver fibrosis [ 14 , 34 ]. However, data exclusively in T2D patients are scarce in Brazil.…”

Factors That Predict the Progression of Non-alcoholic Fatty Liver Disease (NAFLD)

“…This gene is involved in liver secretion of very-low-density lipoprotein; a loss-of-function mutation increases hepatic steatosis while protecting cardiovascular disease (CVD) risk [94]. However, this association has not been replicated in other ethnicities [95]. Genetic risk scores are proposed to stratify the severity of NAFLD based on the identified variants [100].…”