Genetic ancestry analysis in non-alcoholic fatty liver disease patients from Brazil and Portugal

AIM:To study the association between genetic ancestry,non-alcoholic fatty liver disease(NAFLD) metabolic characteristics in two cohorts of patients,from Brazil and Portugal. METHODS:We included 131 subjects from Brazil [(n = 45 with simple steatosis(S. Steatosis) and n = 86 with nonalcoholic steatohepatitis(NASH)] and 90 patients from Portugal(n = 66,S. Steatosis; n = 24,NASH). All patients had biopsy-proven NAFLD. In histologic evaluation NAFLD activity score was used to assess histology and more than 5 points defined NASH in this study. Patients were divided into two groups according to histology diagnosis:simple steatosis or non-alcoholic statohepatitis. Genetic ancestry was assessed using real-time polymerase chain reaction. Seven ancestry informative markers(AT3-I/D,LPL,Sb19.3,APO,FYNull,PV92,and CKMM) with the greatest ethnicgeographical differential frequencies(≥ 48%) were used to define genetic ancestry. Data were analyzed using R PROJECTS software. Ancestry allele frequencies between groups were analyzed by GENEPOP onlineand the estimation of genetic ancestry contribution was evaluated by ADMIX-95 software. The 5% alpha-error was considered as significant(P < 0.05). RESULTS:In the Brazilian sample,NASH was significantly more frequent among the elderly patients with diabetes(NASH 56 ± 1.1 years old vs S. Steatosis 51 ± 1.5 years old,P = 3.7 x 10-9),dyslipidemia(NASH 63% vs S. Steatosis 37%,P = 0.009),higher fasting glucose levels(NASH 124 ± 5.2 vs S. Steatosis 106 ± 5.3,P = 0.001) and Homeostatic Model of Assessment index > 2.5 [NASH 5.3(70.8%) vs S. Steatosis 4.6(29.2%) P = 0.04]. In the Portuguese study population,dyslipidemia was present in all patients with NASH(P = 0.03) and hypertension was present in a larger percentage of subjects in the S. Steatosis group(P = 0.003,respectively). The genetic ancestry contribution among Brazilian and Portuguese individuals with NASH was similar to those with S. Steatosis from each cohort(Brazilian cohort:P = 0.75; Portuguese cohort:P = 0.97). Nonetheless,the genetic ancestry contribution of the Brazilian and Portuguese population were different,and a greater European and Amerindian ancestry contribution was detected in the Portuguese population while a higher African genetic ancestry contribution was observed in Brazilian population of both NASH and S. Steatosis groups.CONCLUSION:There was no difference between the genetic ancestry contribution among Brazilian and Portuguese individuals with NASH and S. Steatosis from each cohort.

A multi-omic landscape of steatosis-to-NASH progression

Nonalcoholic steatohepatitis(NASH)has emerged as a major cause of liver failure and hepatocellular carcinoma.Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understanding the development of NASH pathophysiology.Here,we present comprehensive multi-omic profiles of preclinical animal models to identify genes,non-coding RNAs,proteins,and plasma metabolites involved in this progression.In particular,by transcriptomics analysis,we identified Growth Differentiation Factor 3(GDF3)as a candidate noninvasive biomarker in NASH.Plasma GDF3 levels are associated with hepatic pathological features in patients with NASH,and differences in these levels provide a high diagnostic accuracy of NASH diagnosis(AUROC=0.90;95%confidence interval:0.85−0.95)with a good sensitivity(90.7%)and specificity(86.4%).In addition,by developing integrated proteomic-metabolomic datasets and performing a subsequent pharmacological intervention in a mouse model of NASH,we show that ferroptosis may be a potential target to treat NASH.Moreover,by using competing endogenous RNAs network analysis,we found that several miRNAs,including miR-582-5p and miR-292a-3p,and lncRNAs,including XLOC-085738 and XLOC-041531,are associated with steatosis-to-NASH progression.Collectively,our data provide a valuable resource into the molecular characterization of NASH progression,leading to the novel insight that GDF3 may be a potential noninvasive diagnostic biomarker for NASH while further showing that ferroptosis is a therapeutic target for the disease.