Background: Despite the strong suspicion that genetic variability contribute to NAFLD, previous studies on this topic have suffered from small sample size and lack of histological characterization. Aim: To investigate whether variants of adiponutrin (PNPLA3) and of farnesyl-transferase-1 genes (FDFT1), respectively major determinant of liver fat contents and key regulator of cholesterol biosynthesis, are associated with different histological or biochemical features of NAFLD. Patients: 906 subjects enrolled since 2006 with suspected or histologically confirmed NAFLD or cryptogenic cirrhosis were considered. After exclusion of patients with significant alcohol consumption and competing/alternate aetiologies, and central revision of liver biopsies according to the Brunt scoring system, 434 Caucasian patients with histological diagnosis of NAFLD were selected. 45% of them had NASH. 310 healthy blood donors were considered as control population. Because of the recognized association between NASH and coronary artery diseases (CAD) the genetic analysis was replicated in 111 patients with diagnosis of CAD. Methods: PNPLA3 and FDFT1 were genotyped using TaqMan assay. We used multivariate logistic regression analysis (MLR) and coded the SNPs additively in a model that also included age, BMI, gender, fasting glucose, HDL cholesterol, ALT levels and histology. Results: 23% of the patients enrolled were female, mean BMI 29 ± 4.7. Frequencies of the minor PNPLA3 genotype GG were 8%, 13% and 19% among controls, simple fatty liver and NASH (p=0.0001). In patients with CAD, the frequency of GG was comparable to that of controls (7%). GG did not result significantly associated with more severe fibrosis (p=0.09). GG, GT and AA types of FDFT1 were found in similar proportions in patients and controls (p=0.61) but, within NAFLD subjects, the major GG-type was significantly more frequent among patients with NASH (39%) as compared to simple fatty liver (27%) (p=0.001). At MLR, older age, TG higher than150mg/dl, raised ALT and FDFT1 GG-type, but not PNPLA3 GG-type resulted independent predictors of NASH. Conclusions: In our study, PNPLA3 GG-type results specifically associated with NAFLD but not with severity of fibrosis. By contrast, the major GG variant of FDFT1 seems to predict NASH development
Genetic predictors of steatosis and fibrosis in nonalcoholic fatty liver disease (NAFLD)
VANNI, Ester;BUGIANESI, Elisabetta;
2011-01-01
Abstract
Background: Despite the strong suspicion that genetic variability contribute to NAFLD, previous studies on this topic have suffered from small sample size and lack of histological characterization. Aim: To investigate whether variants of adiponutrin (PNPLA3) and of farnesyl-transferase-1 genes (FDFT1), respectively major determinant of liver fat contents and key regulator of cholesterol biosynthesis, are associated with different histological or biochemical features of NAFLD. Patients: 906 subjects enrolled since 2006 with suspected or histologically confirmed NAFLD or cryptogenic cirrhosis were considered. After exclusion of patients with significant alcohol consumption and competing/alternate aetiologies, and central revision of liver biopsies according to the Brunt scoring system, 434 Caucasian patients with histological diagnosis of NAFLD were selected. 45% of them had NASH. 310 healthy blood donors were considered as control population. Because of the recognized association between NASH and coronary artery diseases (CAD) the genetic analysis was replicated in 111 patients with diagnosis of CAD. Methods: PNPLA3 and FDFT1 were genotyped using TaqMan assay. We used multivariate logistic regression analysis (MLR) and coded the SNPs additively in a model that also included age, BMI, gender, fasting glucose, HDL cholesterol, ALT levels and histology. Results: 23% of the patients enrolled were female, mean BMI 29 ± 4.7. Frequencies of the minor PNPLA3 genotype GG were 8%, 13% and 19% among controls, simple fatty liver and NASH (p=0.0001). In patients with CAD, the frequency of GG was comparable to that of controls (7%). GG did not result significantly associated with more severe fibrosis (p=0.09). GG, GT and AA types of FDFT1 were found in similar proportions in patients and controls (p=0.61) but, within NAFLD subjects, the major GG-type was significantly more frequent among patients with NASH (39%) as compared to simple fatty liver (27%) (p=0.001). At MLR, older age, TG higher than150mg/dl, raised ALT and FDFT1 GG-type, but not PNPLA3 GG-type resulted independent predictors of NASH. Conclusions: In our study, PNPLA3 GG-type results specifically associated with NAFLD but not with severity of fibrosis. By contrast, the major GG variant of FDFT1 seems to predict NASH development
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