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Relationships between Genetic Variations of PNPLA3, TM6SF2 and Histological Features of Nonalcoholic Fatty Liver Disease in Japan.

ABSTRACT: It is important to determine the noninvasive parameters of histological features in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the value of genetic variations as surrogate markers of histological features.The parameters that affected the histological features of NAFLD were investigated in 211 Japanese patients with biopsy-proven NAFLD. The relationships between genetic variations in PNPLA3 rs738409 or TM6SF2 rs58542926 and histological features were analyzed. Furthermore, the impact of genetic variations that affected the pathological criteria for the diagnosis of nonalcoholic steatohepatitis (NASH) (Matteoni classification and NAFLD activity score) was evaluated.The fibrosis stage of PNPLA3 GG was significantly more progressive than that of CG by multiple comparisons. Multivariate analysis identified PNPLA3 genotypes as predictors of fibrosis of stage 2 or more, but the impact tended to decrease at stage 3 or greater. There were no significant differences among the histological features of the three genotypes of TM6SF2. PNPLA3 genotypes partly affected the definition of NASH by the NAFLD activity score, but TM6SF2 genotypes did not affect the definition of NASH.In Japanese patients with biopsy-proven NAFLD, PNPLA3 genotypes may partly affect histological features, including stage of fibrosis, but the TM6SF2 genotype does not affect histological features.

SUBMITTER: Akuta N

PROVIDER: S-EPMC4849698 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Relationships between Genetic Variations of PNPLA3, TM6SF2 and Histological Features of Nonalcoholic Fatty Liver Disease in Japan.

Akuta Norio N Kawamura Yusuke Y Arase Yasuji Y Suzuki Fumitaka F Sezaki Hitomi H Hosaka Tetsuya T Kobayashi Masahiro M Kobayashi Mariko M Saitoh Satoshi S Suzuki Yoshiyuki Y Ikeda Kenji K Kumada Hiromitsu H

Gut and liver 20160501 3

<h4>Background/aims</h4>It is important to determine the noninvasive parameters of histological features in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the value of genetic variations as surrogate markers of histological features.<h4>Methods</h4>The parameters that affected the histological features of NAFLD were investigated in 211 Japanese patients with biopsy-proven NAFLD. The relationships between genetic variations in PNPLA3 rs738409 or TM6SF2 rs585429 ...[more]

PMID: 26610348

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Project description:BackgroundNonalcoholic 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.AimTo investigate PNPLA3 and TM6SF2 genotype frequency and their association with NAFLD development and progression in Brazilian patients.MethodsThis 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.ResultsPNPLA3 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 (P = 0.78). The T allele presence was not associated with NAFLD or NASH, and was not associated with histological features.ConclusionPNPLA3 may be involved in 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, but further studies are required to confirm these findings.

Project description:UnlabelledGenome-wide association studies identified single-nucleotide polymorphisms (SNPs) that are associated with increased hepatic fat or elevated liver enzymes, presumably reflecting nonalcoholic fatty liver disease (NAFLD). To investigate whether these SNPs are associated with histological severity of NAFLD, 1117 (894 adults/223 children) individuals enrolled in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network and National Institutes of Health Clinical Center studies with histologically confirmed NAFLD were genotyped for six SNPs that are associated with hepatic fat or liver enzymes in genome-wide association studies. In adults, three SNPs on chromosome 22 showed associations with histological parameters of NASH. After adjustment for age, sex, diabetes, and alcohol consumption, the minor allele of rs738409 C/G, a nonsynonymous coding SNP in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) (adiponutrin) gene encoding an Ile148Met change, was associated with steatosis (P = 0.03), portal inflammation (P = 2.5 x 10(-4)), lobular inflammation (P = 0.005), Mallory-Denk bodies (P = 0.015), NAFLD activity score (NAS, P = 0.004), and fibrosis (P = 7.7 x 10(-6)). Two other SNPs in the same region demonstrated similar associations. Three SNPs on chromosome 10 near the CHUK (conserved helix-loop-helix ubiquitous kinase) gene were independently associated with fibrosis (P = 0.010). In children, no SNP was associated with histological severity. However, the rs738409 G allele was associated with younger age at the time of biopsy in multivariate analysis (P = 0.045).ConclusionIn this large cohort of histologically proven NAFLD, we confirm the association of the rs738409 G allele with steatosis and describe its association with histological severity. In pediatric patients, the high-risk rs738409 G allele is associated with an earlier presentation of disease. We also describe a hitherto unknown association between SNPs at a chromosome 10 locus and the severity of NASH fibrosis.

Project description:BackgroundThe association between PPARGC1A rs8192678 and nonalcoholic fatty liver disease (NAFLD) requires further confirmation. In addition, it is still unknown whether PPARGC1A rs8192678 is associated with hepatic histological features in NAFLD in the Chinese population.AimTo investigate the interaction between PPARGC1A rs8192678 and nonalcoholic steatohepatitis (NASH), and whether this polymorphism is associated with hepatic histological features.MethodsFifty-nine patients with liver biopsy-proven NAFLD and 93 healthy controls were recruited to a cohort representing the Chinese Han population. The SAF (steatosis, activity, and fibrosis) scoring system was used for hepatic histopathological evaluation. The polymorphisms of PPARGC1A rs8192678 and patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 were genotyped. The intrahepatic mRNA expression of PPARGC1A was evaluated by real-time polymerase chain reaction.ResultsThirty-seven patients with NAFLD had NASH, of which 12 were nonobese. The PPARGC1A rs8192678 risk A allele (carrying GA and AA genotypes) had the lowest P value in the dominant model; the odds ratio (OR) for NAFLD was 2.321 [95% confidence interval (CI): 1.121-4.806]. After adjusting for age, sex, and the PNPLA3 rs738409 risk G allele, the PPARGC1A rs8192678 A allele was a risk factor for NAFLD (OR 2.202, 95%CI: 1.030-4.705, P = 0.042). The genetic analysis showed that patients with NAFLD, moderate-to-severe steatosis (S2-3), and Activity 2-4 (A ≥ 2) were more likely to carry A in PPARGC1A rs8192678 (OR 5.000, 95%CI: 1.343-18.620, P = 0.012; and OR 4.071, 95%CI: 1.076-15.402, P = 0.031). The multivariate logistic regression analysis showed that PPARGC1A rs8192678 risk A allele was also independently associated with S2-3, A ≥ 2, and NASH (OR 6.190, 95%CI: 1.508-25.410, P = 0.011; OR 4.506, 95%CI 1.070-18.978, P = 0.040; and OR 6.337, 95%CI: 1.135-35.392, P = 0.035, respectively) after adjusting for age, sex, body mass index, and PNPLA3 rs738409 risk G allele. The results also showed that this polymorphism was associated with nonobese NASH (OR 22.000, 95%CI: 1.540-314.292, P = 0.021). The intrahepatic expression of PPARGC1A mRNA was significantly lower in the group of patients who carried the risk A allele (P = 0.014).ConclusionThe PPARGC1A rs8192678 risk A allele is associated with NAFLD, and with S2-3, A ≥ 2 and NASH in NAFLD patients, independent of PNPLA3 rs738409, and may be associated with nonobese NASH.

Project description:ObjectiveSeveral single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors.DesignPatients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0-F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study.Results703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3-4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added.ConclusionIn biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.

Dataset Information

Relationships between Genetic Variations of PNPLA3, TM6SF2 and Histological Features of Nonalcoholic Fatty Liver Disease in Japan.

Publications

Relationships between Genetic Variations of PNPLA3, TM6SF2 and Histological Features of Nonalcoholic Fatty Liver Disease in Japan.

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