Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic C...Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic Chinese is unknown.The aim of this study was to investigate the potential associations in Chinese patients.Methods:In total,427 Han Chinese with biopsy-confirmed MAFLD were enrolled.Two single nucleotide polymorphisms in HSD17B13 were genotyped:rs72613567 and rs6531975.Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.Results:In our cohort,the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis[odds ratio(OR):2.93(1.20–7.17),p=0.019 for the additive model;OR:3.32(1.39–7.91),p=0.007 for the recessive model],representing an inverse association as compared to the results from European cohorts.In contrast,we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant[OR:0.48(0.24–0.98),p=0.043 for the additive model;OR:0.62(0.40–0.94),p=0.025 for the dominant model].HSD17B13 variants were only associated with fibrosis but no other histological features.Furthermore,HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis.Conclusions:HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans.These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.展开更多
Background and Aims:Previous studies have reported that the single nucleotide polymorphisms(SNPs)of SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409 are associated with nonalcoholic fatty liver disease(NAFLD).Howev...Background and Aims:Previous studies have reported that the single nucleotide polymorphisms(SNPs)of SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409 are associated with nonalcoholic fatty liver disease(NAFLD).However,no studies have examined the effect of interactions between these three genotypes to affect liver disease severity.We assessed the effect of these three SNPs on nonalcoholic steatohepatitis(NASH)and also examined the gene-gene interactions in a Chinese population with biopsy-confirmed NAFLD.Methods:We enrolled 415 consecutive adult individuals with biopsy-proven NAFLD.Multivariable logistic regres-sion analysis was undertaken to test associations between NASH and SNPs in SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409.Gene-gene interactions were ana-lyzed by performing a generalized multifactor dimensionality reduction(GMDR)analysis.Results:The mean±standard deviation age of these 415 patients was 41.3±12.5 years,and 75.9%were men.Patients with SAMM50-rs738491 TT,PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes had a higher risk of NASH,even after adjustment for age,sex and body mass index.GMDR analysis showed that the combination of all three SNPs was the best model for predicting NASH.Additionally,the odds ratio of the haplotype T-A-G for predicting the risk of NASH was nearly three times higher than that of the haplotype G-C-C.Conclusions:NAFLD patients carrying the SAMM50-rs738491 TT,PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes are at greater risk of NASH.These three SNPs may synergistically interact to increase susceptibility to NASH.展开更多
Background and Aims:Intra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3(PNPLA3)rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver diseas...Background and Aims:Intra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3(PNPLA3)rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver disease(NAFLD).We examined whether the relationship between visceral fat accumulation and liver disease severity may be influenced by PNPLA3 rs738409 polymorphism.Methods:The variant of PNPLA3 rs738409 was genotyped within 523 Han individuals with biopsy-confirmed NAFLD.Visceral fat area(VFA)was measured by bioelectrical impedance.Significant liver fibrosis(SF),defined as stage F≥2 on histology,was the outcome measure of interest.Results:The distribution of PNPLA3 genotypes was CC:27.5%,CG:48.2%,and GG:24.3%.Higher VFA was associated with greater risk of having SF(adjusted-odds ratio[OR]:1.03;95%confidence interval[CI]:1.02–1.04,p<0.05),independent of potential confounders.Among subjects with the same VFA level,the risk of SF was greater among carriers of the rs738409 G genotype than among those who did not.Stratified analysis showed that PNPLA3 rs738409 significantly influenced the association between VFA and SF.VFA remained significantly associated with SF only among the rs738409 G-allele carriers(adjusted-OR:1.05;95%CI:1.03–1.08 for the GG group;and adjusted-OR:1.03;95%CI:1.01–1.04 for the GC group).There was a significant interaction between VFA and PNPLA3 rs738409 genotype(Pinteraction=0.004).Conclusions:PNPLA3 rs738409 G allele has a moderate effect on the association between VFA and risk of SF in adult individuals with biopsy-proven NAFLD.Existence of the PNPLA3 rs738409 G allele and VFA interact to increase risk of SF。展开更多
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 understand...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.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(82070588)High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)+3 种基金Project of New Century 551 Talent Nurturing in Wenzhou.GT was supported in part by grants from the University School of Medicine of Verona(Verona,Italy)CDB was supported in part by the Southampton NIHR Biomedical Research Centre(ISBRC-20004)UK.ME and JG were supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydney(Sydney,Australia)and the National Health and Medical Research Council of Australia(NHMRC)Program(APP1053206,APP1149976)Project(APP1107178 and APP1108422)grants.
文摘Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic Chinese is unknown.The aim of this study was to investigate the potential associations in Chinese patients.Methods:In total,427 Han Chinese with biopsy-confirmed MAFLD were enrolled.Two single nucleotide polymorphisms in HSD17B13 were genotyped:rs72613567 and rs6531975.Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.Results:In our cohort,the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis[odds ratio(OR):2.93(1.20–7.17),p=0.019 for the additive model;OR:3.32(1.39–7.91),p=0.007 for the recessive model],representing an inverse association as compared to the results from European cohorts.In contrast,we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant[OR:0.48(0.24–0.98),p=0.043 for the additive model;OR:0.62(0.40–0.94),p=0.025 for the dominant model].HSD17B13 variants were only associated with fibrosis but no other histological features.Furthermore,HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis.Conclusions:HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans.These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.
基金supported by grants from the National Natural Science Foundation of China(82070588)the High Level Creative Talents from Department of Public Health in Zhejiang Proince(S2032102600032)+2 种基金Project of New Century 551 Talent Nurturing in WenzhouGT was supported in part by grants from the School of Medicine,University of Verona,Verona,ItalyCDB was supported in part by the Southampton NIHR Biomedical Research Centre(IS-BRC-20004),UK.
文摘Background and Aims:Previous studies have reported that the single nucleotide polymorphisms(SNPs)of SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409 are associated with nonalcoholic fatty liver disease(NAFLD).However,no studies have examined the effect of interactions between these three genotypes to affect liver disease severity.We assessed the effect of these three SNPs on nonalcoholic steatohepatitis(NASH)and also examined the gene-gene interactions in a Chinese population with biopsy-confirmed NAFLD.Methods:We enrolled 415 consecutive adult individuals with biopsy-proven NAFLD.Multivariable logistic regres-sion analysis was undertaken to test associations between NASH and SNPs in SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409.Gene-gene interactions were ana-lyzed by performing a generalized multifactor dimensionality reduction(GMDR)analysis.Results:The mean±standard deviation age of these 415 patients was 41.3±12.5 years,and 75.9%were men.Patients with SAMM50-rs738491 TT,PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes had a higher risk of NASH,even after adjustment for age,sex and body mass index.GMDR analysis showed that the combination of all three SNPs was the best model for predicting NASH.Additionally,the odds ratio of the haplotype T-A-G for predicting the risk of NASH was nearly three times higher than that of the haplotype G-C-C.Conclusions:NAFLD patients carrying the SAMM50-rs738491 TT,PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes are at greater risk of NASH.These three SNPs may synergistically interact to increase susceptibility to NASH.
基金supported by grants from the National Natural Science Foundation of China(82070588)High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)the Project of New Century 551 Talent Nurturing in Wenzhou.GT was supported in part by grants from the University School of Medicine of Verona,Verona,Italy.CDB was supported in part by the Southampton NIHR Biomedical Research Centre(ISBRC-20004),UK.
文摘Background and Aims:Intra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3(PNPLA3)rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver disease(NAFLD).We examined whether the relationship between visceral fat accumulation and liver disease severity may be influenced by PNPLA3 rs738409 polymorphism.Methods:The variant of PNPLA3 rs738409 was genotyped within 523 Han individuals with biopsy-confirmed NAFLD.Visceral fat area(VFA)was measured by bioelectrical impedance.Significant liver fibrosis(SF),defined as stage F≥2 on histology,was the outcome measure of interest.Results:The distribution of PNPLA3 genotypes was CC:27.5%,CG:48.2%,and GG:24.3%.Higher VFA was associated with greater risk of having SF(adjusted-odds ratio[OR]:1.03;95%confidence interval[CI]:1.02–1.04,p<0.05),independent of potential confounders.Among subjects with the same VFA level,the risk of SF was greater among carriers of the rs738409 G genotype than among those who did not.Stratified analysis showed that PNPLA3 rs738409 significantly influenced the association between VFA and SF.VFA remained significantly associated with SF only among the rs738409 G-allele carriers(adjusted-OR:1.05;95%CI:1.03–1.08 for the GG group;and adjusted-OR:1.03;95%CI:1.01–1.04 for the GC group).There was a significant interaction between VFA and PNPLA3 rs738409 genotype(Pinteraction=0.004).Conclusions:PNPLA3 rs738409 G allele has a moderate effect on the association between VFA and risk of SF in adult individuals with biopsy-proven NAFLD.Existence of the PNPLA3 rs738409 G allele and VFA interact to increase risk of SF。
基金This study was supported by the National Key Research and Development Program of China(2018YFA0800402)the National Natural Science Foundation of China(81974119,82070887 and 81900771)+2 种基金the Shanghai Outstanding Academic Leaders Projects and Basic Research of Science and Technology Innovation Action Plan by Shanghai Municipal Science and Technology Committee(21XD1423400 and 21JC1401300)Excellent Youth Cultivation Program of Shanghai Sixth People’s Hospital(ynjq202202)the Shenzhen Science and technology R&D Foundation(KCXFZ202002011010445).
文摘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.
