Background： Our previous study showed that 17-beta-hydroxysteroid dehydrogenase 13 （HSD17B13） is down-regulated in hepatocellular carcinoma （HCC）. But its function in HCC remains unknown. This studyaimed to revea...Background： Our previous study showed that 17-beta-hydroxysteroid dehydrogenase 13 （HSD17B13） is down-regulated in hepatocellular carcinoma （HCC）. But its function in HCC remains unknown. This studyaimed to reveal the function of HSD17B13 and its clinical significance in HCC.展开更多
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
Nonalcoholic fatty liver disease(NAFLD)pathogenesis is explained by the complex relationship among diet and lifestyle-predisposing factors,the genetic variance of the nuclear and mitochondrial genome,associated phenot...Nonalcoholic fatty liver disease(NAFLD)pathogenesis is explained by the complex relationship among diet and lifestyle-predisposing factors,the genetic variance of the nuclear and mitochondrial genome,associated phenotypic traits,and the yet not fully explored interactions with epigenetic and other environmental factors,including the microbiome.Despite the wealth of knowledge gained from molecular and genome-wide investigations in patients with NAFLD,the precise mechanisms that explain the variability of the histological phenotypes are not fully understood.Earlier studies of the gut microbiota in patients with NAFLD and nonalcoholic steatohepatitis(NASH)provided clues on the role of the fecal microbiome in the disease pathogenesis.Nevertheless,the composition of the gut microbiota does not fully explain tissue-specific mechanisms associated with the degree of disease severity,including liver inflammation,ballooning of hepatocytes,and fibrosis.The liver acts as a key filtration system of the whole body by receiving blood from the hepatic artery and the portal vein.Therefore,not only microbes would become entrapped in the complex liver anatomy but,more importantly,bacterial derived products that are likely to be potentially powerful stimuli for initiating the inflammatory response.Hence,the study of liver tissue microbiota offers the opportunity of changing the paradigm of host-NAFLD-microbial interactions from a“gut-centric”to a“liver-centric”approach.Here,we highlight the evidence on the role of liver tissue bacterial DNA in the biology of NAFLD and NASH.Besides,we provide evidence of metagenomic findings that can serve as the seed of further hypothesis-raising studies as well as can be leveraged to discover novel therapeutic targets.展开更多
Non-alcoholic fatty liver disease(NAFLD)is estimated to affect 25%of the worldwide population,and is the leading cause of chronic liver disease in developed countries.Genetic research on NAFLD has included heritabilit...Non-alcoholic fatty liver disease(NAFLD)is estimated to affect 25%of the worldwide population,and is the leading cause of chronic liver disease in developed countries.Genetic research on NAFLD has included heritability studies,candidate gene studies,familial aggregation studies,and genome-wide association studies(GWAS).Next-generation sequencing approaches,such as whole-genome sequencing and whole-exon sequencing,are emerging as the post-GWAS era of genetic research.However,GWAS remains more practical for elucidating the genetic factors related to NAFLD,which is affected by thousands of common genetic variants and does not follow Mendelian inheritance.In the present review,we summarize the current knowledge regarding five GWAS-identified genetic loci that are associated with NAFLD.We also discuss the relationships between NAFLD-predisposing polymorphisms and cardiovascular disease,and potential applications for these identified genetic loci.展开更多
Hepatocellular carcinoma(HCC)is the most common primary liver malignancy,with increasing incidence worldwide.Alcohol-related cirrhosis(AC)accounts for 30%of the global incidence of HCC and HCC-related deaths.With the ...Hepatocellular carcinoma(HCC)is the most common primary liver malignancy,with increasing incidence worldwide.Alcohol-related cirrhosis(AC)accounts for 30%of the global incidence of HCC and HCC-related deaths.With the decline of hepatitis C virus(HCV)and decreasing HCV-related HCC,AC will soon become the leading cause of HCC.Excess alcohol consumption(>80 g per day for>10 years)increases the risk of HCC by 5-fold.However,only up to 35%of excessive drinkers develop cirrhosis and its associated HCC risk.Individual variation in susceptibility to HCC is known,but there is limited information to predict who among the patients is at high risk of progressing to HCC.Clinical risk factors for HCC include male gender,older age,severity of cirrhosis,obesity and presence of type 2 diabetes.In addition to ethnic variability in HCC risk,genetic variants are known to alter the risk of alcohol-related HCC.For example,single nucleotide polymorphisms in PNPLA3(rs738409,C>G)and TM6SF2(rs58542926,C>T)increase the risk of AC-related HCC,whereas HSD17B13(T>A)reduces the risk for HCC.Studies have also confirmed PNPLA3 and TM6SF2 to be independent risk factors for AC-related(but not HCV-related)HCC.Combining genetic risk factors with phenotypic/clinical risk factors has been explored for stratification of patients for HCC development.Risk allele rs378409-G in PNPLA3 when combined with phenotypic/clinical risk factors(BMI,age,sex)has enabled HCC risk stratification of AC patients into low-,intermediate-and high-risk subgroups.Similarly,a combination of the two genetic variants PNPLA3-G and TM6SF2-T has been independently associated with risk of HCC onset.Using a polygenic risk score approach of incorporating several genetic variants,prognostic performance of polygenic risk score that included PNPLA3 rs378409 and TM6SF2 rs58542926 improved HCC prediction better than with either variant alone.Incorporating new variants and risk factors has the potential to build better algorithms/models to predict onset,early diagnosis and treatments for AC-related HCC.However,clinical usefulness of these approaches is yet to be determined.展开更多
Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related deaths globally.In recent years,the metabolic syndrome epidemic is changing the etiological landscape of HCC,with metabolic liver disease com...Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related deaths globally.In recent years,the metabolic syndrome epidemic is changing the etiological landscape of HCC,with metabolic liver disease comprising an exponentially increasing proportion of HCC cases.In this review,we discuss HCC in the context of metabolic syndrome,including its epidemiology,its unique clinical and pathological characteristics,and its multifactorial pathogenesis.We also discuss HCC prevention and management as relates to these patients.展开更多
基金supported by grants from General Research Project of Zhejiang Provincial Educational Commission of China(Y201636545)the National Natural Science Funds for Distinguished Young Scholar of China(81625003)+1 种基金Changjiang Scholar Program of Chinese Ministry of EducationMedical and Health Research Projects of Zhejiang Province
文摘Background： Our previous study showed that 17-beta-hydroxysteroid dehydrogenase 13 （HSD17B13） is down-regulated in hepatocellular carcinoma （HCC）. But its function in HCC remains unknown. This studyaimed to reveal the function of HSD17B13 and its clinical significance in HCC.
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This study was partially supported by grants PID-C2012-0061,PICT 2014-0432,PICT 2014-1816,PICT 2015-0551PICT 2016-0135(Agencia Nacional de Promoción Científica y Tecnológica,FONCyT),CONICET Proyectos Unidades Ejecutoras 2017,PUE 0055.
文摘Nonalcoholic fatty liver disease(NAFLD)pathogenesis is explained by the complex relationship among diet and lifestyle-predisposing factors,the genetic variance of the nuclear and mitochondrial genome,associated phenotypic traits,and the yet not fully explored interactions with epigenetic and other environmental factors,including the microbiome.Despite the wealth of knowledge gained from molecular and genome-wide investigations in patients with NAFLD,the precise mechanisms that explain the variability of the histological phenotypes are not fully understood.Earlier studies of the gut microbiota in patients with NAFLD and nonalcoholic steatohepatitis(NASH)provided clues on the role of the fecal microbiome in the disease pathogenesis.Nevertheless,the composition of the gut microbiota does not fully explain tissue-specific mechanisms associated with the degree of disease severity,including liver inflammation,ballooning of hepatocytes,and fibrosis.The liver acts as a key filtration system of the whole body by receiving blood from the hepatic artery and the portal vein.Therefore,not only microbes would become entrapped in the complex liver anatomy but,more importantly,bacterial derived products that are likely to be potentially powerful stimuli for initiating the inflammatory response.Hence,the study of liver tissue microbiota offers the opportunity of changing the paradigm of host-NAFLD-microbial interactions from a“gut-centric”to a“liver-centric”approach.Here,we highlight the evidence on the role of liver tissue bacterial DNA in the biology of NAFLD and NASH.Besides,we provide evidence of metagenomic findings that can serve as the seed of further hypothesis-raising studies as well as can be leveraged to discover novel therapeutic targets.
基金This research was supported by the Bio&Medical Technology Development Program of the National Research Foundation(NRF)funded by the Ministry of Science&ICT(NRF-2020M3A9E4038694).
文摘Non-alcoholic fatty liver disease(NAFLD)is estimated to affect 25%of the worldwide population,and is the leading cause of chronic liver disease in developed countries.Genetic research on NAFLD has included heritability studies,candidate gene studies,familial aggregation studies,and genome-wide association studies(GWAS).Next-generation sequencing approaches,such as whole-genome sequencing and whole-exon sequencing,are emerging as the post-GWAS era of genetic research.However,GWAS remains more practical for elucidating the genetic factors related to NAFLD,which is affected by thousands of common genetic variants and does not follow Mendelian inheritance.In the present review,we summarize the current knowledge regarding five GWAS-identified genetic loci that are associated with NAFLD.We also discuss the relationships between NAFLD-predisposing polymorphisms and cardiovascular disease,and potential applications for these identified genetic loci.
文摘Hepatocellular carcinoma(HCC)is the most common primary liver malignancy,with increasing incidence worldwide.Alcohol-related cirrhosis(AC)accounts for 30%of the global incidence of HCC and HCC-related deaths.With the decline of hepatitis C virus(HCV)and decreasing HCV-related HCC,AC will soon become the leading cause of HCC.Excess alcohol consumption(>80 g per day for>10 years)increases the risk of HCC by 5-fold.However,only up to 35%of excessive drinkers develop cirrhosis and its associated HCC risk.Individual variation in susceptibility to HCC is known,but there is limited information to predict who among the patients is at high risk of progressing to HCC.Clinical risk factors for HCC include male gender,older age,severity of cirrhosis,obesity and presence of type 2 diabetes.In addition to ethnic variability in HCC risk,genetic variants are known to alter the risk of alcohol-related HCC.For example,single nucleotide polymorphisms in PNPLA3(rs738409,C>G)and TM6SF2(rs58542926,C>T)increase the risk of AC-related HCC,whereas HSD17B13(T>A)reduces the risk for HCC.Studies have also confirmed PNPLA3 and TM6SF2 to be independent risk factors for AC-related(but not HCV-related)HCC.Combining genetic risk factors with phenotypic/clinical risk factors has been explored for stratification of patients for HCC development.Risk allele rs378409-G in PNPLA3 when combined with phenotypic/clinical risk factors(BMI,age,sex)has enabled HCC risk stratification of AC patients into low-,intermediate-and high-risk subgroups.Similarly,a combination of the two genetic variants PNPLA3-G and TM6SF2-T has been independently associated with risk of HCC onset.Using a polygenic risk score approach of incorporating several genetic variants,prognostic performance of polygenic risk score that included PNPLA3 rs378409 and TM6SF2 rs58542926 improved HCC prediction better than with either variant alone.Incorporating new variants and risk factors has the potential to build better algorithms/models to predict onset,early diagnosis and treatments for AC-related HCC.However,clinical usefulness of these approaches is yet to be determined.
基金Goossens N is supported by a grant of the Ligue Genevoise contre le cancer(ref number 1906).
文摘Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related deaths globally.In recent years,the metabolic syndrome epidemic is changing the etiological landscape of HCC,with metabolic liver disease comprising an exponentially increasing proportion of HCC cases.In this review,we discuss HCC in the context of metabolic syndrome,including its epidemiology,its unique clinical and pathological characteristics,and its multifactorial pathogenesis.We also discuss HCC prevention and management as relates to these patients.
