AIM： To investigate whether the patatin-/ike phosph- olipase domain containing-3 gene （PNPLA3） I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis （HH）. ME...AIM： To investigate whether the patatin-/ike phosph- olipase domain containing-3 gene （PNPLA3） I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis （HH）. METHODS： We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH （C282Y＋/＋ HH） patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake （〈 30/20 g/d in males or females） or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology （n = 100） or ul- trasound （n = 23）. The PNPLA3 rs738409 single nucle- otide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay （assay on demand, Applied Biosystems）. The association of the PNPLA3 I148M protein variant （p.I148M） with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. RESULTS： PNPLA3 genotype was not associated with metabolic parameters, including body mass index （BMI）, the presence of diabetes, and lipid levels, but the pres- ence of the p.148M variant at risk was independently associated with steatosis [odds ratio （OR） 1.84 per p.148M allele, 95% confidence interval （CI）： 1.05-3.31; P = 0.037], independently of BMI and alanine amino- transaminase （ALT） levels. The p.148M variant was also associated with higher aspartate aminotransferase （P = 0.0014） and ALT levels （P = 0.017） at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity （stage） of fibrosis （estimated coefficient 0.56 ± 0.27, P = 0.041）. In the overall series of patients, the p.148M variant was associated with cirrhosis in lean （P = 0.049）, but not in overweight patients （P = not significant）. At logistic regression analysis, cirrhosis was associated with BMI 〉~ 25 （OR 1.82, 95% CI： 1.02-3.55）, ferritin 〉 1000 ng/mL at diagnosis （OR 19.3, 95% CI： 5.3-125）, and with the G allele in patients with BMI 〈 25 （OR 3.26, 95% CI： 1.3-10.3）. CONCLUSION： The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y＋/＋ HH.展开更多
The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as ...The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.展开更多
AIM:To evaluate steatosis,insulin resistance(IR)and patatin-like phospholipase domain-containing 3(PNPLA3) and their relation to disease progression in hepatitis B and C viruses(HCV-HBV) coinfected patients.METHODS:Th...AIM:To evaluate steatosis,insulin resistance(IR)and patatin-like phospholipase domain-containing 3(PNPLA3) and their relation to disease progression in hepatitis B and C viruses(HCV-HBV) coinfected patients.METHODS:Three hundred and thirty patients with biopsy proven chronic hepatitis were enrolled:66 had HBV-HCV,66 HBV and 198 HCV infection.Prevalence of steatosis,IR and PNPLA3 polymorphisms and their relation to anthropometric,biochemical,virological and histological parameters were evaluated.RESULTS:Prevalence of steatosis in group HBV-HCV was similar to that in HCV(47.0% vs 49.5%,respec-tively);group HBV showed the lowest steatosis(33.3%).Group HBV-HCV had a lesser degree of steatosis than HCV(P = 0.016),lower HCV RNA levels(P = 0.025) and lower prevalence and degree of IR(P = 0.01).PNPLA3 polymorphisms were associated with steatosis.Group HBV-HCV showed higher levels of liver fibrosis than group HCV(P = 0.001),but similar to that ob-served in HBV group.In HBV-HCV group,liver fibrosis was not associated with steatosis,IR or PNPLA3.HBV infection was the independent predictor of advanced liver fibrosis.CONCLUSION:HBV-HCV co-infected patients have lower degree of hepatic steatosis,IR and HCV RNA than HCV mono-infected;co-infected patients showed a more rapid liver fibrosis progression that seems to be due to the double infection and/or HBV dominance.展开更多
AIM To investigate the effect of PNPLA3 polymorphisms on serum lipidomics and pathological characteristics in nonalcoholic fatty liver disease(NAFLD).METHODS Thirty-four biopsy-proven NAFLD patients from Northern, Cen...AIM To investigate the effect of PNPLA3 polymorphisms on serum lipidomics and pathological characteristics in nonalcoholic fatty liver disease(NAFLD).METHODS Thirty-four biopsy-proven NAFLD patients from Northern, Central, and Southern China were subjected to stratification by genotyping their single nucleotide polymorphisms(SNPs) in PNPLA3. Ultra performance liquid chromatography-tandem mass spectrometry was then employed to characterize the effects of PNPLA3 SNPs on serum lipidomics. In succession, correlation analysis revealed the association of PNPLA3-related lipid profile and hepatic pathological characteristics on a basis of steatosis, activity, and fibrosis assessment. The variant-based scoring of hepatocyte steatosis, ballooning, lobular inflammation, and liver fibrosis was finally performed so as to uncover the actions of lipidomics-affecting PNPLA3 SNPs in NAFLD-specific pathological alterations. RESULTS PNPLA3 SNPs(rs139051, rs738408, rs738409, rs 2072906, rs2294918, rs2294919, and rs4823173) demonstrated extensive association with the serum lipidomics, especially phospholipid metabolites [lysophosphatidylcholine(LPC), lysophosphatidylcholine plasmalogen(LPCO), lysophosphatdylethanolamine(LPE), phosphatidylcholine(PC), choline plasmalogen(PCO), phosphatidylethanolamine(PE), ethanolamine plasmalogen(PEO)], of NAFLD patients. PNPLA3 rs139051(A/A genotype) and rs2294918(G/G genotype) dominated the up-regulatory effect on phospholipids of LPCs(LPC 17:0, LPC 18:0, LPC 20:0, LPC 20:1, LPC 20:2) and LPCOs(LPC O-16:1, LPC O-18:1). Moreover, subjects with high-level LPCs/LPCOs were predisposed to low-grade lobular inflammation of NAFLD(rho:-0.407 to-0.585, P < 0.05-0.001). The significant correlation of PNPLA3 rs139051 and inflammation grading [A/A vs A/G + G/G: 0.50(0.00, 1.75) vs 1.50(1.00, 2.00), P < 0.05] further demonstrated its pathological role based on the modulation of phospholipid metabolite profile.CONCLUSION The A/A genotype at PNPLA3 rs139051 exerts an upregulatory effect on serum phospholipids of LPCs and LPCOs, which are associated with low-grade lobular inflammation of NAFLD.展开更多
Non-alcoholic fatty liver disease(NAFLD)has now become the leading cause of chronic liver disease with its growing incidence worldwide.Patatin-like phospholipase domain-containing protein 3(PNPLA3)rs738409 C>G refl...Non-alcoholic fatty liver disease(NAFLD)has now become the leading cause of chronic liver disease with its growing incidence worldwide.Patatin-like phospholipase domain-containing protein 3(PNPLA3)rs738409 C>G reflects one of the critical genetic factors that confers high-risk to NAFLD.However,the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain.Here,the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409(PNPLA3 148M variant)are sensitive to therapies of lifestyle modification,dipeptidyl peptidase-4 inhibitors,and bariatric surgery.They exhibit much significant reduction of liver fat content,in concurrence with weigh loss and abolished insulin resistance,as compared to those of C-allele carriers.In contrast,patients bearing PNPLA3 rs738409 C-allele(PNPLA3 148I variant),instead of G-allele,demonstrate greater beneficial effects by omega-3 poly-unsaturated fatty acids and statin intervention.Improved adipose tissue-liver interaction and decrease in intrahepatic triglyceride efflux may contribute to the PNPLA3 rs738409related diversities in therapeutic efficacy.Therefore,PNPLA3 rs738409 underlies the response to a variety of treatments,which warrants a personalized,precise medicine in NAFLD on the basis of genotype stratification.展开更多
Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoh...Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.展开更多
AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C(CHC).METHODS: We conducted an electronic search on the Pub Med and...AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C(CHC).METHODS: We conducted an electronic search on the Pub Med and MEDLINE(2000-2014) databases and Cochrane library(2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.RESULTS: Several studies associated polymorphisms in the interleukin 28 B gene on chromosome 19(19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon(PegIFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation. CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.展开更多
Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day(diabetes, cardiovascular disease, hypertension and obesity) are...Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day(diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease(NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual's genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD.展开更多
Non-alcoholic fatty liver disease(NAFLD) has a prevalence of approximately 30% in western countries, and is emerging as the first cause of liver cirrhosis and hepatocellular carcinoma(HCC). Therefore, risk stratificat...Non-alcoholic fatty liver disease(NAFLD) has a prevalence of approximately 30% in western countries, and is emerging as the first cause of liver cirrhosis and hepatocellular carcinoma(HCC). Therefore, risk stratification emerges as fundamental in order to optimize human and economic resources, and genetics displays intrinsic characteristics suitable to fulfill this task. According to the available data, heritability estimates for hepatic fat content range from 20% to 70%, and an almost 80% of shared heritability has been found between hepatic fat content and fibrosis. The rs738409 single nucleotide polymorphism(SNP) in patatin-like phospholipase domain-containing protein 3 gene and the rs58542926 SNP in transmembrane 6 superfamily member 2 gene have been robustly associated with NAFLD and with its progression, but promising results have been obtained with many other SNPs. Moreover, there has been proof of the additive role of the different SNPs in determining liver damage, and there have been preliminary experiences in which risk scores created through a few genetic variants, alone or in combination with clinical variables, were associated with a strongly potentiated risk of NAFLD, non-alcoholic steatohepatitis(NASH), NASH fibrosis or NAFLD-HCC. However, to date, clinical translation of genetics in the field of NAFLD has been poor or absent. Fortunately, the research we have done seems to have placed us on the right path: We should rely on longitudinal rather than on cross-sectional studies; we should focus on relevant outcomes rather than on simple liver fat accumulation; and we should put together the genetic and clinical information. The hope is that combined genetic/clinical scores, derived from longitudinal studies and built on a few strong genetic variants and relevant clinical variables, will reach a significant predictive power, such as to have clinical utility for risk stratification at the single patient level and even to esteem the impact of intervention on the risk of disease-related outcomes. Well-structured future studies would demonstrate if this vision can become a reality.展开更多
基金Supported by FIRST Università degli Studi di Milano 2007,2008 to Valenti L, Fargion SRicerca corrente Ospedale Maggiore Policlinico 2006 and 2008 to Valenti L, Fargion SCentro per lo Studio delle Malattie del Fegato e del Metabolismo
文摘AIM： To investigate whether the patatin-/ike phosph- olipase domain containing-3 gene （PNPLA3） I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis （HH）. METHODS： We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH （C282Y＋/＋ HH） patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake （〈 30/20 g/d in males or females） or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology （n = 100） or ul- trasound （n = 23）. The PNPLA3 rs738409 single nucle- otide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay （assay on demand, Applied Biosystems）. The association of the PNPLA3 I148M protein variant （p.I148M） with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. RESULTS： PNPLA3 genotype was not associated with metabolic parameters, including body mass index （BMI）, the presence of diabetes, and lipid levels, but the pres- ence of the p.148M variant at risk was independently associated with steatosis [odds ratio （OR） 1.84 per p.148M allele, 95% confidence interval （CI）： 1.05-3.31; P = 0.037], independently of BMI and alanine amino- transaminase （ALT） levels. The p.148M variant was also associated with higher aspartate aminotransferase （P = 0.0014） and ALT levels （P = 0.017） at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity （stage） of fibrosis （estimated coefficient 0.56 ± 0.27, P = 0.041）. In the overall series of patients, the p.148M variant was associated with cirrhosis in lean （P = 0.049）, but not in overweight patients （P = not significant）. At logistic regression analysis, cirrhosis was associated with BMI 〉~ 25 （OR 1.82, 95% CI： 1.02-3.55）, ferritin 〉 1000 ng/mL at diagnosis （OR 19.3, 95% CI： 5.3-125）, and with the G allele in patients with BMI 〈 25 （OR 3.26, 95% CI： 1.3-10.3）. CONCLUSION： The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y＋/＋ HH.
基金Supported by Associazione Malattie Metaboliche del Fegato ONLUS(Non-profit organization for the Study and Care of Metabolic Liver Diseases)Centro Studi Malattie Metaboliche del Fegato,Universitàdegli Studi di Milano
文摘The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.
文摘AIM:To evaluate steatosis,insulin resistance(IR)and patatin-like phospholipase domain-containing 3(PNPLA3) and their relation to disease progression in hepatitis B and C viruses(HCV-HBV) coinfected patients.METHODS:Three hundred and thirty patients with biopsy proven chronic hepatitis were enrolled:66 had HBV-HCV,66 HBV and 198 HCV infection.Prevalence of steatosis,IR and PNPLA3 polymorphisms and their relation to anthropometric,biochemical,virological and histological parameters were evaluated.RESULTS:Prevalence of steatosis in group HBV-HCV was similar to that in HCV(47.0% vs 49.5%,respec-tively);group HBV showed the lowest steatosis(33.3%).Group HBV-HCV had a lesser degree of steatosis than HCV(P = 0.016),lower HCV RNA levels(P = 0.025) and lower prevalence and degree of IR(P = 0.01).PNPLA3 polymorphisms were associated with steatosis.Group HBV-HCV showed higher levels of liver fibrosis than group HCV(P = 0.001),but similar to that ob-served in HBV group.In HBV-HCV group,liver fibrosis was not associated with steatosis,IR or PNPLA3.HBV infection was the independent predictor of advanced liver fibrosis.CONCLUSION:HBV-HCV co-infected patients have lower degree of hepatic steatosis,IR and HCV RNA than HCV mono-infected;co-infected patients showed a more rapid liver fibrosis progression that seems to be due to the double infection and/or HBV dominance.
基金Supported by National Key Research and Development Plan "Precision Medicine Research",No.2017YFC0908903National Natural Science Foundation of China,No.81070346,No.81270492,No.81470859,No.81270491 and No.81470840+2 种基金State Key Development Program for Basic Research of China,No.2012CB517501100 Talents Program,No.XBR2011007hProgram of the Committee of Science and Technology,No.09140903500
文摘AIM To investigate the effect of PNPLA3 polymorphisms on serum lipidomics and pathological characteristics in nonalcoholic fatty liver disease(NAFLD).METHODS Thirty-four biopsy-proven NAFLD patients from Northern, Central, and Southern China were subjected to stratification by genotyping their single nucleotide polymorphisms(SNPs) in PNPLA3. Ultra performance liquid chromatography-tandem mass spectrometry was then employed to characterize the effects of PNPLA3 SNPs on serum lipidomics. In succession, correlation analysis revealed the association of PNPLA3-related lipid profile and hepatic pathological characteristics on a basis of steatosis, activity, and fibrosis assessment. The variant-based scoring of hepatocyte steatosis, ballooning, lobular inflammation, and liver fibrosis was finally performed so as to uncover the actions of lipidomics-affecting PNPLA3 SNPs in NAFLD-specific pathological alterations. RESULTS PNPLA3 SNPs(rs139051, rs738408, rs738409, rs 2072906, rs2294918, rs2294919, and rs4823173) demonstrated extensive association with the serum lipidomics, especially phospholipid metabolites [lysophosphatidylcholine(LPC), lysophosphatidylcholine plasmalogen(LPCO), lysophosphatdylethanolamine(LPE), phosphatidylcholine(PC), choline plasmalogen(PCO), phosphatidylethanolamine(PE), ethanolamine plasmalogen(PEO)], of NAFLD patients. PNPLA3 rs139051(A/A genotype) and rs2294918(G/G genotype) dominated the up-regulatory effect on phospholipids of LPCs(LPC 17:0, LPC 18:0, LPC 20:0, LPC 20:1, LPC 20:2) and LPCOs(LPC O-16:1, LPC O-18:1). Moreover, subjects with high-level LPCs/LPCOs were predisposed to low-grade lobular inflammation of NAFLD(rho:-0.407 to-0.585, P < 0.05-0.001). The significant correlation of PNPLA3 rs139051 and inflammation grading [A/A vs A/G + G/G: 0.50(0.00, 1.75) vs 1.50(1.00, 2.00), P < 0.05] further demonstrated its pathological role based on the modulation of phospholipid metabolite profile.CONCLUSION The A/A genotype at PNPLA3 rs139051 exerts an upregulatory effect on serum phospholipids of LPCs and LPCOs, which are associated with low-grade lobular inflammation of NAFLD.
基金Supported by National Key Research and Development Plan"Precision Medicine Research",No.2017YFC0908903National Natural Science Foundation of China,No.81070346,No.81270492,No.81470859,No.81270491 and No.81470840+2 种基金State Key Development Program for Basic Research of China,No.2012CB517501100 Talents Program,No.XBR2011007hProgram of the Committee of Science and Technology,No.09140903500
文摘Non-alcoholic fatty liver disease(NAFLD)has now become the leading cause of chronic liver disease with its growing incidence worldwide.Patatin-like phospholipase domain-containing protein 3(PNPLA3)rs738409 C>G reflects one of the critical genetic factors that confers high-risk to NAFLD.However,the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain.Here,the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409(PNPLA3 148M variant)are sensitive to therapies of lifestyle modification,dipeptidyl peptidase-4 inhibitors,and bariatric surgery.They exhibit much significant reduction of liver fat content,in concurrence with weigh loss and abolished insulin resistance,as compared to those of C-allele carriers.In contrast,patients bearing PNPLA3 rs738409 C-allele(PNPLA3 148I variant),instead of G-allele,demonstrate greater beneficial effects by omega-3 poly-unsaturated fatty acids and statin intervention.Improved adipose tissue-liver interaction and decrease in intrahepatic triglyceride efflux may contribute to the PNPLA3 rs738409related diversities in therapeutic efficacy.Therefore,PNPLA3 rs738409 underlies the response to a variety of treatments,which warrants a personalized,precise medicine in NAFLD on the basis of genotype stratification.
文摘Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.
文摘AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C(CHC).METHODS: We conducted an electronic search on the Pub Med and MEDLINE(2000-2014) databases and Cochrane library(2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.RESULTS: Several studies associated polymorphisms in the interleukin 28 B gene on chromosome 19(19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon(PegIFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation. CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.
文摘Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day(diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease(NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual's genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD.
文摘Non-alcoholic fatty liver disease(NAFLD) has a prevalence of approximately 30% in western countries, and is emerging as the first cause of liver cirrhosis and hepatocellular carcinoma(HCC). Therefore, risk stratification emerges as fundamental in order to optimize human and economic resources, and genetics displays intrinsic characteristics suitable to fulfill this task. According to the available data, heritability estimates for hepatic fat content range from 20% to 70%, and an almost 80% of shared heritability has been found between hepatic fat content and fibrosis. The rs738409 single nucleotide polymorphism(SNP) in patatin-like phospholipase domain-containing protein 3 gene and the rs58542926 SNP in transmembrane 6 superfamily member 2 gene have been robustly associated with NAFLD and with its progression, but promising results have been obtained with many other SNPs. Moreover, there has been proof of the additive role of the different SNPs in determining liver damage, and there have been preliminary experiences in which risk scores created through a few genetic variants, alone or in combination with clinical variables, were associated with a strongly potentiated risk of NAFLD, non-alcoholic steatohepatitis(NASH), NASH fibrosis or NAFLD-HCC. However, to date, clinical translation of genetics in the field of NAFLD has been poor or absent. Fortunately, the research we have done seems to have placed us on the right path: We should rely on longitudinal rather than on cross-sectional studies; we should focus on relevant outcomes rather than on simple liver fat accumulation; and we should put together the genetic and clinical information. The hope is that combined genetic/clinical scores, derived from longitudinal studies and built on a few strong genetic variants and relevant clinical variables, will reach a significant predictive power, such as to have clinical utility for risk stratification at the single patient level and even to esteem the impact of intervention on the risk of disease-related outcomes. Well-structured future studies would demonstrate if this vision can become a reality.
