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
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.
