ABSTRACT
OBJECTIVE: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. DESIGN: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. RESULTS: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). CONCLUSION: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
Subject(s)
Genetic Predisposition to Disease/epidemiology , Heterozygote , Liver Cirrhosis, Alcoholic/genetics , alpha 1-Antitrypsin/genetics , Age Distribution , Austria , Biopsy, Needle , Case-Control Studies , Confidence Intervals , Female , Genetic Carrier Screening , Genetic Variation , Germany , Humans , Immunohistochemistry , Incidence , Liver Cirrhosis, Alcoholic/epidemiology , Liver Cirrhosis, Alcoholic/pathology , Male , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/pathology , Odds Ratio , Polymorphism, Single Nucleotide , Prognosis , Risk Assessment , Sex DistributionABSTRACT
INTRODUCTION: Maternal serum LDL concentrations are lower in IUGR pregnancies as compared to controls (CTRL). We now hypothesized that an increased oxidative stress results in the formation of oxidized LDL (oxLDL) particles which than accumulates within the placenta. This is particularly hypothesized for the severe early onset subgroup of IUGR with preeclampsia (PE). METHODS: OxLDL (minimal modified and fully oxidized LDL) levels in placental biopsies from term IUGR (>37 weeks, t-IUGR, n=5), preterm IUGR (<34 weeks, p-IUGR, n=5), and preterm IUGR with PE (PE-IUGR, n=5) were compared to a CTRL group consisted of gestational age matched preterm (p-CTRL, n=10) and term (t-CTRL, n=5) placentas by ELISA and immunohistochemistry (IHC). RESULTS: Fully oxidized LDL but not minimally oxidized LDL concentrations were higher in p-IUGR and tend to be increased in PE-IUGR when compared to p-CTRL (p=0.040 and p=0.075). There was virtually no difference of fully oxidized LDL levels between p-CTRL, t-CTRL, and t-IUGR. We confirmed a higher oxLDL accumulation in trophoblasts of p-IUGR and PE-IUGR as compared to both CTRL groups by IHC though this was not statistically significant. CONCLUSION: Conformational changes of LDL during the process of oxidation might lead to an accumulation of oxLDL particles in placental tissue of IUGR. The pathogenesis of early onset IUGR might differ from those of late onset IUGR.
