White Donna L, Liu Yanhong, Garcia Jose, El-Serag Hashem B, Jiao Li, Tsavachidis Spiridon, Franco Luis M, Lee Ju-Seog, Tavakoli-Tabasi Shahriar, Moore David, Goldman Radoslav, Kuzniarek Jill, Ramsey David J, Kanwal Fasiha, Marcelli Marco
Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA ; Texas Medical Center Digestive Disease Center Houston, TX, USA ; Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, TX, USA ; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center Houston, TX, USA.
Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, TX, USA ; Department of Pediatrics, Baylor College of Medicine Houston, TX, USA.
Int J Mol Epidemiol Genet. 2014 Oct 22;5(3):164-76. eCollection 2014.
Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear.
To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males.
We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction.
Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation.
The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.
男性患晚期肝病和肝硬化的风险更高，包括慢性丙型肝炎病毒（HCV）感染所致，但其原因尚不清楚。
研究参与雄激素和雌激素生物合成及代谢的基因变异在男性HCV相关肝病风险中所起的作用。
我们进行了一项横断面研究，评估参与雄激素和雌激素配体及受体合成的16个候选基因中的单核苷酸多态性（SNP），以及晚期肝纤维化（F3/F4 - F4）和炎症（A2/A3 - A3）的风险。我们使用逻辑回归计算调整后的比值比（OR），并使用多因素降维（MDR）分析来评估基因 - 环境相互作用。
在466例慢性HCV感染男性中，59%（n = 274）有晚期纤维化，54%（n = 252）有晚期炎症。472个SNP中的9个与纤维化风险显著相关；4个在AKR1C3中（例如，AKR1C3 rs2186174：ORadj = 2.04，95%CI 1.38 - 3.02），AKR1C2和ESR1各有1个，HSD17B6中有1个。4个SNP与炎症风险相关，2个在SRD5A1中（例如，SRD5A1 rs248800：ORadj = 1.86，95%CI 1.20 - 2.88），AKR1C2和AKR1C3各有1个。MDR分析确定单个AKR1C3位点（rs2186174）是晚期纤维化的最佳模型；而糖尿病、AKR1C2 rs12414884、SRD5A1 rs6555406和SRD5A1 rs248800的4位点模型对炎症最为合适。
我们研究结果的一致性表明，AKR1C同工酶2和3以及可能的SRD5A1可能在男性HCV相关肝病进展中起作用。需要进一步研究来验证这些发现，并评估女性中是否存在类似关联。
