Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas.
Clin Gastroenterol Hepatol. 2023 Apr;21(4):1023-1030.e39. doi: 10.1016/j.cgh.2022.05.020. Epub 2022 Jun 6.
BACKGROUND & AIMS: Cirrhosis is the main predisposing condition for hepatocellular carcinoma. Host genetic risk factors have been reported for cirrhosis; however, whether there is a genetic contribution to racial disparities in cirrhosis requires further investigation.
We used an affected-only mapping by admixture linkage disequilibrium analysis to characterize the genetic risk of cirrhosis in 227 African American patients with cirrhosis genotyped at 19,804 ancestry-informative marker single nucleotide polymorphisms. We additionally performed analyses stratified by hepatitis C virus (HCV) infection status. To replicate our findings, we conducted a case-control analysis in an external study population (452 cases and 196 controls).
The mean age of patients was 63.3 years and 98.2% were male. Risk factors for cirrhosis included HCV infection (83.7%) and alcohol abuse (56.4%). In the admixture mapping analysis, we found that European ancestry on chromosome 2q21.1 and African ancestry on chromosome 6p21.2 were associated with increased risk of cirrhosis in African Americans. In the fine-mapping analysis, we identified regions near POTEKP on 2q21.1 (P = .0001) and DNAH8 on 6p21.2 (P = .0017) that were associated with cirrhosis. As the admixture peaks in the HCV-positive patients were the same as those in the overall group, findings in the analysis are reflective of the HCV-positive group. In the replication analysis, the results on chromosome 2 were not significant after adjusting for multiple comparisons, and we could not replicate the results on chromosome 6.
We used admixture mapping to identify novel genomic regions on 2q21.1 and 6p21.2 that may be associated with HCV-related cirrhosis risk in African Americans.
肝硬化是肝细胞癌的主要诱发因素。已经有研究报道了与肝硬化相关的宿主遗传风险因素；然而，种族间肝硬化差异是否存在遗传贡献仍需进一步研究。
我们使用仅受影响个体的混合连锁不平衡分析方法，对 227 名经 19804 个祖先信息标记单核苷酸多态性基因分型的患有肝硬化的非裔美国人患者的肝硬化遗传风险进行了特征描述。我们还按丙型肝炎病毒（HCV）感染状态进行了分层分析。为了验证我们的发现，我们在一个外部研究人群（452 例病例和 196 例对照）中进行了病例对照分析。
患者的平均年龄为 63.3 岁，98.2%为男性。肝硬化的危险因素包括 HCV 感染（83.7%）和酒精滥用（56.4%）。在混合映射分析中，我们发现 2 号染色体 2q21.1 上的欧洲血统和 6 号染色体 6p21.2 上的非洲血统与非裔美国人肝硬化的风险增加相关。在精细映射分析中，我们在 2q21.1 上靠近 POTEKP 的区域（P =.0001）和 6p21.2 上靠近 DNAH8 的区域（P =.0017）发现了与肝硬化相关的区域。由于 HCV 阳性患者的混合峰与总体组的混合峰相同，因此分析结果反映了 HCV 阳性组的情况。在复制分析中，经过多次比较调整后，2 号染色体上的结果不再显著，而我们无法复制 6 号染色体上的结果。
我们使用混合映射方法在 2q21.1 和 6p21.2 上识别到了与非裔美国人 HCV 相关肝硬化风险相关的新基因组区域。
