Johns Hopkins University, School of Medicine, Baltimore, Maryland.
Research Triangle Institute International, Research Triangle Park, North Carolina; Atlanta, Georgia; San Francisco, California.
Gastroenterology. 2019 Apr;156(5):1496-1507.e7. doi: 10.1053/j.gastro.2018.12.014. Epub 2018 Dec 26.
BACKGROUND & AIMS: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry.
We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed.
In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10) and the MHC locus 6p21.32 (P = 1.15 × 10). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants.
In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.
约 30%的 HCV 感染者会自发清除 HCV，而非洲裔人群的自发清除率则较低。主要组织相容性复合体（MHC）和干扰素 lambda 基因的变异与 HCV 的自发清除有关，但在非洲裔人群中对这些变异的研究较少。我们对非洲裔人群进行了 HCV 自发清除的密集多血统全基因组关联研究。
我们对来自 3 个血统群体的 4423 人进行了基因型分析：2201 名非洲裔（445 名 HCV 清除和 1756 名 HCV 持续感染）、1739 名欧洲裔（701 名 HCV 清除和 1036 名 HCV 持续感染）和 486 名多血统西班牙裔（173 名 HCV 清除和 313 名 HCV 持续感染）。使用 Illumina（圣地亚哥，CA）芯片进行样本基因分型，并通过统计方法推断到 1000 基因组项目。对于每个血统群体，通过对数加性分析检验单核苷酸多态性与 HCV 清除的关联，然后进行荟萃分析。
荟萃分析证实，干扰素 lambda 基因座 IFNL4-IFNL3（19q13.2）（P = 5.99×10）和 MHC 基因座 6p21.32（P = 1.15×10）与 HCV 清除显著相关。我们还发现 G 蛋白偶联受体 158 基因（GPR158）在 10p12.1 处的 HCV 清除与多态性相关（P = 1.80×10）。这 3 个基因座对 HCV 清除具有独立的加性效应，分别占欧洲裔和非洲裔 HCV 清除变异性的 6.8%和 5.9%。携带所有 6 种变异的非洲裔或欧洲裔个体清除 HCV 感染的可能性分别是不携带或仅携带 1 种清除相关变异个体的 24 倍和 11 倍。
在 3 项研究数据的荟萃分析中，我们发现 MHC 基因、IFNL4-IFNL3 和 GPR158 中的变异增加了欧洲裔和非洲裔患者 HCV 清除的几率。这些发现可以增加我们对 HCV 感染免疫反应和清除的理解。
