Peking University People's Hospital, Beijing, China.
Peking University Hepatology Institute, Beijing, China.
J Viral Hepat. 2019 Sep;26(9):1040-1049. doi: 10.1111/jvh.13107. Epub 2019 Jul 23.
In a multicentre, genome-wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa-2a for ≥ 24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post-treatment, using serological and/or virological endpoints. Thirty-six single-marker analyses and a gene-by-gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome-wide significance (P < 5 × 10 ) in single-marker analyses, but suggestive associations (P < 1 × 10 ) were identified for 116 SNPs. In gene-by-gene analyses, one gene, FCER1A (rs7549785), reached genome-wide significance (P = 2.65 × 10 ) in East Asian patients for hepatitis B surface antigen (HBsAg) clearance, with a moderate effect size (odds ratio = 4.74). Eleven of 44 carriers (25%) of the A allele at rs7549785 achieved HBsAg clearance compared with 69/1051 (7%) noncarriers. FCER1A encodes the alpha subunit of the immunoglobulin E receptor. In a post hoc analysis of a homogenous patient subset, the strongest intragenic association was for rs7712322 (POLR3G, P = 7.21 × 10 ). POLR3G encodes the G subunit of the polymerase (RNA) III enzyme, involved in sensing and limiting infection by intracellular bacteria and DNA viruses, and as a DNA sensor in innate immune responses. FCER1A (rs7549785) and possibly POLR3G (rs7712322) are shown to be associated with peginterferon alfa-2a response in adult patients with chronic hepatitis B. Independent confirmation of these findings is warranted (clinicaltrials.gov number NCT01855997).
在一项多中心全基因组关联研究中,我们旨在鉴定与成人慢性乙型肝炎患者治疗应答相关的宿主遗传因素。该研究纳入了 1669 例接受聚乙二醇干扰素 alfa-2a 治疗至少 24 周(联合或不联合核苷(酸)类似物)的患者,通过微阵列分析获得了基因型数据。治疗应答在治疗结束至少 24 周时采用血清学和/或病毒学终点进行评估。进行了 36 项单标记分析和基因间分析。在单标记分析中,没有单个核苷酸多态性(SNP)达到全基因组显著性(P<5×10),但在 116 个 SNP 中发现了提示性关联(P<1×10)。在基因间分析中,一个基因 FCER1A(rs7549785)在东亚患者中达到乙型肝炎表面抗原(HBsAg)清除的全基因组显著性(P=2.65×10),具有中等的效应大小(比值比=4.74)。在 rs7549785 的 A 等位基因携带者中,有 44 名(25%)患者达到 HBsAg 清除,而非携带者 1051 名(7%)患者中有 69 名达到 HBsAg 清除。FCER1A 编码免疫球蛋白 E 受体的 alpha 亚单位。在同质患者亚组的事后分析中,最强的基因内关联是 rs7712322(POLR3G,P=7.21×10)。POLR3G 编码聚合酶(RNA)III 酶的 G 亚单位,该酶参与感应和限制细胞内细菌和 DNA 病毒的感染,并且作为先天免疫反应中的 DNA 传感器。FCER1A(rs7549785)和可能的 POLR3G(rs7712322)与聚乙二醇干扰素 alfa-2a 在慢性乙型肝炎成年患者中的应答相关。这些发现需要独立证实(临床试验.gov 编号 NCT01855997)。