Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B
Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B
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包括 CFB 和 CD40 在内的 5 个新位点的遗传变异易患慢性乙型肝炎。
DOI：
10.1002/hep.27794
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发表时间：
2015-07-01
期刊：
影响因子：
13.5
通讯作者：
Yu, Long
中科院分区：
文献类型：
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作者：
Jiang, De-Ke;Ma, Xiao-Pin;Yu, Long
乙型肝炎病毒影响全球超过20亿人，其中3.5亿人患有慢性乙型肝炎（CHB）。导致慢性乙型肝炎风险的遗传因素在很大程度上仍然未知。我们试图确定中国人群中CHB易感性的遗传变异。我们对来自中国东部的2514例慢性乙型肝炎患者和1130例正常人进行了全基因组关联研究（GWAS）。通过两阶段验证，我们在四个独立人群中复制了33个最有希望的信号和8个先前报道的CHB风险位点，共6600例CHB病例和8127例对照，其中两个人群来自中国东部，一个来自中国北方，一个来自中国南方。对9114例慢性乙型肝炎病例和9257例对照者的联合分析显示，5个新的基因位点与慢性乙型肝炎风险显著相关。4个基因座位于人类白细胞抗原（HLA）区域6p21.3，包括两个非同义变体(补体因子B [CFB]中的rs12614 [R32W]， P-meta=1.28 x 10(-34)；和rs422951 [T320A]在NOTCH4， P-meta=5.33 × 10(-16))；1个同义变体（HLA-DOA中的rs378352对应HLA-DOA*010101， P-meta=1.04 × 10(-23)）；1个非编码变异（rs2853953靠近HLA-C， P-meta=5.06 × 10(-20)）。另一个位点位于CD40的Kozak序列的20q13.1 （rs1883832, P-meta=2.95 × 10(-15)）。此外，我们验证了先前报道的8个CHB易感位点中的7个(HLA- c位点rs3130542， TCF19位点rs1419881， EHMT2位点rs652888， HLA- dqb1位点rs2856718， HLA- dqb2位点rs7453920， HLA- dpa1位点rs3077， HLA- dpa2位点rs9277535，它们都位于HLA区域，9.84 × 10(-71)P（meta)9.92 × 10(-7)）。结论：GWAS鉴定出5个新的慢性乙型肝炎易感位点。这些发现提高了对慢性乙型肝炎病因的认识，并可能为该病的预防和治疗提供新的靶点。(肝脏病学62:118 2015;128)
Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], P-meta=1.28 x 10(-34); and rs422951 [T320A] in NOTCH4, P-meta=5.33 x 10(-16)); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, P-meta=1.04 x 10(-23)); and one noncoding variant (rs2853953 near HLA-C, P-meta=5.06 x 10(-20)). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, P-meta=2.95 x 10(-15)). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 x 10(-71)P(meta)9.92 x 10(-7)). Conclusion: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease. (Hepatology 2015;62:118-128)