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Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia.
American Journal of Human Genetics ( IF 9.8 ) Pub Date : 2020-01-30 , DOI: 10.1016/j.ajhg.2020.01.004
Sharon A Savage 1 , Mathias Viard 2 , Colm O'hUigin 3 , Weiyin Zhou 4 , Meredith Yeager 4 , Shengchao Alfred Li 4 , Tao Wang 5 , Veron Ramsuran 6 , Nicolas Vince 7 , Aurelie Vogt 4 , Belynda Hicks 8 , Laurie Burdett 4 , Charles Chung 8 , Michael Dean 1 , Kelvin C de Andrade 1 , Neal D Freedman 1 , Sonja I Berndt 1 , Nathaniel Rothman 1 , Qing Lan 1 , James R Cerhan 9 , Susan L Slager 9 , Yawei Zhang 10 , Lauren R Teras 11 , Michael Haagenson 12 , Stephen J Chanock 1 , Stephen R Spellman 5 , Youjin Wang 1 , Amanda Willis 13 , Medhat Askar 13 , Stephanie J Lee 14 , Mary Carrington 15 , Shahinaz M Gadalla 1
Affiliation  

Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 × 10-13) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 × 10-6). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB1∗03:01, (OR 1.66, p = 1.52 × 10-7), DPB1∗10:01 (OR 2.12, p = 0.0003), and DPB1∗01:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 × 10-9) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.

中文翻译:

全基因组关联研究确定 HLA-DPB1 是严重再生障碍性贫血的重要危险因素。

严重再生障碍性贫血(SAA)是一种罕见疾病,其特征是骨髓发育不良和进行性全血细胞减少。获得性 SAA 的病因尚不清楚,但可能与异常的免疫反应和环境暴露有关。我们对发现组(359 例,1,396 例对照)和验证组(17​​5 例,1,059 例对照)中与健康对照基因匹配的 SAA 个体进行了全基因组关联研究。综合分析确定了 6p21 上主要组织相容性复合物内不同块中的连锁 SNP。顶部 SNP 编码 HLA II 类基因 HLA-DPB1 的 P4 结合袋中的 p.Met76Val(rs1042151A>G,比值比 [OR] 1.75,95% 置信区间 [CI] 1.50-2.03,p = 1.94 × 10- 13) 并且与健康个体的 HLA-DP 细胞表面表达相关 (p = 2.04 × 10-6)。系统发育分析表明,Val76 不是单系的,并且可能与不同的 HLA-DP 结合沟构象一起出现。HLA-DPB1 等位基因的估算显示,与 Val76 编码等位基因 DPB1*03:01(OR 1.66,p = 1.52 × 10-7)、DPB1*10:01(OR 2.12,p = 0.0003)相关的 SAA 风险增加,和 DPB1*01:01(OR 1.60,p = 0.0008)。HLA-B 附近的第二个 SNP,rs28367832G>A,在联合分析中达到全基因组显着性(OR 1.49,95% CI 1.22-1.78,p = 7.27 × 10-9);在排除影响 I 类 HLA 基因的克隆拷贝中性杂合性丢失的病例后,这种关联仍然显着(8.6% 的病例和 0% 的对照)。HLA II 类基因 HLA-DPB1 和可能的 I 类 (HLA-B) 中的 SNP 与 SAA 相关。某些 HLA-DPB1 等位基因中 Met76 替换为 Val76 可能通过涉及 DP 肽结合特异性、表达和/或影响 DP 功能的其他因素的机制影响 SAA 风险。
更新日期:2020-01-31
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