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研究揭示1型糖尿病的因果变异和药物靶点
2021-06-20 13:52

英国牛津大学John A. Todd研究组揭示1型糖尿病的因果变异和药物靶点。相关论文于2021年6月14日在线发表在《自然—遗传》杂志上。

研究人员报告了迄今为止最大和最多样化的1型糖尿病(T1D)遗传研究(61,427 名参与者),产生了78个全基因组显著(P<5×10-8)区域,其中包括36个新区域。研究人员定义了可靠的T1D相关变异集,并表明它们富含免疫细胞可及的染色质,尤其是CD4+效应T细胞。使用来自115名个体的CD4+T细胞染色质可及性分析,研究人员绘制出染色质可及性数量性状基因座并确定T1D风险变异与染色质可及性数量性状基因座共定位的五个区域。结果表明,BACH2中的rs72928038是候选的T1D因果变体,并导致T细胞中增强子可及性和BACH2表达降低。

最后,通过整合遗传证据、功能基因组图谱和免疫蛋白-蛋白质相互作用,研究人员确定了12个与T1D相关的基因,这些基因已被用于自身免疫性疾病的临床试验,从而对潜在的药物靶点进行优先排序。这些发现为T1D提供了拓展的基因组图谱。

附:英文原文

Title: Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes

Author: Catherine C. Robertson, Jamie R. J. Inshaw, Suna Onengut-Gumuscu, Wei-Min Chen, David Flores Santa Cruz, Hanzhi Yang, Antony J. Cutler, Daniel J. M. Crouch, Emily Farber, S. Louis Bridges, Jeffrey C. Edberg, Robert P. Kimberly, Jane H. Buckner, Panos Deloukas, Jasmin Divers, Dana Dabelea, Jean M. Lawrence, Santica Marcovina, Amy S. Shah, Carla J. Greenbaum, Mark A. Atkinson, Peter K. Gregersen, Jorge R. Oksenberg, Flemming Pociot, Marian J. Rewers, Andrea K. Steck, David B. Dunger, Linda S. Wicker, Patrick Concannon, John A. Todd, Stephen S. Rich

Issue&Volume: 2021-06-14

Abstract: We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P<5×108) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein–protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.

DOI: 10.1038/s41588-021-00880-5

Source: https://www.nature.com/articles/s41588-021-00880-5

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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