巴基斯坦卡拉奇市非传染性疾病中心Danish Saleheen团队在研究中取得进展。他们通过对140万参与者进行多族群荟萃分析，揭示了318个2型糖尿病（T2D）和相关血管疾病的新风险位点。该项研究成果发表在2020年6月15日出版的《自然—遗传学》上。

研究人员通过对百万退伍军人计划（MVP）、DIAMANTE、日本生物银行和其他研究的228,499例病例和1,178,783例对照进行了多谱系荟萃分析，探究了T2D的遗传易感性。研究人员发现了以前未报道的568个关联，包括286个常染色体关联、7个X染色体关联和25个在家族特定分析中鉴定的关联。全转录组关联分析检测到687个新基因中有3568个与T2D遗传预测的基因表达关联；其中，已知有54种与FDA批准的药物相互作用。多基因风险评分（PRS）与T2D相关视网膜病变的风险增加密切相关，而与慢性肾脏疾病（CKD）、周围动脉疾病（PAD）和神经病变的相关程度一般。

研究人员探究了MVP中与T2D相关血管疾病的遗传病因，并观察了13种变异的统计SNP–T2D相互作用，包括冠心病（CHD）、CKD、PAD和神经疾病。这些发现可能有助于鉴定T2D的潜在治疗靶点和确定与T2D相关血管疾病的基因组途径。

附：英文原文

Title: Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis

Author: Marijana Vujkovic, Jacob M. Keaton, Julie A. Lynch, Donald R. Miller, Jin Zhou, Catherine Tcheandjieu, Jennifer E. Huffman, Themistocles L. Assimes, Kimberly Lorenz, Xiang Zhu, Austin T. Hilliard, Renae L. Judy, Jie Huang, Kyung M. Lee, Derek Klarin, Saiju Pyarajan, John Danesh, Olle Melander, Asif Rasheed, Nadeem H. Mallick, Shahid Hameed, Irshad H. Qureshi, Muhammad Naeem Afzal, Uzma Malik, Anjum Jalal, Shahid Abbas, Xin Sheng, Long Gao, Klaus H. Kaestner, Katalin Susztak, Yan V. Sun, Scott L. DuVall, Kelly Cho, Jennifer S. Lee, J. Michael Gaziano, Lawrence S. Phillips, James B. Meigs, Peter D. Reaven, Peter W. Wilson, Todd L. Edwards, Daniel J. Rader, Scott M. Damrauer, Christopher J. ODonnell, Philip S. Tsao, Kyong-Mi Chang, Benjamin F. Voight, Danish Saleheen

Issue&Volume: 2020-06-15

Abstract: We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP–T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.

DOI: 10.1038/s41588-020-0637-y

Source: https://www.nature.com/articles/s41588-020-0637-y