全基因组关联分析突出了新定义的糖尿病亚型背后的病因差异。

Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes.

作者信息

Mansour Aly Dina, Dwivedi Om Prakash, Prasad Rashmi B, Käräjämäki Annemari, Hjort Rebecka, Thangam Manonanthini, Åkerlund Mikael, Mahajan Anubha, Udler Miriam S, Florez Jose C, McCarthy Mark I, Brosnan Julia, Melander Olle, Carlsson Sofia, Hansson Ola, Tuomi Tiinamaija, Groop Leif, Ahlqvist Emma

机构信息

Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.

Finnish Institute for Molecular Medicine, Helsinki University, Helsinki, Finland.

出版信息

Nat Genet. 2021 Nov;53(11):1534-1542. doi: 10.1038/s41588-021-00948-2. Epub 2021 Nov 4.

DOI:10.1038/s41588-021-00948-2

PMID:34737425

Abstract

Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.

摘要

2型糖尿病已被反复聚类为五种具有不同疾病进展和并发症风险的亚型；然而，病因差异尚不清楚。我们使用全基因组关联和遗传风险评分（GRS）分析来比较潜在的遗传驱动因素。将瑞典ANDIS（斯科讷地区所有新诊断糖尿病患者）研究中的个体与无糖尿病个体进行比较；芬兰的DIREVA（瓦萨糖尿病登记处）和博特尼亚研究用于重复验证。我们发现，各亚型在糖尿病家族史以及与糖尿病相关性状的GRS关联方面存在差异。严重胰岛素抵抗亚型与空腹胰岛素的GRS独特相关，但与TCF7L2基因座中的变异或反映胰岛素分泌的GRS无关。此外，LRMDA附近的一个单核苷酸多态性（SNP，rs10824307）与轻度肥胖相关糖尿病独特相关。因此，我们得出结论，这些亚型具有部分不同的遗传背景，表明存在病因差异。