A Systems Genetics Approach Identifies Genes and Pathways for Type 2 Diabetes in Human Islets

被引：301

作者：

Taneera, Jalal ^{[1
]}

Lang, Stefan ^{[1
]}

Sharma, Amitabh ^{[1
,3
,4
]}

Fadista, Joao ^{[1
]}

Zhou, Yuedan ^{[1
]}

Ahlqvist, Emma ^{[1
]}

Jonsson, Anna ^{[1
]}

Lyssenko, Valeriya ^{[1
]}

Vikman, Petter ^{[1
]}

Hansson, Ola ^{[1
]}

Parikh, Hemang ^{[5
]}

Korsgren, Olle ^{[6
]}

Soni, Arvind ^{[2
]}

Krus, Ulrika ^{[1
]}

Zhang, Enming ^{[2
]}

Jing, Xing-Jun ^{[2
]}

Esguerra, Jonathan L. S. ^{[2
]}

Wollheim, Claes B. ^{[1
]}

Salehi, Albert ^{[2
]}

Rosengren, Anders ^{[1
,2
]}

Renstrom, Erik ^{[2
]}

Groop, Leif ^{[1
]}

机构：

[1] Lund Univ, Skane Univ Hosp Malmo, Dept Clin Sci Diabet & Endocrinol, Lund Univ Diabet Ctr, S-20502 Malmo, Sweden

[2] Lund Univ, Skane Univ Hosp Malmo, Dept Clin Sci, S-20502 Malmo, Sweden

[3] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA

[4] Northeastern Univ, Dept Phys, Boston, MA 02115 USA

[5] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD 20877 USA

[6] Uppsala Univ, Inst Immunol Genet & Pathol, Rudbecklab, S-75185 Uppsala, Sweden

来源：

CELL METABOLISM | 2012年 / 16卷 / 01期

基金：

瑞典研究理事会; 欧洲研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; HUMAN PANCREATIC-ISLETS; SUSCEPTIBILITY LOCI; INTERACTION NETWORKS; INSULIN-RESISTANCE; RISK; VARIANTS; MELLITUS; GLUCOSE; EXPRESSION;

D O I：

10.1016/j.cmet.2012.06.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Close to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability. In an attempt to identify additional T2D genes, we analyzed global gene expression in human islets from 63 donors. Using 48 genes located near T2D risk variants, we identified gene coexpression and protein-protein interaction networks that were strongly associated with islet insulin secretion and HbA(1c). We integrated our data to form a rank list of putative T2D genes, of which CHL1, LRFN2, RASGRP1, and PPM1K were validated in INS-1 cells to influence insulin secretion, whereas GPR120 affected apoptosis in islets. Expression variation of the top 20 genes explained 24% of the variance in HbA(1c) with no claim of the direction. The data present a global map of genes associated with islet dysfunction and demonstrate the value of systems genetics for the identification of genes potentially involved in T2D.

引用

页码：122 / 134

页数：13

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