从旧秩序阿米什人的全基因组关联扫描中鉴定2型糖尿病的新型候选基因：来自糖尿病相关数量性状和独立人群的复制证据。

Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations.

作者信息

Rampersaud Evadnie, Damcott Coleen M, Fu Mao, Shen Haiqing, McArdle Patrick, Shi Xiaolian, Shelton John, Yin Jing, Chang Yen-Pei C, Ott Sandra H, Zhang Li, Zhao Yiju, Mitchell Braxton D, O'Connell Jeffery, Shuldiner Alan R

机构信息

Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 West Redwood St., Room 494, Baltimore, MD 21201, USA.

出版信息

Diabetes. 2007 Dec;56(12):3053-62. doi: 10.2337/db07-0457. Epub 2007 Sep 10.

DOI:10.2337/db07-0457

PMID:17846126

Abstract

OBJECTIVE

We sought to identify type 2 diabetes susceptibility genes through a genome-wide association scan (GWAS) in the Amish.

RESEARCH DESIGN AND METHODS

DNA from 124 type 2 diabetic case subjects and 295 control subjects with normal glucose tolerance were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array. A total of 82,485 SNPs were tested for association with type 2 diabetes. Type 2 diabetes-associated SNPs were further prioritized by the following: 1) associations with 5 oral glucose tolerance test (OGTT) traits in 427 nondiabetic Amish subjects, and 2) in silico replication from three independent 100L SNP GWASs (Framingham Heart Study Caucasians, Pima Indians, and Mexican Americans) and a 500K GWAS in Scandinavians.

RESULTS

The strongest association (P = 1.07 x 10(-5)) was for rs2237457, which is located in growth factor receptor-bound protein 10 (Grb10), an adaptor protein that regulate insulin receptor signaling. rs2237457 was also strongly associated with OGTT glucose area under the curve in nondiabetic subjects (P = 0.001). Of the 1,093 SNPs associated with type 2 diabetes at P < 0.01, 67 SNPs demonstrated associations with at least one OGTT trait in nondiabetic individuals; 80 SNPs were nominally associated with type 2 diabetes in one of the three independent 100K GWASs, 3 SNPs (rs2540317 in MFSD9, rs10515353 on chromosome 5, and rs2242400 in BCAT1 were associated with type 2 diabetes in more than one population), and 11 SNPs were nominally associated with type 2 diabetes in Scandinavians. One type 2 diabetes-associated SNP (rs3845971, located in FHIT) showed replication with OGTT traits and also in another population.

CONCLUSIONS

Our GWAS of type 2 diabetes identified several gene variants associated with type 2 diabetes, some of which are worthy of further study.

摘要

目的

我们试图通过对阿米什人进行全基因组关联扫描（GWAS）来鉴定2型糖尿病易感基因。

研究设计与方法

对124例2型糖尿病病例受试者和295例糖耐量正常的对照受试者的DNA进行Affymetrix 100K单核苷酸多态性（SNP）芯片基因分型。共检测了82,485个SNP与2型糖尿病的关联性。与2型糖尿病相关的SNP通过以下方式进一步排序：1）与427例非糖尿病阿米什受试者的5项口服葡萄糖耐量试验（OGTT）指标的关联性，以及2）来自三项独立的100L SNP GWAS（弗雷明汉心脏研究白种人、皮马印第安人和墨西哥裔美国人）和一项斯堪的纳维亚人的500K GWAS的电子复制。

结果

最强的关联性（P = 1.07 x 10(-5)）是针对rs2237457，其位于生长因子受体结合蛋白10（Grb10）中，Grb10是一种调节胰岛素受体信号传导的衔接蛋白。rs2237457在非糖尿病受试者中也与OGTT葡萄糖曲线下面积密切相关（P = 0.001）。在P < 0.01时与2型糖尿病相关的1,093个SNP中，67个SNP在非糖尿病个体中与至少一项OGTT指标有关联；80个SNP在三项独立的100K GWAS之一中与2型糖尿病存在名义上的关联，3个SNP（MFSD9中的rs2540317、5号染色体上的rs10515353和BCAT1中的rs2242400）在不止一个人群中与2型糖尿病相关，11个SNP在斯堪的纳维亚人中与2型糖尿病存在名义上的关联。一个与2型糖尿病相关的SNP（rs3845971，位于FHIT）在OGTT指标以及另一人群中显示出重复性。