Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes

被引：141

作者：

Winckler, Wendy

Weedon, Michael N.

Graham, Robert R.

McCarrolll, Steven A.

Purcell, Shaun

Almgren, Peter

Tuomi, Tiinamaija

Gaudet, Daniel

Bostrom, Kristina Bengtsson

Walker, Mark

Hitman, Graham

Hattersley, Andrew T.

McCarthy, Mark I.

Ardlie, Kristin G.

Hirschhorn, Joel N.

Daly, Mark J.

Frayling, Timothy M.

Groop, Leif

Altshuler, David ^{[1
]}

机构：

[1] Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[2] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Dept Genet, Cambridge, MA 02142 USA

[4] MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[5] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England

[6] Lund Univ, Univ Hosp MAS, Dept Endocrinol, Malmo, Sweden

[7] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland

[8] Univ Helsinki, Folkhalsan Inst Genet, Folkhalsan Res Ctr, Helsinki, Finland

[9] Univ Helsinki, Res Program Mol Med, Helsinki, Finland

[10] Univ Montreal, Community Genom Ctr, Chicoutimi Hosp, Chicoutimi, PQ, Canada

[11] Lund Univ, Univ Hosp MAS, Dept Clin Sci, Malmo, Sweden

[12] Newcastle Univ, Dept Med, Sch Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[13] Univ London, Dept Diabet & Metab Med, Barts & London Queen Mary Sch Med & Dent, London, England

[14] Churchill Hosp, Dept Endocrinol & Metab, Diabet Res Labs, Oxford Ctr Diabet, Oxford OX3 7LJ, England

[15] Genom Collaborat, Cambridge, MA USA

[16] Childrens Hosp, Div Genet, Boston, MA 02115 USA

[17] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[18] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA

[19] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

来源：

DIABETES | 2007年 / 56卷 / 03期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

D O I：

10.2337/db06-0202

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation irk the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, lpf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value < 0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values < 0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value < 10(-6) in > 15,000 samples. We combined these results with our previous studies on HNF4 alpha and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.

引用

页码：685 / 693

页数：9

共 58 条

[1] The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes [J].