Detailed Investigation of the Role of Common and Low-Frequency WFS1 Variants in Type 2 Diabetes Risk

被引：31

作者：

Fawcett, Katherine A. ^{[1
]}

Wheeler, Eleanor ^{[1
]}

Morris, Andrew P. ^{[2
]}

Ricketts, Sally L. ^{[3
]}

Hallmans, Goran ^{[4
]}

Rolandsson, Olov ^{[5
]}

Daly, Allan ^{[1
]}

Wasson, Jon ^{[6
]}

Permutt, Alan ^{[7
]}

Hattersley, Andrew T. ^{[8
]}

Glaser, Benjamin ^{[9
]}

Franks, Paul W. ^{[4
,10
]}

McCarthy, Mark I. ^{[11
,12
]}

Wareham, Nicholas J. ^{[13
]}

Sandhu, Manjinder S. ^{[3
,13
]}

Barroso, Ines ^{[1
]}

机构：

[1] Wellcome Trust Sanger Inst, Metab Dis Grp, Hinxton, Cambs, England

[2] Univ Oxford, Genet & Genom Epidemiol Unit, Wellcome Trust Ctr Human Genet, Oxford, England

[3] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge, England

[4] Umea Univ Hosp, Sect Nutr Res, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden

[5] Umea Univ Hosp, Sect Family Med, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden

[6] Washington Univ, Sch Med, Dept Med, Metab Diabet & Lipid Res Div, St Louis, MO 63110 USA

[7] Washington Univ, Sch Med, Dept Internal Med, Metab Diabet & Lipid Res Div, St Louis, MO 63110 USA

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

[9] Hadassah Hebrew Univ, Med Ctr, Endocrine & Metab Serv, Jerusalem, Israel

[10] Umea Univ Hosp, Med Sect, Dept Publ Hlth & Clin Med, Genet Epidemiol & Clin Res Grp, S-90185 Umea, Sweden

[11] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Churchill Hosp, Oxford, England

[12] Churchill Hosp, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Oxford OX3 7LJ, England

[13] Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England

来源：

DIABETES | 2010年 / 59卷 / 03期

基金：

英国惠康基金;

关键词：

ENDOPLASMIC-RETICULUM; OPTIC ATROPHY; GENE-EXPRESSION; ASSOCIATION; MELLITUS; PROTEIN; SUSCEPTIBILITY; INSIPIDUS; CELLS;

D O I：

10.2337/db09-0920

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

OBJECTIVE-Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk. RESEARCH DESIGN AND METHODS-For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects. RESULTS-Of 31 tagging SNPs, the strongest associated was the previously untested 3' untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 X 10(-7) on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r(2) = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] <0.01) nonsynonymous variants between type 2 diabetic case and control subjects (P = 0.79). Two intermediate frequency (MAF 0.01-0.05) nonsynonymous changes also showed no statistical association with type 2 diabetes. CONCLUSIONS-We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing. Diabetes 59:741-746, 2010

引用

页码：741 / 746

页数：6

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