Open Access Research article

Construction and analysis of tag single nucleotide polymorphism maps for six human-mouse orthologous candidate genes in type 1 diabetes

Lisa M Maier1*, Deborah J Smyth1, Adrian Vella1, Felicity Payne1, Jason D Cooper1, Rebecca Pask1, Christopher Lowe1, John Hulme1, Luc J Smink1, Heather Fraser1, Carolyn Moule1, Kara M Hunter1, Giselle Chamberlain1, Neil Walker1, Sarah Nutland1, Dag E Undlien2, Kjersti S Rønningen3, Cristian Guja4, Constantin Ionescu-Tîrgovişte4, David A Savage5, David P Strachan6, Laurence B Peterson7, John A Todd1, Linda S Wicker1 and Rebecca C Twells1*

Author Affiliations

1 Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge, UK

2 Institute and Department of Medical Genetics, Ulleval University Hospital, University of Oslo, Oslo, Norway

3 Laboratory of Molecular Epidemiology, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway

4 Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases 'N. Paulescu', Bucharest, Romania

5 Department of Medical Genetics, Queen's University Belfast, Belfast City Hospital, Belfast, UK

6 Department of Community Health Sciences, St George's Hospital Medical School, London, UK

7 Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey, USA

For all author emails, please log on.

BMC Genetics 2005, 6:9  doi:10.1186/1471-2156-6-9

Published: 18 February 2005

Abstract

Background

One strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder. The nonobese diabetic (NOD) mouse is a model for human type 1 diabetes. Linkage and congenic strain analyses have identified several NOD mouse Idd (insulin dependent diabetes) loci, which have been mapped to small chromosome intervals, for which the orthologous regions in the human genome can be identified. Here, we have conducted re-sequencing and association analysis of six orthologous genes identified in NOD Idd loci: NRAMP1/SLC11A1 (orthologous to Nramp1/Slc11a1 in Idd5.2), FRAP1 (orthologous to Frap1 in Idd9.2), 4-1BB/CD137/TNFRSF9 (orthologous to 4-1bb/Cd137/Tnrfrsf9 in Idd9.3), CD101/IGSF2 (orthologous to Cd101/Igsf2 in Idd10), B2M (orthologous to B2m in Idd13) and VAV3 (orthologous to Vav3 in Idd18).

Results

Re-sequencing of a total of 110 kb of DNA from 32 or 96 type 1 diabetes cases yielded 220 single nucleotide polymorphisms (SNPs). Sixty-five SNPs, including 54 informative tag SNPs, and a microsatellite were selected and genotyped in up to 1,632 type 1 diabetes families and 1,709 cases and 1,829 controls.

Conclusion

None of the candidate regions showed evidence of association with type 1 diabetes (P values > 0.2), indicating that common variation in these key candidate genes does not play a major role in type 1 diabetes susceptibility in the European ancestry populations studied.