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Published Online March 5, 2009
Science DOI: 10.1126/science.1167728

Reports

Submitted on October 27, 2008
Accepted on February 19, 2009

Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes

Sergey Nejentsev 1*, Neil Walker 2, David Riches 3, Michael Egholm 3, John A. Todd 2

1 Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.; Department of Medicine, University of Cambridge, CB2 2QQ, UK.
2 Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
3 454 Life Sciences, A Roche Company, Branford, CT, 06405, USA.

* To whom correspondence should be addressed.
Sergey Nejentsev , E-mail: sn262{at}cam.ac.uk

Genome-wide association studies (GWAS) are widely used to map genomic regions contributing to common human diseases, but they often do not identify the precise causative genes and sequence variants. To identify causative type 1 diabetes (T1D) variants, we resequenced exons and splice sites of ten candidate genes in pools of DNA from 480 patients and 480 controls and tested their disease association in over 30,000 subjects. We discovered four rare variants that lowered T1D risk independently of each other (OR = 0.51 – 0.74; P = 1.3 x 10-3 – 2.1 x 10-16) in IFIH1, a gene located in a region previously associated with T1D by GWAS. These variants are predicted to alter the expression and structure of IFIH1 (MDA5), a cytoplasmic helicase that mediates induction of interferon response to viral RNA. This firmly establishes the role of IFIH1 in T1D and demonstrates that resequencing studies can pinpoint disease-causing genes in genomic regions initially identified by GWAS.


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