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Rare Variants of IFIH1 , a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes
Open accessAbstract
Genome-wide association studies (GWASs) are regularly 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 10 candidate genes in pools of DNA from 480 patients and 480 controls and tested their disease association in over 30,000 participants. We discovered four rare variants that lowered T1D risk independently of each other (odds ratio = 0.51 to 0.74; P = 1.3 × 10 –3 to 2.1 × 10 –16 ) in IFIH1 ( interferon induced with helicase C domain 1 ), a gene located in a region previously associated with T1D by GWASs. These variants are predicted to alter the expression and structure of IFIH1 [MDA5 (melanoma differentiation-associated protein 5)], a cytoplasmic helicase that mediates induction of interferon response to viral RNA. This finding firmly establishes the role of IFIH1 in T1D and demonstrates that resequencing studies can pinpoint disease-causing genes in genomic regions initially identified by GWASs.
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“only 1 of 63 genes in an initial screen for inflammatory bowel disease found evidence for rare variant effects (and these were protective114, but see also115)”
From Rare and common variants: twenty arguments (2012) · cites this paper as [113]
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- We thank the patients control participants and family members for participating in the study. S.N. held the Diabetes Research and Wellness Foundation Non-Clinical Fellowship at the early stages of the project and now holds the Royal Society University Research Fellowship. The Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory is funded by the Juvenile Diabetes Research Foundation the Wellcome Trust and the National Institute for Health Research Biomedical Research Centre. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895). Full acknowledgements are in the supporting online material. Previously unseen SNPs were submitted to dbSNP database (www.ncbi.nlm.nih.gov/SNP/); their submission numbers are in table S3.
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Metadata
- Authors
- Nejentsev, S., Walker, N., Riches, D., Egholm, M., & Todd, J. A.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Nejentsev, Sergey
- Venue
- Science
- Published
- 2009-04-17
- Volume
- 324
- Issue
- 5925
- Pages
- 387-389
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2707798
- OpenAlex
- W2020040634
- Cited by
- 958
- References
- 25
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 11 · 2023: 25 · 2022: 22 · 2021: 29 · 2020: 30 · 2019: 30 · 2018: 27 · 2017: 47 · 2016: 36 · 2015: 72 · 2014: 72 · 2013: 109 · 2012: 115
- FWCI
- 82.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Wellcome Trust (061858, 079895)
- National Institute for Health and Care Research (NF-SI-0508-10275)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- type 1 diabetes, MDA5, rare variants, antiviral response, interferon induction, viral RNA sensing, disease-associated genes, genetic risk
- MeSH terms
- Interferon-Induced Helicase, IFIH1, Base Sequence, Diabetes Mellitus, Type 1, Gene Frequency, Humans, Molecular Sequence Data, Risk, Risk Factors, Genetic Variation, Linkage Disequilibrium, Case-Control Studies, Sequence Analysis, DNA, Codon, Nonsense, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, RNA Splice Sites, DEAD-box RNA Helicases, Genome-Wide Association Study
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