Article

Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Pro-tect Against Type 1 Diabetes

Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
Science (Impact Factor: 33.61). 04/2009; 324(5925):387-9. DOI: 10.1126/science.1167728
Source: PubMed

ABSTRACT

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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    • "Mean inflammation score of Adar fl/fl Mavs À/À UBC:Ert2Cre + intestines compared to either control is significant by one-way ANOVA, p = 0.002. that affect only the p150 isoform of ADAR1 (Crow et al., 2015; Rice et al., 2012), and a biological framework for understanding the numerous IFIH1 polymorphisms in humans that are associated with type I diabetes, systemic lupus erythematosus, and Graves disease (Gateva et al., 2009; Nejentsev et al., 2009; Smyth et al., 2006; Sutherland et al., 2007). Given the embryonic lethality and robust IFN signature of Adar À/À mice, as well as the rapid MAVS-dependent inflammatory response that arises after abrupt Adar deletion in adults, we propose that the ADAR1-regu- lated endogenous MDA5 RNA ligands are broadly expressed, highly immunostimulatory, or both. "
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    • "Several lines of evidences support this " common diseaserare variants " hypothesis (Iyengar and Elston 2007). First, many studies have related rare genetic variants to complex human diseases, such as type 2 diabetes, hypertriglyceridemia, sick sinus syndrome (McClellan et al. 2007; Nejentsev et al. 2009; Johansen et al. 2010; Holm et al. 2011; Rivas et al. 2011; Need et al. 2012; Lohmueller et al. 2013). Second, disease-causing variants should be selectively unfavorable (i.e., should decrease fitness). "
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    ABSTRACT: Genetic variation arising from single nucleotide polymorphisms (SNPs) is ubiquitously found among human populations. While disease-causing variants are known in some cases, identifying functional or causative variants for most human diseases remains a challenging task. Rare SNPs, rather than common ones, are thought to be more important in the pathology of most human diseases. We propose that rare SNPs should be divided into two categories dependent on whether the minor alleles are derived or ancestral. Derived alleles are less likely to have been purified by evolutionary processes and may be more likely to induce deleterious effects. We therefore hypothesized that the rare SNPs with derived minor alleles would be more important for human diseases and predicted that these variants would have larger functional or structural consequences relative to the rare variants for which the minor alleles are ancestral. We systematically investigated the consequences of the exonic SNPs on protein function, mRNA structure, and translation. We found that the functional and structural consequences are more significant for the rare exonic variants for which the minor alleles are derived. However, this pattern is reversed when the minor alleles are ancestral. Thus, the rare exonic SNPs with derived minor alleles are more likely to be deleterious. Age estimation of rare SNPs confirms that these potentially deleterious SNPs are recently evolved in the human population. These results have important implications for understanding the function of genetic variations in human exonic regions and for prioritizing functional SNPs in genome wide association studies of human diseases.
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    • "Further complicating causal variant identification is the possibility that multiple as opposed to a single variant within an LD block may be functional and contribute to the observed association . Analogous to examples in which multiple coding variants in the same gene independently contribute to disease risk (Kotowski et al. 2006; Nejentsev et al. 2009; Rivas et al. 2011), Corradin and colleagues recently suggested a " multiple enhancer variant " (MEV) hypothesis (Corradin et al. 2014) based on investigation into six different autoimmune diseases. In that study, they provide evidence that multiple variants within an LD block impact the activity of multiple different enhancers, and those effects coordinately alter target gene expression. "
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