Autoimmune diseases are often common chronic conditions that involve immune attack of one or more organ systems and affect approximately 5% of the population. Although the specific aetiologies of human autoimmune diseases remain largely unknown, in the case of type 1 diabetes [OMIM: 222100], four susceptibility loci have been identified and convincingly replicated: the HLA class II genes on chromosome 6p21, the insulin gene on chromosome 11p15[2, 3], the CTLA-4 gene on chromosome 2q33[4, 5], and the PTPN22 gene on chromosome 1p13[6, 7]. Evidence for a fifth gene has recently been reported, IL2RA (CD25), encoding the α-subunit of the IL-2 receptor on chromosome 10p15. Here, we have adopted a linkage disequilibrium mapping approach to test for an association between T1D and three regions encompassing 13 IFNA genes (IFNA1 [OMIM: 147660], IFNA2 [OMIM: 147562], IFNA4 [OMIM: 147564], IFNA5 [OMIM: 147565], IFNA6 [OMIM: 147566], IFNA7 [OMIM: 147567], IFNA8 [OMIM: 147568], IFNA10 [OMIM: 147577], IFNA13 [OMIM: 147578], IFNA14 [OMIM: 147579], IFNA16 [OMIM: 147580], IFNA17 [OMIM: 147583] and IFNA21 [OMIM: 147584]), IFNW1 [OMIM: 147553], IFNB1 [OMIM: 147640], IFNG [OMIM: 147570] and ICSBP1 [OMIM: 601565], using tag SNPs [9–11] in a collection of 472 multiplex families. We have previously shown that the tag SNP approach can reduce genotyping costs by approximately two-thirds [10–12].
The type I interferons, including the IFNAs, IFNB1 and IFNW1, are a large, evolutionarily-conserved family of homologous pro-inflammatory antiviral, immune-regulatory, cytokines, encoded by a cluster of single exon genes in a 400 kb region of human chromosome 9p21.3, and the orthologous ~400 kb region of mouse chromosome 4. The type II interferon, IFNG, encoded by a four-exon gene on chromosome 12, also exhibits antiviral activity but in contrast to the type I interferons, its main biological activity appears to be immunomodulatory. Type I interferons have increased prior probability in terms of being associated with susceptibility to human immune-mediated disease because this region has been linked with susceptibility to a number of mouse models of autoimmune diseases and related traits [13–16], although, to date, there is no evidence of linkage in humans.
We also assessed the related ICSBP1, the product of which, a transcription factor of the interferon regulatory factor (IRF) family, plays a major role in interferon signalling. Although nine distinct IRFs have been described, we analysed ICSBP1, specifically because chromosome 16q24.1, the region containing the nine-exon gene encoding ICSBP1, has shown some evidence of linkage to T1D previously [18–20].