Type 1 diabetes and the OAS gene cluster: association with splicing polymorphism or haplotype?
- PMID: 16014697
- PMCID: PMC2564627
- DOI: 10.1136/jmg.2005.035212
Type 1 diabetes and the OAS gene cluster: association with splicing polymorphism or haplotype?
Abstract
Background: The 2',5'-oligoadenylate synthetase genes (OAS1, OAS2, and OAS3) map to human chromosome 12q24 and encode a family of enzymes pivotal to innate antiviral defence. Recently, the minor allele of an OAS1 single nucleotide polymorphism (SNP) that alters splicing (rs10774671) was found to be associated with increased enzymatic activity and, in a case-sibling control study, with type 1 diabetes (T1D).
Methods: We have confirmed this T1D association in 784 nuclear families (two parents and at least one affected offspring) by the transmission disequilibrium test (TDT; G:A = 386:329, p = 0.033). However, because of linkage disequilibrium within OAS1 and with the other two OAS genes, functional attribution of the association to this SNP cannot be assumed. To help answer this question, we also genotyped two non-synonymous SNPs in OAS1 exons 3 and 7.
Results: All three SNPs showed significant transmission distortion. Three of the eight possible haplotypes accounted for 98.4% of parental chromosomes and two of them carried the non-predisposing A allele at rs10774671. Parents heterozygous for these two haplotypes showed significant transmission distortion (p = 0.009) despite being homozygous at rs10774671.
Conclusions: We confirm the T1D association with rs10774671, but we conclude that it cannot be attributed (solely) to the splicing variant rs10774671. A serine/glycine substitution in OAS1 exon 3 is more likely a functional variant.
Conflict of interest statement
Competing interests: none declared
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References
-
- Pociot F, McDermott M F. Genetics of type 1 diabetes mellitus. Genes Immun 20023(5)235–249. - PubMed
-
- Undlien D E, Lie B A, Thorsby E. HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? Trends Genet 200117(2)93–100. - PubMed
-
- Barratt B J, Payne F, Lowe C E, Hermann R, Healy B C, Harold D, Concannon P, Gharani N, McCarthy M I, Olavesen M G, McCormack R, Guja C, Ionescu‐Tirgoviste C, Undlien D E, Ronningen K S, Gillespie K M, Tuomilehto‐Wolf E, Tuomilehto J, Bennett S T, Clayton D G, Cordell H J, Todd J A. Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 200453(7)1884–1889. - PubMed
-
- Ueda H, Howson J M, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow D B, Hunter K M, Smith A N, Di Genova G, Herr M H, Dahlman I, Payne F, Smyth D, Lowe C, Twells R C, Howlett S, Healy B, Nutland S, Rance H E, Everett V, Smink L J, Lam A C, Cordell H J, Walker N M, Bordin C, Hulme J, Motzo C, Cucca F, Hess J F, Metzker M L, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto‐Wolf E, Tuomilehto J, Bingley P, Gillespie K M, Undlien D E, Ronningen K S, Guja C, Ionescu‐Tirgoviste C, Savage D A, Maxwell A P, Carson D J, Patterson C C, Franklyn J A, Clayton D G, Peterson L B, Wicker L S, Todd J A, Gough S C. Association of the T‐cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003423(6939)506–511. - PubMed
-
- Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni G F, Lucarelli P, Pellecchia M, Eisenbarth G S, Comings D, Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 200436(4)337–338. - PubMed
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