title: Interaction analysis of the CBLB and CTLA4 genes in type 1 diabetes.
abstract: Gene-gene interaction analyses have been suggested as a potential strategy to help identify common disease susceptibility genes. Recently, evidence of a statistical interaction between polymorphisms in two negative immunoregulatory genes, CBLB and CTLA4, has been reported in type 1 diabetes (T1D). This study, in 480 Danish families, reported an association between T1D and a synonymous coding SNP in exon 12 of the CBLB gene (rs3772534 G>A; minor allele frequency, MAF=0.24; derived relative risk, RR for G allele=1.78; P=0.046). Furthermore, evidence of a statistical interaction with the known T1D susceptibility-associated CTLA4 polymorphism rs3087243 (laboratory name CT60, G>A) was reported (P<0.0001), such that the CBLB SNP rs3772534 G allele was overtransmitted to offspring with the CTLA4 rs3087243 G/G genotype. We have, therefore, attempted to obtain additional support for this finding in both large family and case-control collections. In a primary analysis, no evidence for an association of the CBLB SNP rs3772534 with disease was found in either sample set (2162 parent-child trios, P=0.33; 3453 cases and 3655 controls, P=0.69). In the case-only statistical interaction analysis between rs3772534 and rs3087243, there was also no support for an effect (1994 T1D affected offspring, and 3215 cases, P=0.92). These data highlight the need for large, well-characterized populations, offering the possibility of obtaining additional support for initial observations owing to the low prior probability of identifying reproducible evidence of gene-gene interactions in the analysis of common disease-associated variants in human populations.
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust, Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.forename: Jason D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.forename: Alex C
authors.initials: AC
authors.lastname: Lam
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Smink
authors.forename: Sarah
authors.initials: S
authors.lastname: Nutland
authors.forename: Helen E
authors.initials: HE
authors.lastname: Stevens
authors.forename: Jayne
authors.initials: J
authors.lastname: Hutchings
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D003718:Denmark; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D051381:Rats
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl