Interaction analysis of the CBLB and CTLA4 genes in type 1 diabetes
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). T...
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Published in | Journal of leukocyte biology Vol. 81; no. 3; pp. 581 - 583 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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Society for Leukocyte Biology
01.03.2007
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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. |
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AbstractList | 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. 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. |
Author | Jason D. Cooper Neil M. Walker Alex C. Lam Sarah Nutland Helen E. Stevens Luc J. Smink John A. Todd Felicity Payne Jayne Hutchings |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/17209142$$D View this record in MEDLINE/PubMed |
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Cites_doi | 10.1038/ng927 10.1159/000073729 10.2337/diabetes.53.2.505 10.1214/aoms/1177692459 10.1038/ng1653 10.1002/gepi.20077 10.1038/ng0706-731 10.1189/jlb.0904524 |
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References | 2004; 53 1972; 43 2005; 37 2002; 31 2005; 29 2005; 77 2006; 38 2003; 56 Clayton (2023033007014751400_) 2005; 37 Payne (2023033007014751400_) 2004; 53 Bergholdt (2023033007014751400_) 2005; 77 Howson (2023033007014751400_) 2005; 29 Todd (2023033007014751400_) 2006; 38 Yokoi (2023033007014751400_) 2002; 31 Huber (2023033007014751400_) 1972; 43 Chapman (2023033007014751400_) 2003; 56 |
References_xml | – volume: 53 start-page: 505 year: 2004 end-page: 509 article-title: Haplotype tag single nucleotide polymorphism analysis of the human orthologues of the rat type 1 diabetes genes Ian4 (Lyp/Iddm1) and Cblb publication-title: Diabetes – volume: 77 start-page: 579 year: 2005 end-page: 585 article-title: CBLB variants in type 1 diabetes and their genetic interaction with publication-title: CTLA4. J. Leukoc. Biol. – volume: 56 start-page: 18 year: 2003 end-page: 31 article-title: Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power publication-title: Hum. Hered. – volume: 43 start-page: 1041 year: 1972 end-page: 1067 article-title: Robust statistics: a review publication-title: Ann. Math. Statist. – volume: 37 start-page: 1243 year: 2005 end-page: 1246 article-title: Population structure, differential bias and genomic control in a large‐scale, case‐control association study publication-title: Nat. Genet. – volume: 38 start-page: 731 year: 2006 end-page: 733 article-title: Statistical false positive or true disease pathway? publication-title: Nat. Genet. – volume: 31 start-page: 391 year: 2002 end-page: 394 article-title: Cblb is a major susceptibility gene for rat type 1 diabetes mellitus publication-title: Nat. Genet. – volume: 29 start-page: 51 year: 2005 end-page: 67 article-title: Comparison of population‐ and family‐based methods for genetic association analysis in the presence of interacting loci publication-title: Genet. Epidemiol. – volume: 31 start-page: 391 year: 2002 ident: 2023033007014751400_ article-title: Cblb is a major susceptibility gene for rat type 1 diabetes mellitus publication-title: Nat. Genet. doi: 10.1038/ng927 contributor: fullname: Yokoi – volume: 56 start-page: 18 year: 2003 ident: 2023033007014751400_ article-title: Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power publication-title: Hum. Hered. doi: 10.1159/000073729 contributor: fullname: Chapman – volume: 53 start-page: 505 year: 2004 ident: 2023033007014751400_ article-title: Haplotype tag single nucleotide polymorphism analysis of the human orthologues of the rat type 1 diabetes genes Ian4 (Lyp/Iddm1) and Cblb publication-title: Diabetes doi: 10.2337/diabetes.53.2.505 contributor: fullname: Payne – volume: 43 start-page: 1041 year: 1972 ident: 2023033007014751400_ article-title: Robust statistics: a review publication-title: Ann. Math. Statist. doi: 10.1214/aoms/1177692459 contributor: fullname: Huber – volume: 37 start-page: 1243 year: 2005 ident: 2023033007014751400_ article-title: Population structure, differential bias and genomic control in a large-scale, case-control association study publication-title: Nat. Genet. doi: 10.1038/ng1653 contributor: fullname: Clayton – volume: 29 start-page: 51 year: 2005 ident: 2023033007014751400_ article-title: Comparison of population- and family-based methods for genetic association analysis in the presence of interacting loci publication-title: Genet. Epidemiol. doi: 10.1002/gepi.20077 contributor: fullname: Howson – volume: 38 start-page: 731 year: 2006 ident: 2023033007014751400_ article-title: Statistical false positive or true disease pathway? publication-title: Nat. Genet. doi: 10.1038/ng0706-731 contributor: fullname: Todd – volume: 77 start-page: 579 year: 2005 ident: 2023033007014751400_ article-title: CBLB variants in type 1 diabetes and their genetic interaction with publication-title: CTLA4. J. Leukoc. Biol. doi: 10.1189/jlb.0904524 contributor: fullname: Bergholdt |
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Snippet | Gene‐gene interaction analyses have been suggested as a potential strategy to help identify common disease susceptibility genes. Recently, evidence of a... Gene-gene interaction analyses have been suggested as a potential strategy to help identify common disease susceptibility genes. Recently, evidence of a... Abstract Gene-gene interaction analyses have been suggested as a potential strategy to help identify common disease susceptibility genes. Recently, evidence of... |
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SubjectTerms | Adaptor Proteins, Signal Transducing - genetics Animals Antigens, CD - genetics Antigens, Differentiation - genetics Case-Control Studies CBLB CTLA-4 Antigen CTLA4 Denmark Diabetes Mellitus, Type 1 - genetics Gene Frequency Genetic Predisposition to Disease Genetic Testing Humans Polymorphism, Single Nucleotide - genetics Proto-Oncogene Proteins c-cbl - genetics Rats rs3087243 rs3772534 Type 1 diabetes |
Title | Interaction analysis of the CBLB and CTLA4 genes in type 1 diabetes |
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