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Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes

BACKGROUND/HYPOTHESIS: HLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies have systematically investigated the joint effect of multiple genetic variants. We evaluated joint e...

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Autores principales: Bjørnvold, M., Undlien, D. E., Joner, G., Dahl-Jørgensen, K., Njølstad, P. R., Akselsen, H. E., Gervin, K., Rønningen, K. S., Stene, L. C.
Formato: Texto
Lenguaje:English
Publicado: Springer-Verlag 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270365/
https://www.ncbi.nlm.nih.gov/pubmed/18292987
http://dx.doi.org/10.1007/s00125-008-0932-0
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author Bjørnvold, M.
Undlien, D. E.
Joner, G.
Dahl-Jørgensen, K.
Njølstad, P. R.
Akselsen, H. E.
Gervin, K.
Rønningen, K. S.
Stene, L. C.
author_facet Bjørnvold, M.
Undlien, D. E.
Joner, G.
Dahl-Jørgensen, K.
Njølstad, P. R.
Akselsen, H. E.
Gervin, K.
Rønningen, K. S.
Stene, L. C.
author_sort Bjørnvold, M.
collection PubMed
description BACKGROUND/HYPOTHESIS: HLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies have systematically investigated the joint effect of multiple genetic variants. We evaluated joint effects of the four established genes on the risk of childhood-onset type 1 diabetes. METHODS: We genotyped 421 nuclear families, 1,331 patients and 1,625 controls for polymorphisms of HLA-DRB1, −DQA1 and −DQB1, the insulin gene (INS, −23 HphI), CTLA4 (JO27_1) and PTPN22 (Arg620Trp). RESULTS: The joint effect of HLA and PTPN22 on type 1 diabetes risk was significantly less than multiplicative in the case-control data, but a multiplicative model could not be rejected in the trio data. All other two-way gene–gene interactions fitted multiplicative models. The high-risk HLA genotype conferred a very high risk of type 1 diabetes (OR 20.6, using the neutral-risk HLA genotype as reference). When including also intermediate-risk HLA genotypes together with risk genotypes at the three non-HLA loci, the joint odds ratio was 61 (using non-risk genotypes at all loci as reference). CONCLUSION: Most established susceptibility genes seem to act approximately multiplicatively with other loci on the risk of disease except for the joint effect of HLA and PTPN22. The joint effect of multiple susceptibility loci conferred a very high risk of type 1 diabetes, but applies to a very small proportion of the general population. Using multiple susceptibility genotypes compared with HLA genotype alone seemed to influence the prediction of disease only marginally. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-008-0932-0) contains supplementary material, which is available to authorised users.
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spelling pubmed-22703652008-03-21 Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes Bjørnvold, M. Undlien, D. E. Joner, G. Dahl-Jørgensen, K. Njølstad, P. R. Akselsen, H. E. Gervin, K. Rønningen, K. S. Stene, L. C. Diabetologia Article BACKGROUND/HYPOTHESIS: HLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies have systematically investigated the joint effect of multiple genetic variants. We evaluated joint effects of the four established genes on the risk of childhood-onset type 1 diabetes. METHODS: We genotyped 421 nuclear families, 1,331 patients and 1,625 controls for polymorphisms of HLA-DRB1, −DQA1 and −DQB1, the insulin gene (INS, −23 HphI), CTLA4 (JO27_1) and PTPN22 (Arg620Trp). RESULTS: The joint effect of HLA and PTPN22 on type 1 diabetes risk was significantly less than multiplicative in the case-control data, but a multiplicative model could not be rejected in the trio data. All other two-way gene–gene interactions fitted multiplicative models. The high-risk HLA genotype conferred a very high risk of type 1 diabetes (OR 20.6, using the neutral-risk HLA genotype as reference). When including also intermediate-risk HLA genotypes together with risk genotypes at the three non-HLA loci, the joint odds ratio was 61 (using non-risk genotypes at all loci as reference). CONCLUSION: Most established susceptibility genes seem to act approximately multiplicatively with other loci on the risk of disease except for the joint effect of HLA and PTPN22. The joint effect of multiple susceptibility loci conferred a very high risk of type 1 diabetes, but applies to a very small proportion of the general population. Using multiple susceptibility genotypes compared with HLA genotype alone seemed to influence the prediction of disease only marginally. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-008-0932-0) contains supplementary material, which is available to authorised users. Springer-Verlag 2008-02-22 2008-04 /pmc/articles/PMC2270365/ /pubmed/18292987 http://dx.doi.org/10.1007/s00125-008-0932-0 Text en © Springer-Verlag 2008
spellingShingle Article
Bjørnvold, M.
Undlien, D. E.
Joner, G.
Dahl-Jørgensen, K.
Njølstad, P. R.
Akselsen, H. E.
Gervin, K.
Rønningen, K. S.
Stene, L. C.
Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes
title Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes
title_full Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes
title_fullStr Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes
title_full_unstemmed Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes
title_short Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes
title_sort joint effects of hla, ins, ptpn22 and ctla4 genes on the risk of type 1 diabetes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270365/
https://www.ncbi.nlm.nih.gov/pubmed/18292987
http://dx.doi.org/10.1007/s00125-008-0932-0
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