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. 2008 Apr;51(4):589-96.
doi: 10.1007/s00125-008-0932-0. Epub 2008 Feb 22.

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

M Bjørnvold  1 , D E Undlien, G Joner, K Dahl-Jørgensen, P R Njølstad, H E Akselsen, K Gervin, K S Rønningen, L C Stene
Affiliations

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

M Bjørnvold et al. Diabetologia. 2008 Apr.

Abstract

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.

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Figures

Fig. 1
Fig. 1
ROC curve for HLA genotypes in four categories and for combinations of genotypes defined by HLA and non-HLA susceptibility loci. The area under the curve (95% confidence interval) was 0.820 (0.803–0.836) for HLA (dark blue line), 0.828 (0.811–0.844) for HLA+CTLA4 (purple line), 0.835 (0.819–0.851) for HLA+PTPN22 (grey line), 0.840 (0.824–0.855) for HLA+INS (green line), 0.848 (0.833–0.863) for HLA+INS+PTPN22 (yellow line) and 0.852 (0.837–0.867) for HLA+INS+PTPN22+CTLA4 (red line). Turquoise dashed line, reference line
See this image and copyright information in PMC

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