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


CONCLUSIONS
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.
Bjørnvold
M
M
Institute of Medical Genetics, Faculty Division Ullevål University Hospital, University of Oslo, P.O. Box 1036, Blindern, NO-0315 Oslo, Norway. marit.bjornvold@medisin.uio.no
Undlien
D E
DE
Joner
G
G
Dahl-Jørgensen
K
K
Njølstad
P R
PR
Akselsen
H E
HE
Gervin
K
K
Rønningen
K S
KS
Stene
L C
LC
D000293:Adolescent; D017668:Age of Onset; D015703:Antigens, CD / Q000235:genetics*; D060908:CTLA-4 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics*; D008297:Male; D009679:Nuclear Family; D016017:Odds Ratio; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012307:Risk Factors; D012680:Sensitivity and Specificity
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006680:HLA Antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D007328:Insulin; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22