Bjørnvold M, Undlien D E, Joner G, Dahl-Jørgensen K, Njølstad P R, Akselsen H E, Gervin K, Rønningen K S, Stene L C
Institute of Medical Genetics, Faculty Division Ullevål University Hospital, University of Oslo, P.O. Box 1036, Blindern, NO-0315 Oslo, Norway.
Diabetologia. 2008 Apr;51(4):589-96. doi: 10.1007/s00125-008-0932-0. Epub 2008 Feb 22.
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.
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).
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).
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.
背景/假说：HLA、胰岛素基因（INS）、蛋白酪氨酸磷酸酶非受体型22（PTPN22）和细胞毒性T淋巴细胞相关抗原4（CTLA4）被认为是已确定的1型糖尿病易感基因。已知HLA、PTPN22和CTLA4参与免疫调节。很少有研究系统地调查多个基因变异的联合效应。我们评估了这四个已确定基因对儿童期发病的1型糖尿病风险的联合效应。
我们对421个核心家庭、1331例患者和1625名对照进行了HLA-DRB1、-DQA1和-DQB1、胰岛素基因（INS，-23 HphI）、CTLA4（JO27_1）和PTPN22（Arg620Trp）多态性的基因分型。
在病例对照数据中，HLA和PTPN22对1型糖尿病风险的联合效应显著小于相乘效应，但在三联体数据中不能拒绝相乘模型。所有其他双向基因-基因相互作用符合相乘模型。高危HLA基因型赋予1型糖尿病非常高的风险（比值比为20.6，以中性风险HLA基因型为参照）。当将中危HLA基因型与三个非HLA位点的风险基因型一起考虑时，联合比值比为61（以所有位点的非风险基因型为参照）。
除了HLA和PTPN22的联合效应外，大多数已确定的易感基因似乎与其他位点对疾病风险的作用近似相乘。多个易感位点的联合效应赋予1型糖尿病非常高的风险，但仅适用于一般人群中非常小的一部分。与单独使用HLA基因型相比，使用多个易感基因型似乎仅对疾病预测有轻微影响。
