Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes.
Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes.
复制标题
DOI：
10.1007/s00125-008-0932-0
复制
发表时间：
2008-04
期刊：
影响因子：
8.2
通讯作者：
Stene, L. C.
中科院分区：
文献类型：
--
作者：
Bjornvold, M.;Undlien, D. E.;Joner, G.;Dahl-Jorgensen, K.;Njolstad, P. R.;Akselsen, H. E.;Gervin, K.;Ronningen, K. S.;Stene, L. C.
人类白细胞抗原（HLA）、胰岛素（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。很少有研究系统地探究多种基因变异的联合效应。我们评估了这四个已确定的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名患者和1625名对照进行了HLA - DRB1、−DQA1和−DQB1、胰岛素基因（INS，−23 HphI）、CTLA4（JO27_1）以及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，但在三人组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。高风险HLA基因型使1型糖尿病的患病风险非常高（比值比为20.6，以中性风险HLA基因型作为参照）。当同时包括中等风险HLA基因型以及三个非HLA位点的风险基因型时，联合比值比为61（以所有位点的非风险基因型作为参照）。
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大致呈相乘关系。多个易感位点的联合效应使1型糖尿病的患病风险非常高，但仅适用于普通人群中极小的一部分。与仅使用HLA基因型相比，使用多种易感基因型似乎对疾病预测只有轻微影响。
本文的网络版（doi:10.1007/s00125 - 008 - 0932 - 0）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1007/s00125-008-0932-0) contains supplementary material, which is available to authorised users.
登录
查看更多内容
影响因子：
--
作者：
OLERUP, O;ALDENER, A;FOGDELL, A
通讯作者：
FOGDELL, A
影响因子：
2
作者：
PIEGORSCH, WW;WEINBERG, CR;TAYLOR, JA
通讯作者：
TAYLOR, JA
影响因子：
16.2
作者：
Sabbah, E;Savola, K;Knip, M
通讯作者：
Knip, M
影响因子：
1.8
作者：
Moore, JH
通讯作者：
Moore, JH
影响因子：
2.1
作者：
Dudbridge, F
通讯作者：
Dudbridge, F