Cooper Jason D, Smyth Deborah J, Bailey Rebecca, Payne Felicity, Downes Kate, Godfrey Lisa M, Masters Jennifer, Zeitels Lauren R, Vella Adrian, Walker Neil M, Todd John A
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
BMC Med Genet. 2007 Nov 28;8:71. doi: 10.1186/1471-2350-8-71.
As genes associated with immune-mediated diseases have an increased prior probability of being associated with other immune-mediated diseases, we tested three such genes, IL23R, IRF5 and CD40, for an association with type 1 diabetes. In addition, we tested seven genes, TAF5L, PDCD1, TCF7, IL12B, IL6, ICAM1 and TBX21, with published marginal or inconsistent evidence of an association with type 1 diabetes.
We genotyped reported polymorphisms of the ten genes, nonsynonymous SNPs (nsSNPs) and, for the IL12B and IL6 regions, tag SNPs in up to 7,888 case, 8,858 control and 3,142 parent-child trio samples. In addition, we analysed data from the Wellcome Trust Case Control Consortium genome-wide association study to determine whether there was any further evidence of an association in each gene region.
We found some evidence of associations between type 1 diabetes and TAF5L, PDCD1, TCF7 and IL6 (ORs = 1.05 - 1.13; P = 0.0291 - 4.16 x 10-4). No evidence of an association was obtained for IL12B, IRF5, IL23R, ICAM1, TBX21 and CD40, although there was some evidence of an association (OR = 1.10; P = 0.0257) from the genome-wide association study for the ICAM1 region.
We failed to exclude the possibility of some effect in type 1 diabetes for TAF5L, PDCD1, TCF7, IL6 and ICAM1. Additional studies, of these and other candidate genes, employing much larger sample sizes and analysis of additional polymorphisms in each gene and its flanking region will be required to ascertain their contributions to type 1 diabetes susceptibility.
由于与免疫介导疾病相关的基因与其他免疫介导疾病相关的先验概率增加，我们检测了三个这样的基因，即白细胞介素23受体（IL23R）、干扰素调节因子5（IRF5）和肿瘤坏死因子受体超家族成员40（CD40）与1型糖尿病的关联。此外，我们还检测了七个基因，即转录起始因子TAF5样蛋白（TAF5L）、程序性死亡蛋白1（PDCD1）、转录因子7（TCF7）、白细胞介素12B（IL12B）、白细胞介素6（IL6）、细胞间黏附分子1（ICAM1）和T-box转录因子21（TBX21），这些基因有已发表的与1型糖尿病关联的边缘性或不一致的证据。
我们对这十个基因报道的多态性进行基因分型，包括非同义单核苷酸多态性（nsSNPs），对于IL12B和IL6区域，在多达7888例病例、8858例对照和3142例亲子三联体样本中检测标签单核苷酸多态性（tag SNPs）。此外，我们分析了威康信托病例对照协会全基因组关联研究的数据，以确定每个基因区域是否有任何进一步的关联证据。
我们发现1型糖尿病与TAF5L、PDCD1、TCF7和IL6之间存在一些关联证据（比值比[ORs]=1.05 - 1.13；P=0.0291 - 4.16×10⁻⁴）。对于IL12B、IRF5、IL23R、ICAM1、TBX21和CD40，未获得关联证据，尽管全基因组关联研究在ICAM1区域有一些关联证据（OR = 1.？10；P = 0.0257）。
我们未能排除TAF5L、PDCD1、TCF7、IL6和ICAM1在1型糖尿病中产生某些影响的可能性。需要对这些基因和其他候选基因进行更多研究，采用更大的样本量，并分析每个基因及其侧翼区域的更多多态性，以确定它们对1型糖尿病易感性的贡献。
