尽管在瑞典北部CT60基因型与1型糖尿病和自身免疫性甲状腺疾病相关，但它并不影响CTLA-4异构体的表达。
CT60 genotype does not affect CTLA-4 isoform expression despite association to T1D and AITD in northern Sweden.
作者信息
Mayans Sofia, Lackovic Kurt, Nyholm Caroline, Lindgren Petter, Ruikka Karin, Eliasson Mats, Cilio Corrado M, Holmberg Dan
机构信息
Medical and Clinical Genetics, Dept of Medical Biosciences, Umeå University SE-90185 Umeå, Sweden.
出版信息
BMC Med Genet. 2007 Feb 6;8:3. doi: 10.1186/1471-2350-8-3.
BACKGROUND
Polymorphisms in and around the CTLA-4 gene have previously been associated to T1D and AITD in several populations. One such single nucleotide polymorphism (SNP), CT60, has been reported to affect the expression level ratio of the soluble (sCTLA-4) to full length CTLA-4 (flCTLA-4) isoforms. The aims of our study were to replicate the association previously published by Ueda et al. of polymorphisms in the CTLA-4 region to T1D and AITD and to determine whether the CT60 polymorphism affects the expression level ratio of sCTLA-4/flCTLA-4 in our population.
METHODS
Three SNPs were genotyped in 253 cases (104 AITD cases and 149 T1D cases) and 865 ethnically matched controls. Blood from 23 healthy individuals was used to quantify mRNA expression of CTLA-4 isoforms in CD4+ cells using real-time PCR. Serum from 102 cases and 59 healthy individuals was used to determine the level of sCTLA-4 protein.
RESULTS
Here we show association of the MH30, CT60 and JO31 polymorphisms to T1D and AITD in northern Sweden. We also observed a higher frequency of the CT60 disease susceptible allele in our controls compared to the British, Italian and Dutch populations, which might contribute to the high frequency of T1D in Sweden. In contrast to previously published findings, however, we were unable to find differences in the sCTLA-4/flCTLA-4 expression ratio based on the CT60 genotype in 23 healthy volunteers, also from northern Sweden. Analysis of sCTLA-4 protein levels in serum showed no correlation between sCTLA-4 protein levels and disease status or CT60 genotype.
CONCLUSION
Association was found between T1D/AITD and all three polymorphisms investigated. However, in contrast to previous investigations, sCTLA-4 RNA and protein expression levels did not differ based on CT60 genotype. Our results do not rule out the CT60 SNP as an important polymorphism in the development of T1D or AITD, but suggest that further investigations are necessary to elucidate the effect of the CTLA-4 region on the development of T1D and AITD.
背景
CTLA - 4基因及其周围的多态性先前已在多个群体中与1型糖尿病（T1D）和自身免疫性甲状腺疾病（AITD）相关联。一种这样的单核苷酸多态性（SNP），即CT60，据报道会影响可溶性（sCTLA - 4）与全长CTLA - 4（flCTLA - 4）异构体的表达水平比值。我们研究的目的是重复上田等人先前发表的CTLA - 4区域多态性与T1D和AITD的关联，并确定CT60多态性是否会影响我们群体中sCTLA - 4/flCTLA - 4的表达水平比值。
方法
对253例患者（104例AITD患者和149例T1D患者）以及865名种族匹配的对照者进行了三个SNP的基因分型。使用23名健康个体的血液，通过实时PCR定量CD4 +细胞中CTLA - 4异构体的mRNA表达。使用102例患者和59名健康个体的血清来测定sCTLA - 4蛋白的水平。
结果
在此我们展示了MH30、CT60和JO31多态性与瑞典北部的T1D和AITD之间的关联。我们还观察到，与英国、意大利和荷兰人群相比，我们的对照者中CT60疾病易感等位基因的频率更高，这可能是瑞典T1D高发的原因。然而，与先前发表的研究结果相反，在同样来自瑞典北部的23名健康志愿者中，我们未能发现基于CT60基因型的sCTLA - 4/flCTLA - 4表达比值存在差异。血清中sCTLA - 4蛋白水平的分析表明，sCTLA - 4蛋白水平与疾病状态或CT60基因型之间没有相关性。
结论
在T1D/AITD与所研究的所有三种多态性之间发现了关联。然而，与先前的研究不同，基于CT60基因型，sCTLA - 4的RNA和蛋白表达水平并无差异。我们的结果并不排除CT60 SNP是T1D或AITD发生过程中的一个重要多态性，但表明有必要进一步研究以阐明CTLA - 4区域对T1D和AITD发生的影响。
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