King A L, Moodie S J, Fraser J S, Curtis D, Reid E, Dearlove A M, Ciclitira P J
Gastroenterology Unit, GKT, The Rayne Institute, St. Thomas' Hospital, London, UK.
Eur J Immunogenet. 2003 Dec;30(6):427-32. doi: 10.1111/j.1365-2370.2003.00430.x.
Coeliac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically predisposed individuals. Patients with CD have an increased prevalence of other autoimmune disorders, including type 1 diabetes (T1D) and Graves' disease (GD). CD shares with these conditions certain HLA susceptibility alleles. A number of studies have also shown association of autoimmune diseases, including CD, with the CD28-cytotoxic T lymphocyte antigen 4 (CTLA4)-inducible costimulator (ICOS) region of chromosome 2q33, but until recently the precise causal variant has remained unknown. Recently, it was shown that, in GD, CT60 (+6230G>A), a single nucleotide polymorphism (SNP) at the end of the CTLA4 transcript, is associated with an alteration in the ratio of splice forms of the CTLA4 gene and that this ratio affects disease susceptibility. A similar but weaker association was found with T1D. There is also an independent association of GD and T1D with the SNP MH30 (-23 327G>C), which possibly affects promoter region function. Hypothesizing that CT60 and MH30 may be causal variants in other autoimmune disorders, we investigated these SNPs in CD using 149 family trios and 100 unrelated/unaffected controls. No association was detected with either SNP using both the transmission disequilibrium test (TDT) and case-control methods. Our study appears to have good power to detect moderate genetic effects, but possibly these SNPs exert too weak an effect on risk of CD to have been detected in our sample. Alternatively, the previously noted association of CD with the CTLA4 gene region may be due to different causal variants. Unlike T1D and GD, CD is not a true autoimmune disease, and CD has different associations at the CTLA4 exon 1 SNP +49G>A from all other autoimmune disorders. MH30, CT60, and other SNPs in the region may still warrant further investigation in other CD samples.
乳糜泻（CD）是一种由麸质引发的免疫介导性肠病，发生于具有遗传易感性的个体。CD患者患其他自身免疫性疾病的几率增加，包括1型糖尿病（T1D）和格雷夫斯病（GD）。CD与这些疾病共享某些HLA易感等位基因。多项研究还表明，包括CD在内的自身免疫性疾病与2号染色体2q33区域的CD28 - 细胞毒性T淋巴细胞抗原4（CTLA4）- 诱导共刺激分子（ICOS）相关，但直到最近，确切的致病变异仍不清楚。最近研究表明，在GD中，CTLA4转录本末端的单核苷酸多态性（SNP）CT60（+6230G>A）与CTLA4基因剪接形式比例的改变有关，且该比例影响疾病易感性。在T1D中发现了类似但较弱的关联。GD和T1D还与SNP MH30（-23 327G>C）独立相关，这可能影响启动子区域功能。假设CT60和MH30可能是其他自身免疫性疾病的致病变异，我们使用149个三联体家庭和100个无血缘关系/未患病对照对CD中的这些SNP进行了研究。使用传递不平衡检验（TDT）和病例对照方法均未检测到与任一SNP的关联。我们的研究似乎有足够的能力检测中等程度的遗传效应，但可能这些SNP对CD风险的影响太弱，以至于在我们的样本中未被检测到。或者，之前提到的CD与CTLA4基因区域的关联可能是由于不同的致病变异。与T1D和GD不同，CD并非真正的自身免疫性疾病，且CD在CTLA4外显子1 SNP +49G>A处与所有其他自身免疫性疾病有不同的关联。该区域的MH30、CT60和其他SNP可能仍值得在其他CD样本中进一步研究。
