Zhernakova Alexandra, Eerligh Peter, Barrera Pilar, Wesoly Joanna Z, Huizinga Tom W J, Roep Bart O, Wijmenga Cisca, Koeleman Bobby P C
Department of Medical Genetics, University Medical Centre, Wilhelmina Children's Hospital, PO Box 85090, 3508, AB, Utrecht, The Netherlands.
Hum Genet. 2005 Oct;118(1):58-66. doi: 10.1007/s00439-005-0006-z. Epub 2005 Jul 16.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is an important negative regulator of T-cell response and its genetic association with type 1 diabetes (T1D) has recently been demonstrated. The frequent co-association of autoimmune diseases (AID) and the implication from multiple genome scans that the CTLA4 gene region is a general autoimmune region, led us to study the role of CTLA4 in independent cohorts of T1D, coeliac disease (CD) and rheumatoid arthritis (RA) patients. We present independent data that confirm the association of CTLA4 in Dutch patients with juvenile onset T1D and show differential association of CTLA4 with CD and RA. The CTLA4 gene polymorphisms were tested for association in 350 T1D, 310 CD, 520 RA patients and 900 controls. In addition, 218 families were tested by the transmission disequilibrium test (TDT). T1D patients showed the highest association with the MH30G: -1147C: +49G: CT60G: JO37_3G (haplotype 2) in both a case/control cohort (P=0.002, OR=1.42) and by TDT (P=0.02, OR=1.43). In contrast, this haplotype showed no association in the RA and CD cohorts. However, we observed an increased frequency of the MH30G: -1147T: +49A: CT60G: JO37_3A (haplotype 3) in the CD patients diagnosed at a young age (OR=1.6, P=0.026, P (c)=0.052). Furthermore, when T1D and CD patients were stratified based on the HLA risk, the T1D susceptible CTLA4 haplotype 2 was over-represented in the high HLA-risk T1D and CD groups. In conclusion, we confirmed association between CTLA4 haplotype 2 and T1D in the Dutch population. Association with another CTLA4 haplotype (haplotype 3) was confirmed for CD, but only in those patients who had an early age of expression. No effect was found between RA and CTLA4. The association of the CTLA4 haplotype 2 with the high-risk HLA genotype in T1D and CD, which share DQ2 as the one of high-risk alleles, might provide a clue to understanding the common genetic background of AID.
细胞毒性T淋巴细胞相关抗原4（CTLA4）是T细胞反应的重要负调节因子，最近已证实其与1型糖尿病（T1D）存在基因关联。自身免疫性疾病（AID）的频繁共关联以及多项基因组扫描结果提示CTLA4基因区域是一个常见的自身免疫区域，这促使我们研究CTLA4在T1D、乳糜泻（CD）和类风湿关节炎（RA）患者独立队列中的作用。我们提供的独立数据证实了CTLA4在荷兰青少年起病的T1D患者中的关联，并显示CTLA4与CD和RA存在差异关联。对350例T1D患者、310例CD患者、520例RA患者和900名对照进行了CTLA4基因多态性的关联测试。此外，通过传递不平衡检验（TDT）对218个家庭进行了检测。在病例/对照队列（P = 0.002，OR = 1.42）和TDT检测中（P = 0.02，OR = 1.43），T1D患者与MH30G: -1147C: +49G: CT60G: JO37_3G（单倍型2）的关联最为显著。相比之下，该单倍型在RA和CD队列中无关联。然而，我们观察到在幼年诊断的CD患者中，MH30G: -1147T: +49A: CT60G: JO37_3A（单倍型3）的频率增加（OR = 1.6，P = 0.026，P（c）= 0.052）。此外，当根据HLA风险对T1D和CD患者进行分层时，T1D易感的CTLA4单倍型2在高HLA风险的T1D和CD组中过度表达。总之，我们证实了荷兰人群中CTLA4单倍型2与T1D之间的关联。CD与另一种CTLA4单倍型（单倍型3）的关联得到证实，但仅在那些发病年龄较早的患者中。未发现RA与CTLA4之间存在关联。CTLA4单倍型2与T1D和CD中的高风险HLA基因型相关，这两种疾病都将DQ2作为高风险等位基因之一，这可能为理解AID的共同遗传背景提供线索。
