A common CTLA4 haplotype associated with coeliac disease
A common CTLA4 haplotype associated with coeliac disease
复制标题
DOI：
10.1038/sj.ejhg.5201357
复制
发表时间：
2005-04-01
影响因子：
5.2
通讯作者：
van Heel, DA
中科院分区：
文献类型：
--
作者：
Hunt, KA;McGovern, DPB;van Heel, DA
乳糜泻是一种常见的肠病，具有很强的遗传风险，其特征是饮食中的小麦、黑麦和大麦诱导的T细胞活化。虽然存在与2 q33的重复连锁，但与最有希望的候选基因（CD 28/CTLA 4/ICOS簇）的关联研究结果不一致。CTLA 4在调节T淋巴细胞介导的炎症反应中起关键作用，并且30区域中的变体影响糖尿病和甲状腺疾病的发展。我们对340例白色英国高加索人乳糜泻病例中的CTLA 4变异体（-1722 C/T、-658 T/C、-318 C/T、+49 A/G、+1822 C/T、CT60 A/G）进行基因分型，以标记所有常见单倍型（45%频率）和ICOS变异体（IVS+173 C/T）。腹腔病例的严格确诊标准要求诊断时绒毛萎缩和血清学阳性。总共有973名健康对照可用于SNP，705名可用于CTLA 4单倍型，基于关联分析。乳糜泻与CTLA 4 + 1822 T（P = 0.019）和CT60 G（P = 0.047）等位基因的相关性较弱。与常见CTLA 4单倍型（P = 0.00067，比值比1.41）密切相关，在乳糜泻患者中频率为32.7%，在健康对照组中频率为25.5%。一种常见的CTLA 4单倍型显示与乳糜泻有很强的相关性，并含有多个报道影响免疫功能的等位基因。乳糜泻患者对饮食抗原耐受性的丧失可能部分由调节T细胞反应的共信号基因的遗传变异介导。
Coeliac disease is a common enteropathy with a strong inherited risk characterised by dietary wheat, rye and barley induced T-cell activation. Although there is replicated linkage to 2q33, results are inconsistent from association studies of the most promising candidate genes: the CD28/CTLA4/ICOS cluster. CTLA4 plays a key role in regulating T lymphocyte mediated inflammatory responses, and variants in the 30 region influence development of diabetes and thyroid disease. We genotyped CTLA4 variants ( - 1722 C/T, - 658 T/C, - 318 C/T, +49 A/G, +1822 C/T, CT60 A/G) to tag all common haplotypes (45% frequency) and an ICOS variant ( IVS+173 C/T) in 340 white UK Caucasian coeliac disease cases. Strict ascertainment criteria for coeliac cases required both villous atrophy at diagnosis and positive serology. In total, 973 healthy controls were available for SNP, and 705 for CTLA4 haplotype, based association analyses. Coeliac disease showed weak association with the CTLA4 +1822T ( P = 0.019) and CT60 G ( P = 0.047) alleles. Strong association was seen with a common CTLA4 haplotype ( P = 0.00067, odds ratio 1.41) of frequency 32.7% in coeliac disease and 25.5% in healthy controls. A common CTLA4 haplotype shows strong association with coeliac disease, and contains multiple alleles reported to affect immunological function. Loss of tolerance to dietary antigens in coeliac disease may be mediated in part by heritable variants in co-signalling genes regulating T-cell responses.