Ban Y, Davies T F, Greenberg D A, Kissin A, Marder B, Murphy B, Concepcion E S, Villanueva R B, Barbesino G, Ling V, Tomer Y
Division of Endocrinology, Diabetes, and Bone Diseases, Mount Sinai School of Medicine Box 1055, New York, NY 10029, USA.
Genes Immun. 2003 Dec;4(8):586-93. doi: 10.1038/sj.gene.6364018.
The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G single-nucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P=0.01, OR=1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.
位于2q33的细胞毒性T淋巴细胞相关抗原4（CTLA-4）基因与自身免疫性甲状腺疾病（AITD）相关。我们早期对56个家族的研究表明，2q33与甲状腺抗体（TAbs）的存在存在连锁关系。本研究的目的是确认2q33区域与TAbs的连锁关系，对该区域进行精细定位，并研究ICOS基因。我们在一个由99个多基因座AITD-TAb家族（529名个体）组成的扩展数据集中进行了连锁研究。在2q33的标记D2S325处获得了最高的两点LOD分数2.9。为了对该基因座进行精细定位，我们对238名白种人AITD患者和137名对照者在包含CTLA-4、CD28和ICOS基因的连锁基因座中的另外五个标记进行了基因分型。CTLA-4第49位的A/G单核苷酸多态性与AITD相关（P=0.01，OR=1.5），而CD28和ICOS内部的标记则不相关。功能研究表明，G等位基因与CTLA-4对T细胞增殖的抑制作用降低有关。我们得出以下结论：（1）2q33基因座中的AITD基因是CTLA-4基因，而不是CD28或ICOS基因；（2）G等位基因与CTLA-4功能降低有关。
