Donner H, Rau H, Walfish P G, Braun J, Siegmund T, Finke R, Herwig J, Usadel K H, Badenhoop K
Medical Department I, Klinikum of the J. W. Goethe University, Frankfurt/Main, Germany.
J Clin Endocrinol Metab. 1997 Jan;82(1):143-6. doi: 10.1210/jcem.82.1.3699.
The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.
格雷夫斯病和1型（胰岛素依赖型）糖尿病的遗传易感性由位于6号染色体短臂上的人类白细胞抗原区域中的基因赋予，但据推测还有其他几个基因决定疾病易感性。这些候选基因之一是人类位于2q33染色体上的细胞毒性T淋巴细胞抗原4（CTLA4）。我们研究了CTLA4外显子1多态性（49 A/G）在格雷夫斯病和胰岛素依赖型糖尿病中的分布情况。该密码子17处的二态性导致表达蛋白前导肽中的氨基酸交换（苏氨酸/丙氨酸），并通过聚合酶链反应、单链构象多态性和限制性片段长度多态性分析，对305例格雷夫斯病患者、293例胰岛素依赖型糖尿病患者和325名对照进行了分析。格雷夫斯病患者的丙氨酸等位基因明显多于对照组，无论是纯合子（21%对13%）还是杂合子（53%对46%），而苏氨酸纯合子则较少（26%对42%；P < 2×10⁻⁴）。丙氨酸阳性患者的表型频率（73%）显著高于对照组（58%；P = 10⁻⁴；相对风险 = 2）。胰岛素依赖型糖尿病患者的丙氨酸等位基因作为纯合子（19%）或杂合子（50%；P = 0.01）也明显更多。总之，CTLA4第17密码子处的丙氨酸与格雷夫斯病以及胰岛素依赖型糖尿病的遗传易感性相关。
