Allelic variant in CTLA4 is associated with thyroid failure and faster β‐cell exhaustion in latent autoimmune diabetes in adults CTLA4等位基因变异与成人迟发型自身免疫性糖尿病患者的甲状腺功能衰竭以及β‐细胞加速衰竭有关

Background The aim of the study was to investigate the role of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) G6230A variant on the susceptibility of latent autoimmune diabetes in adults (LADA) as a whole and in the subset of patients who share autoimmune thyroid disease (AITD). Methods The study included 202 LADA, 1373 patients with early onset type 1 diabetes (T1D), 130 patients with late-onset T1D, 188 patients with non-autoimmune diabetes and 1904 healthy controls. Thyrotropin (thyrotropin-stimulating hormone; TSH) and antibodies against thyroid peroxidase were analyzed in all patients. The CTLA4 G6230A variant was assessed in LADA, early and late-onset T1D patients as well as in the controls. Results The frequency of CTLA4 G alleles and genotypes in LADA patients did not differ significantly from that in the other groups, regardless of its association with AITD. We found an increased frequency of G allele-containing genotypes within LADA patients who had higher TSH compared with those with normal TSH (P = 0.002). Moreover, LADA patients carrying G allele-containing genotypes were more likely to require insulin therapy within 4 years of diagnosis (P = 0.002). Conclusions The G6230A CTLA4 variant does not confer susceptibility to LADA in Sardinian patients even when associated with AITD. However, it helps identify a particular subset of LADA patients with more clinically severe disease, both for thyroid dysfunction and diabetes. 摘要 背景：本研究的目的是调查细胞毒性T淋巴细胞相关蛋白-4（cytotoxic T-lymphocyte-associated protein 4，CTLA4）G6230A变异对成人迟发型自身免疫性糖尿病（latent autoimmune diabetes in adults，LADA）整体易感性的影响，以及对合并自身免疫性甲状腺疾病（autoimmune thyroid disease，AITD）的亚组患者的影响。 方法：这项研究总共入选了202名LADA患者、1373名早发型的1型糖尿病患者、130名迟发型的1型糖尿病患者、188名非自身免疫性糖尿病患者以及1904名健康对照者。测定所有患者的甲状腺激素（促甲状腺激素；TSH）以及抗甲状腺过氧化物酶抗体水平。在LADA、早发型与迟发型1型糖尿病患者以及对照者中评估CTLA4 G6230A是否出现变异。 结果：LADA患者的CTLA4 G等位基因频率以及基因型与其它组患者相比没有显著性差异，无论是否合并有AITD。我们发现在LADA患者组中，与TSH正常的患者相比，TSH较高患者的基因型出现含有G等位基因的频率明显更高（P = 0.002）。此外，携带含有G等位基因的基因型的LADA患者在诊断后的4年内更有可能需要使用胰岛素治疗（P = 0.002）。 结论：在撒丁岛患者中G6230A CTLA4变异并不会导致患者易感LADA，即使患者合并有AITD。然而，它能帮助我们从LADA患者中鉴别出有可能出现更严重的临床疾病的特殊亚组患者，包括甲状腺功能减退与糖尿病。