University of Birmingham Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease
University of Birmingham Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease
复制标题
DOI：
--
复制
发表时间：
2014
期刊：
影响因子：
--
通讯作者：
E. Porcu;G. Pistis;A. Teumer;S. Brown;R. Jensen;R. Rawal;G. Roef;T. Plantinga;S. Vermeulen;
中科院分区：
文献类型：
--
作者：
E. Porcu;G. Pistis;A. Teumer;S. Brown;R. Jensen;R. Rawal;G. Roef;T. Plantinga;S. Vermeulen;
自身免疫性甲状腺疾病(AITD)很常见，占总人口的2%-5%。甲状腺过氧化物酶抗体(TPOAbbs)阳性的个体患自身免疫性甲状腺功能减退症(桥本氏甲状腺炎)和自身免疫性甲状腺机能亢进症(Graves病)的风险增加。由于TPOAb和AITD的可能致病基因仍不清楚，我们对18,297名TPOAb阳性(1769名TPOAb阳性和16,528名TPOAb阴性)和12,353名TPOAb血清水平进行了GWASMeta分析，其中8,990名重复。TPO-rs11675434、ATXN-rs653178、BACH2-rs10944479为TPOAb阳性，TPO-rs11675434、MAGI3-rs1230666、KALRN-rs2010099为显著关联(P，5 6 10 2 8)。研究了这些变异对(亚临床)甲低和甲亢、甲状腺肿大和甲状腺癌的单独和联合效应(遗传风险分数)。遗传风险评分高的个体除了TPOAb阳性的风险增加(OR：2.18，95%CI 1.68~2.81，P=8.16 10 28)外，促甲状腺激素水平升高的风险也高(OR：1.51，95%CI 1.26~1.82，P=2.9 6 10 26，P=2.9 6 10 26)，患甲状腺肿的风险降低(OR：0.77，95%CI 0.66~0.89，P=6.5 6 10 24)。MAGI3和BACH2基因变异与甲状腺功能亢进症的风险增加有关，在Graves病患者的独立队列中出现了这种情况(OR：1.37，95%CI 1.22~1.54，P=1.2 6 10 27，OR：1.25，95%CI 1.12~1.39，P=6.2 6 10 25)。MAGI3基因变异还与甲状腺功能减退的风险增加相关(OR：1.57，95%CI 1.18~2.10，P=1.9 6 10 23)。这项首次对TPOAbs进行的GWASMeta分析确定了五个新的相关基因座，其中三个也与临床甲状腺疾病相关。通过这些标记物，我们在普通人群中发现了TPOAbs风险显著增加的一个大亚群。这些结果为甲状腺自身免疫的个体最终会或不会患上甲状腺疾病提供了洞察力，因此这些标记物可能会预测哪些TPOAb阳性者特别有可能发展为临床甲状腺功能障碍。
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto’s thyroiditis), as well as autoimmune hyperthyroidism (Graves’ disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations ( P , 5 6 10 2 8 ) were detected at TPO -rs11675434, ATXN2 -rs653178, and BACH2- rs10944479 for TPOAb-positivity, and at TPO- rs11675434, MAGI3 -rs1230666, and KALRN -rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P =8.1 6 10 2 8 ), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P =2.9 6 10 2 6 ), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P =6.5 6 10 2 4 ). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves’ disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2 6 10 2 7 and OR: 1.25, 95% CI 1.12–1.39, P =6.2 6 10 2 5 ). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P =1.9 6 10 2 3 ). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.