与甲状腺过氧化物酶抗体及临床甲状腺疾病相关的新型基因位点的鉴定。
Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.
作者信息
Medici Marco, Porcu Eleonora, Pistis Giorgio, Teumer Alexander, Brown Suzanne J, Jensen Richard A, Rawal Rajesh, Roef Greet L, Plantinga Theo S, Vermeulen Sita H, Lahti Jari, Simmonds Matthew J, Husemoen Lise Lotte N, Freathy Rachel M, Shields Beverley M, Pietzner Diana, Nagy Rebecca, Broer Linda, Chaker Layal, Korevaar Tim I M, Plia Maria Grazia, Sala Cinzia, Völker Uwe, Richards J Brent, Sweep Fred C, Gieger Christian, Corre Tanguy, Kajantie Eero, Thuesen Betina, Taes Youri E, Visser W Edward, Hattersley Andrew T, Kratzsch Jürgen, Hamilton Alexander, Li Wei, Homuth Georg, Lobina Monia, Mariotti Stefano, Soranzo Nicole, Cocca Massimiliano, Nauck Matthias, Spielhagen Christin, Ross Alec, Arnold Alice, van de Bunt Martijn, Liyanarachchi Sandya, Heier Margit, Grabe Hans Jörgen, Masciullo Corrado, Galesloot Tessel E, Lim Ee M, Reischl Eva, Leedman Peter J, Lai Sandra, Delitala Alessandro, Bremner Alexandra P, Philips David I W, Beilby John P, Mulas Antonella, Vocale Matteo, Abecasis Goncalo, Forsen Tom, James Alan, Widen Elisabeth, Hui Jennie, Prokisch Holger, Rietzschel Ernst E, Palotie Aarno, Feddema Peter, Fletcher Stephen J, Schramm Katharina, Rotter Jerome I, Kluttig Alexander, Radke Dörte, Traglia Michela, Surdulescu Gabriela L, He Huiling, Franklyn Jayne A, Tiller Daniel, Vaidya Bijay, de Meyer Tim, Jørgensen Torben, Eriksson Johan G, O'Leary Peter C, Wichmann Eric, Hermus Ad R, Psaty Bruce M, Ittermann Till, Hofman Albert, Bosi Emanuele, Schlessinger David, Wallaschofski Henri, Pirastu Nicola, Aulchenko Yurii S, de la Chapelle Albert, Netea-Maier Romana T, Gough Stephen C L, Meyer Zu Schwabedissen Henriette, Frayling Timothy M, Kaufman Jean-Marc, Linneberg Allan, Räikkönen Katri, Smit Johannes W A, Kiemeney Lambertus A, Rivadeneira Fernando, Uitterlinden André G, Walsh John P, Meisinger Christa, den Heijer Martin, Visser Theo J, Spector Timothy D, Wilson Scott G, Völzke Henry, Cappola Anne, Toniolo Daniela, Sanna Serena, Naitza Silvia, Peeters Robin P
机构信息
Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy ; Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
出版信息
PLoS Genet. 2014 Feb 27;10(2):e1004123. doi: 10.1371/journal.pgen.1004123. eCollection 2014 Feb.
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<5×10(-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 = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-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 = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-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.
自身免疫性甲状腺疾病（AITD）很常见，影响着2%至5%的普通人群。甲状腺过氧化物酶抗体（TPOAb）呈阳性的个体患自身免疫性甲状腺功能减退症（桥本甲状腺炎）以及自身免疫性甲状腺功能亢进症（格雷夫斯病）的风险增加。由于TPOAb和AITD的可能致病基因在很大程度上仍不明确，我们对18297名个体进行了全基因组关联研究（GWAS）荟萃分析，以确定TPOAb阳性情况（1769名TPOAb阳性者和16528名TPOAb阴性者），并对12353名个体的TPOAb血清水平进行了分析，同时在8990名个体中进行了重复验证。在TPO-rs11675434、ATXN2-rs653178和BACH2-rs10944479位点检测到与TPOAb阳性显著相关（P<5×10⁻⁸），在TPO-rs11675434、MAGI3-rs1230666和KALRN-rs2010099位点检测到与TPOAb水平显著相关。研究了这些变异对（亚临床）甲状腺功能减退和亢进、甲状腺肿和甲状腺癌的个体及联合效应（遗传风险评分）。遗传风险评分高的个体，除了TPOAb阳性风险增加（比值比：2.18，95%置信区间1.68 - 2.81，P = 8.1×10⁻⁸）外，促甲状腺激素水平升高的风险也更高（比值比：1.51，95%置信区间1.26 - 1.82，P = 2.9×10⁻⁶），而甲状腺肿的风险降低（比值比：0.77，95%置信区间0.66 - 0.89，P = 6.5×10⁻⁴）。MAGI3和BACH2变异与甲状腺功能亢进风险增加相关，这在格雷夫斯病患者的独立队列中得到了重复验证（比值比：1.37，95%置信区间1.22 - 1.54，P = 1.2×10⁻⁷；比值比：1.25，95%置信区间1.12 - 1.39，P = 6.2×10⁻⁵）。MAGI3变异还与甲状腺功能减退风险增加相关（比值比：1.57，95%置信区间1.18 - 2.10，P = 1.9×10⁻³）。这项针对TPOAb的首次GWAS荟萃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。利用这些标记物，我们在普通人群中识别出了一个TPOAb风险大幅增加的大亚组。研究结果有助于深入了解甲状腺自身免疫个体最终是否会发展为甲状腺疾病，因此这些标记物可能预测哪些TPOAb阳性个体尤其有发展为临床甲状腺功能障碍的风险。
Zotero 插件