Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.
Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.
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DOI：
10.1371/journal.pgen.1004123
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发表时间：
2014-02
期刊：
影响因子：
4.5
通讯作者：
Peeters RP
中科院分区：
文献类型：
--
作者：
Medici M;Porcu E;Pistis G;Teumer A;Brown SJ;Jensen RA;Rawal R;Roef GL;Plantinga TS;Vermeulen SH;Lahti J;Simmonds MJ;Husemoen LL;Freathy RM;Shields BM;Pietzner D;Nagy R;Broer L;Chaker L;Korevaar TI;Plia MG;Sala C;Völker U;Richards JB;Sweep FC;Gieger C;Corre T;Kajantie E;Thuesen B;Taes YE;Visser WE;Hattersley AT;Kratzsch J;Hamilton A;Li W;Homuth G;Lobina M;Mariotti S;Soranzo N;Cocca M;Nauck M;Spielhagen C;Ross A;Arnold A;van de Bunt M;Liyanarachchi S;Heier M;Grabe HJ;Masciullo C;Galesloot TE;Lim EM;Reischl E;Leedman PJ;Lai S;Delitala A;Bremner AP;Philips DI;Beilby JP;Mulas A;Vocale M;Abecasis G;Forsen T;James A;Widen E;Hui J;Prokisch H;Rietzschel EE;Palotie A;Feddema P;Fletcher SJ;Schramm K;Rotter JI;Kluttig A;Radke D;Traglia M;Surdulescu GL;He H;Franklyn JA;Tiller D;Vaidya B;de Meyer T;Jørgensen T;Eriksson JG;O'Leary PC;Wichmann E;Hermus AR;Psaty BM;Ittermann T;Hofman A;Bosi E;Schlessinger D;Wallaschofski H;Pirastu N;Aulchenko YS;de la Chapelle A;Netea-Maier RT;Gough SC;Meyer Zu Schwabedissen H;Frayling TM;Kaufman JM;Linneberg A;Räikkönen K;Smit JW;Kiemeney LA;Rivadeneira F;Uitterlinden AG;Walsh JP;Meisinger C;den Heijer M;Visser TJ;Spector TD;Wilson SG;Völzke H;Cappola A;Toniolo D;Sanna S;Naitza S;Peeters RP
自身免疫性甲状腺疾病（AITD）是常见的，影响2-5%的一般人群。甲状腺过氧化物酶抗体（TPOAb）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）和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然未知，我们对18，297名TPOAb阳性个体（1769名TPOAb阳性和16，528名TPOAb阴性）和12，353名TPOAb血清水平个体进行了GWAS荟萃分析，并在8，990名个体中进行了重复。在TPO-rs 11675434、ATXN 2-rs653178和BACH 2-rs 10944479检测到TPOAb阳性的显著相关性（P<5×10−8），在TPO-rs 11675434、MAGI 3-rs 1230666和KALRN-rs 2010099检测到TPOAb水平的显著相关性。研究了这些变异体对（亚临床）甲状腺功能减退和甲状腺功能亢进、甲状腺肿和甲状腺癌的个体和联合效应（遗传风险评分）。具有高遗传风险评分的个体除了TPOAb阳性风险增加（OR：2.18，95% CI 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（OR：1.51，95% CI 1.26-1.82，P = 2.9×10−6），甲状腺肿风险降低（OR：0.77，95% CI 0.66-0.89，P = 6.5×10−4）。 MAGI 3和BACH 2变异体与甲状腺功能亢进风险增加相关，这在Graves病患者的独立队列中得到了重复（OR：1.37，95% CI 1.22-1.54，P = 1.2×10−7和OR：1.25，95% CI 1.12-1.39，P = 6.2×10−5）。 MAGI 3变异也与甲状腺功能减退风险增加相关（OR：1.57，95%CI 1.18-2.10，P = 1.9×10−3）。 第一个针对TPOAb的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。通过这些标记物，我们在一般人群中发现了一个大的亚组，其TPOAbs风险显著增加。结果提供了深入了解为什么甲状腺自身免疫个体最终会或不会发展为甲状腺疾病，因此这些标志物可以预测哪些TPOAb阳性特别有发展为临床甲状腺功能障碍的风险。甲状腺过氧化物酶抗体（TPOAb）的个体具有自身免疫性甲状腺疾病（AITD）的风险增加，AITD在一般人群中常见，并与心血管、代谢和精神病发病率和死亡率增加相关。由于TPOAbs和AITD的致病基因在很大程度上仍然未知，我们对18，297名个体进行了TPOAbs全基因组扫描，并在8，990名个体中进行了复制。在TPO、ATXN 2、BACH 2、MAGI 3和KALRN的变异中检测到显著的关联。携带多种风险变异的个体也有较高的促甲状腺激素水平升高的风险（包括亚临床和明显的甲状腺功能减退症），甲状腺肿的风险降低。MAGI 3和BACH 2变异与甲状腺功能亢进风险增加相关，MAGI 3变异也与甲状腺功能减退风险增加相关。首次全基因组扫描TPOAb发现了5个新的相关位点，其中3个也与临床甲状腺疾病相关。通过这些标记物，我们在一般人群中发现了一个大的亚组，其TPOAbs风险显著增加。这些结果提供了深入了解为什么甲状腺自身免疫个体最终会或不会发展为甲状腺疾病，因此这些标志物可以预测哪些个体特别有发展为临床甲状腺功能障碍的风险。
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. Individuals with thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune thyroid diseases (AITD), which are common in the general population and associated with increased cardiovascular, metabolic and psychiatric morbidity and mortality. As the causative genes of TPOAbs and AITD remain largely unknown, we performed a genome-wide scan for TPOAbs in 18,297 individuals, with replication in 8,990 individuals. Significant associations were detected with variants at TPO, ATXN2, BACH2, MAGI3, and KALRN. Individuals carrying multiple risk variants also had a higher risk of increased thyroid-stimulating hormone levels (including subclinical and overt hypothyroidism), and a decreased risk of goiter. The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, and the MAGI3 variant was also associated with an increased risk of hypothyroidism. This first genome-wide scan 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. These results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which individuals are particularly at risk of developing clinical thyroid dysfunction.
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影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.1016/s0889-8529(05)70130-4
发表时间：
2000-06-01
影响因子：
4.5
作者：
Gough, SCL
通讯作者：
Gough, SCL
影响因子：
--
作者：
Collet, Tinh-Hai;Gussekloo, Jacobijn;Bauer, Douglas C.;den Elzen, Wendy P. J.;Cappola, Anne R.;Balmer, Philippe;Iervasi, Giorgio;Asvold, Bjorn O.;Sgarbi, Jose A.;Voelzke, Henry;Gencer, Baris;Maciel, Rui M. B.;Molinaro, Sabrina;Bremner, Alexandra;Luben, Robert N.;Maisonneuve, Patrick;Cornuz, Jacques;Newman, Anne B.;Khaw, Kay-Tee;Westendorp, Rudi G. J.;Franklyn, Jayne A.;Vittinghoff, Eric;Walsh, John P.;Rodondi, Nicolas
通讯作者：
Rodondi, Nicolas
影响因子：
30.8
作者：
Jin Y;Birlea SA;Fain PR;Ferrara TM;Ben S;Riccardi SL;Cole JB;Gowan K;Holland PJ;Bennett DC;Luiten RM;Wolkerstorfer A;van der Veen JP;Hartmann A;Eichner S;Schuler G;van Geel N;Lambert J;Kemp EH;Gawkrodger DJ;Weetman AP;Taïeb A;Jouary T;Ezzedine K;Wallace MR;McCormack WT;Picardo M;Leone G;Overbeck A;Silverberg NB;Spritz RA
通讯作者：
Spritz RA