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1.
JAMA Netw Open ; 2(5): e193348, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050781

RESUMO

Importance: Thyrotoxic periodic paralysis (TPP) is a potentially lethal complication of hyperthyroidism. However, only 1 specific susceptibility locus for TPP has been identified. Additional genetic determinants should be detected so that a prediction model can be constructed. Objective: To investigate the genetic architecture of TPP and distinguish TPP from Graves disease cohorts. Design, Setting, and Participants: This population-based case-control study used a 2-stage genome-wide association study to investigate the risk loci of TPP and weighted genetic risk score to construct a TPP prediction model with data from a Chinese Han population recruited in hospitals in China from March 2003 to December 2015. The analysis was conducted from November 2014 to August 2016. Main Outcomes and Measures: Loci specifically associated with TPP risk and those shared with Graves disease and prediction model of joint effects of TPP-specific loci. Results: A total of 537 patients with TPP (mean [SD] age, 35 [11] years; 458 male) 1519 patients with Graves disease and no history of TPP (mean [SD] age, 38 [13] years; 366 male), and 3249 healthy participants (mean [SD] age, 46 [10] years; 1648 male) were recruited from the Han population by hospitals throughout China. Two new TPP-specific susceptibility loci were identified: DCHS2 on 4q31.3 (rs1352714: odds ratio [OR], 1.58; 95% CI, 1.35-1.85; P = 1.24 × 10-8) and C11orf67 on 11q14.1 (rs2186564: OR, 1.50; 95% CI, 1.29-1.74; P = 2.80 × 10-7). One previously reported specific locus was confirmed on 17q24.3 near KCNJ2 (rs312729: OR, 2.08; 95% CI, 1.83-2.38; P = 8.02 × 10-29). Meanwhile, 2 risk loci (MHC and Xq21.1) were shared by Graves disease and TPP. After 2 years of treatment, the ratio of persistent thyrotropin receptor antibody positivity was higher in patients with TPP than in patients with Graves disease and no history of TPP (OR, 3.82; 95% CI, 2.04-7.16; P = 7.05 × 10-6). The prediction model using a weighted genetic risk score and 11 candidate TPP-specific single-nucleotide polymorphisms had an area under the curve of 0.80. Conclusions and Relevance: These findings provide evidence that TPP is a novel molecular subtype of Graves disease. The newly identified loci, along with other previously reported loci, demonstrate the growing complexity of the heritable contribution to TPP pathogenesis. A complete genetic architecture will be helpful to understand the pathophysiology of TPP, and a useful prediction model could prevent the onset of TPP.

2.
Hum Genet ; 133(5): 661-71, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24346624

RESUMO

The BACH2 gene regulates B cell differentiation and function and has been reported to be a shared susceptibility gene for several autoimmune diseases. Our previous genome-wide association study (GWAS) indicated that several single nucleotide polymorphisms (SNPs) in the BACH2 gene are associated with Graves' disease (GD) in the Chinese Han population; however, the association did not achieve genome-wide significance levels. Recently, this association of BACH2 with GD was confirmed in Caucasians in the UK population, but fine mapping in this region has not yet been reported. Here, we provide a refined analysis of a 331-kb region in the BACH2 gene, which harbors 359 SNPs, using GWAS data from 1,442 GD patients and 1,468 controls. The SNPs rs2474619 and rs9344996 were implied as the independent variants associated with GD by forward and two-locus logistic regression analysis. We genotyped eight out of 10 tagSNPs with P < 1 × 10(-3) in 3,508 GD patients and 3,209 controls, the results also showed that rs2474619 was independently associated with GD in the combined population from GWAS and the second stage (P = 1.81 × 10(-5)). The rs2474619 and rs9344996 were further genotyped in the third stage cohorts, and rs2474619 showed evidence of association with GD at genome-wide significance levels in the combined population (P = 3.28 × 10(-8), odds ratio = 1.13). The association of rs9344996 with GD can be explained by its linkage to rs2474619 in the combined population. Our study clearly demonstrated that BACH2 is a susceptibility gene for GD in the Chinese Han population and further supported rs2474619, in intron 2 of BACH2, is the best association signal with GD. However, the mechanism by which BACH2 confers increased risk of GD requires further study.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Grupos Étnicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Graves/genética , Doenças Autoimunes/genética , Sequência de Bases , China , Primers do DNA , Humanos , Modelos Logísticos , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real
3.
Eur J Endocrinol ; 170(1): 109-19, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24144966

RESUMO

BACKGROUND: Convincing evidence has demonstrated the association of TSH receptor (TSHR) with Graves' disease (GD) in the Chinese Han population. OBJECTIVE: The aim of this study was to identify the causal variants for GD in the region encompassing TSHR by a refining association study. DESIGN AND METHODS: GD patients (1536) and 1516 sex-matched controls were recruited in the first stage, and an additional 3832 GD patients and 3426 sex-matched controls were recruited in the replication stage. Genotyping was performed using Illumina Human660-Quad BeadChips or TaqMan single nucleotide polymorphism (SNP) Genotyping Assays and the Fluidigm EP1 platform. RESULTS: When the results of regression analysis for 74 genotyped SNPs and 922 imputed SNPs in the first-stage cohort were combined, rs179243 and rs3783949 were the probable susceptibility SNPs associated with GD in TSHR. Eleven SNPs, including rs179243 and rs3783949, were selected to further refine the association in the replication study. Finally, rs12101261 and rs179243 were confirmed as independent GD susceptibility variants in the replication and combined populations. Further, we also found that the rate of persistent TSHR autoantibody positivity (pTRAb+) was significantly higher in the GD patients with the susceptible genotypes rs12101261 or rs179243 than in the GD patients carrying the protective genotypes, after the GD patients had been treated for more than 1 year. CONCLUSIONS: These findings indicate that rs12101261 and rs179243 are the possible causal SNPs for GD susceptibility in the TSHR gene and could serve as genetic markers to predict the outcome of pTRAb+ in GD patients.


Assuntos
Predisposição Genética para Doença , Doença de Graves/genética , Polimorfismo de Nucleotídeo Único , Receptores da Tireotropina/genética , Antitireóideos/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China , Estudos de Coortes , Terapia Combinada , Resistência a Medicamentos , Feminino , Estudos de Associação Genética , Loci Gênicos , Doença de Graves/imunologia , Doença de Graves/metabolismo , Doença de Graves/terapia , Humanos , Imunoglobulinas Glândula Tireoide-Estimulantes/análise , Radioisótopos do Iodo/uso terapêutico , Masculino , Compostos Radiofarmacêuticos/uso terapêutico , Receptores da Tireotropina/antagonistas & inibidores , Receptores da Tireotropina/metabolismo , Reprodutibilidade dos Testes
4.
Hum Mol Genet ; 22(16): 3347-62, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23612905

RESUMO

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174-ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3-13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10(-8)). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.


Assuntos
Predisposição Genética para Doença , Doença de Graves/genética , RNA não Traduzido/genética , Fatores de Necrose Tumoral/genética , Sistema do Grupo Sanguíneo ABO/genética , Adulto , Antígenos CD/genética , Sequência de Bases , Estudos de Casos e Controles , Colágeno , DNA Intergênico , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas-G/genética , Família de Moléculas de Sinalização da Ativação Linfocitária , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária
5.
PLoS One ; 8(3): e57758, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23505439

RESUMO

To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring FCRL1-5 and CD5L genes, we carried out a refined association study in the entire FCRL region in 1,536 patients with Graves' disease (GD) and 1,516 sex-matched controls by imputation analysis, logistic regression, and cis-eQTL analysis. Among 516 SNPs with P<0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to FCRL3 expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on FCRL3 expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of FCRL3 whether in PBMCs or its subsets, especially in CD19(+) B cells and CD8(+) T subsets. Next, the combined analysis with 5,300 GD cases and 4,916 control individuals confirmed FCRL3 was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level (P(combined) = 2.27×10(-12) and 7.11×10(-13), respectively). Moreover, the haplotypes with the risk allele A of rs3761959 and risk allele C of rs7528684 were associated with GD risk. Finally, our epigenetic analysis suggested the disease-associated C allele of rs7528684 increased affinity for NF-KB transcription factor. Above data indicated that FCRL3 gene and its proxy SNP rs7528684 may be involved in the pathogenesis of GD by excessive inhibiting B cell receptor signaling and the impairment of suppressing function of Tregs.


Assuntos
Estudo de Associação Genômica Ampla , Doença de Graves/genética , Receptores Fc/genética , Cromossomos Humanos Par 1 , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
6.
Clin Endocrinol (Oxf) ; 79(2): 267-74, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23170961

RESUMO

OBJECTIVE: Associations between IL2RA and various autoimmune diseases have been reported in Caucasians. We investigated whether genetic polymorphisms at the IL2RA locus were associated with Graves' disease (GD) in the Chinese Han population. DESIGN: We performed a genome-wide association study (GWAS) in 1 536 GD patients and 1 516 controls. The 1000 Genomes Project data were adopted as references for imputation analysis. After forward and conditional logistic regressions, we found that rs11256313 was the major risk variant in the CD25/IL2RA region. Thus, we further genotyped rs11256313 in a replication cohort with 3 694 GD patients and 3 510 controls using ABI 7900HT TaqMan Real-Time PCR System. RESULTS: Nine single nucleotide polymorphisms (SNPs) in the IL2RA block were nominally associated with GD in our GWAS (0·01 < P < 0·05). After imputation analysis, 13 imputed SNPs in the IL2RA block were weakly associated with GD (P ≤ 0·05). Logistic regression analysis suggested that the imputed rs11256313 could represent the IL2RA block (P = 0·003). However, we failed to replicate the association of rs11256313 in a larger cohort (P = 0·145). A subphenotype analysis of rs11256313 on thyroid hormone receptor antibody (TRAb) and gender showed that there was no association in any of the subphenotype groups (P > 0·05). CONCLUSIONS: The results suggested that common genetic polymorphisms at IL2RA do not exert a significant genetic effect on the development of GD in the Chinese Han population. Previously reported associations between CD25/IL2RA and autoimmune diseases including GD in Caucasians again imply that heterogeneity exists in different ethnic populations.


Assuntos
Doença de Graves/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Grupo com Ancestrais do Continente Asiático/genética , China/epidemiologia , Grupos Étnicos/genética , Estudo de Associação Genômica Ampla , Genótipo , Doença de Graves/epidemiologia , Humanos , Polimorfismo de Nucleotídeo Único
7.
Mol Cell Biochem ; 360(1-2): 321-8, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21938403

RESUMO

Mimecan, a secretary protein that is expressed in mouse and human pituitary corticotroph cells, is up-regulated by glucocorticoids (GC) in the corticotroph cells via classical glucocorticoid receptor (GR) pathways. In this study, we further explore the GC mechanism for mimecan expression in these cells. Five putative GR response elements (GREs) were identified in ~2 kb of the mimecan promoter by programme analysis. An EMSA assay further indicated that these putative GREs were bound by the GR. Moreover, three proximal GREs are conserved between species. Although luciferase assays showed that the -1474/+43 region of the mimecan promoter achieved the highest expression of mimecan, the -803/+43 mimecan promoter region was sufficient for the GC-mediated expression of mimecan. The mutations of three conserved GREs located in the -1474/+43 mimecan promoter region did not affect mimecan transcription, which suggests that the effects of GC on mimecan are independent of the GREs in the promoter. In addition, cycloheximide, a protein synthesis inhibitor, blocked GC-induced mimecan expression in AtT-20 cells. Taken together, these results suggest that, although there are 3-5 GREs in the mimecan promoter, GC may regulate mimecan transcription indirectly through the synthesis of intermediate proteins and not through the GREs in pituitary corticotroph cells.


Assuntos
Corticotrofos/metabolismo , Glucocorticoides/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Transcrição Genética , Animais , Sequência de Bases , Linhagem Celular , Sequência Conservada , Regulação da Expressão Gênica , Glucocorticoides/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Dados de Sequência Molecular , Receptores de Glucocorticoides/metabolismo , Elementos de Resposta
8.
Nat Genet ; 43(9): 897-901, 2011 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-21841780

RESUMO

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Doença de Graves/genética , Receptores da Tireotropina/genética , Autoanticorpos/sangue , Feminino , Estudo de Associação Genômica Ampla , Doença de Graves/epidemiologia , Doença de Graves/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Masculino , Dados de Sequência Molecular , Receptores da Tireotropina/imunologia , Risco
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