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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.
J Clin Endocrinol Metab ; 104(6): 2121-2130, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649410

RESUMO

CONTEXT: Graves disease (GD) is a common thyroid-specific autoimmune disease and one of the most heritable diseases in the population. We present a risk-prediction model, including confirmed, known genetic variants associated with GD. DESIGN: To construct a stable-prediction model, we used known GD susceptibility single nucleotide polymorphisms (SNPs) as markers and trained and tested our model in a cohort of 4897 patients with GD and 5098 healthy controls. We weighted the contribution of each SNP to the disease to calculate the weighted genetic risk score (wGRS) for each individual. The efficiency of this model can be estimated by the area under the curve (AUC) receiver operator characteristic curve and the specificity and sensitivity of each wGRS. RESULTS: With the 20 confirmed GD risk-related SNPs, our wGRS-prediction model could predict patients with GD from the general population (AUC 0.70 [95% CI: 0.69 to 0.71]) and did especially well in predicting patients with GD with persisting thyroid-stimulating hormone receptor antibody positive [pTRAb+; AUC 0.74 (95% CI: 0.72 to 0.76)]. We also evaluated how the four pTRAb+ specific risk SNPs predicted patients with GD with pTRAb+ among all patients with GD [AUC 0.62 (95% CI: 0.61 to 0.63)]. For clinical use, we partitioned subjects in each set into different risk categories to generate the wGRS cutoff of high risk for reference. CONCLUSIONS: Our study provides an approach to predict GD risk in the general population by the calculation of the wGRS of 20 known GD susceptibility variants. The wGRS-prediction model was more stable and convenient, whereas the prediction performance was still modest.

3.
Clin Endocrinol (Oxf) ; 89(6): 840-848, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30176063

RESUMO

OBJECTIVE: We aimed to investigate the six susceptibility loci of GD identified from European population in Chinese Han population and further to estimate the genetic heterogeneity of them in stratification of our GD patients. DESIGN: Dense mapping studies based on GWAS. PATIENTS: A total of 1536 GD patients and 1516 controls in GWAS stage and 1994 GD patients and 2085 controls and 5033 GD patients and 5389 controls in two replication stages. MEASUREMENTS: Based on our previous GWAS data, independently GD-associated SNPs in each region were identified by TagSNP analysis and logistic regression analysis. The association of these SNPs was investigated in 1994 GD patients and 2085 controls, and then, the significantly associated SNPs (P < 0.05) were further genotyped in a second cohort including 5033 GD patients and 5389 controls. RESULTS: After the first replication stage, four SNPs from three regions with Pfirst  < 0.05 were further selected and genotyped in another independent cohort. The association of two SNPs with GD was confirmed in combined Chinese cohorts: rs12575636 at 11q21 (Pcombined  = 7.55 × 10-11 , OR = 1.27) and rs1881145 in TRIB2 at 2p25.1 (Pcombined  = 5.59 × 10-8 , OR = 1.14). Further study disclosed no significant difference for these SNPs between GD subsets. However, eQTL data revealed that SESN3 could be a potential susceptibility gene of GD in 11q21 region. CONCLUSIONS: Out of the six susceptibility loci of GD identified from European population, two risk loci were confirmed in a large Chinese Han population. There is variability in GD genetic susceptibility in different ethnic groups. SESN3 is a potential susceptible gene of GD in 11q21.

4.
Eur J Endocrinol ; 178(6): 623-633, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29650690

RESUMO

OBJECTIVE: Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited. DESIGN AND METHODS: One hundred ten patients with primary CH were recruited in this study. All exons and exon-intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees. RESULTS: Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands. CONCLUSIONS: Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hipotireoidismo Congênito/genética , China , Oxidases Duais/genética , Feminino , Fatores de Transcrição Forkhead/genética , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Iodeto Peroxidase/genética , Masculino , Proteínas de Membrana/genética , Mutação , Fator de Transcrição PAX8/genética , Linhagem , Receptores da Tireotropina/genética , Análise de Sequência de DNA , Tireoglobulina/genética , Disgenesia da Tireoide/genética , Fator Nuclear 1 de Tireoide/genética , Fatores de Transcrição/genética
5.
Oncotarget ; 8(56): 96126-96138, 2017 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-29221192

RESUMO

Background: Studies have shown an association of the UNC5D gene with kidney and bladder cancer and neuroblastoma. We investigated whether UNC5D acts as a tumor suppressor in papillary thyroid carcinoma (PTC). Methods: Primary PTC tumors and matched normal thyroid tissues were obtained from 112 patients to detect UNC5D mRNA by real-time PCR. Genomic DNA sequencing was performed to detect BRAF mutation in PTC tumors. The association between UNC5D expression and clinicopathological data from PTC patients was reviewed retrospectively. PTC-derived cancer cell lines TPC-1 and K1 with stable transfection of UNC5D were used to investigate the functions of UNC5D. Flow cytometry, CCK-8, Transwell assay and scratch tests were used to examine cell cycle distribution, proliferation and migration. Results: The expression of UNC5D was significantly decreased in PTC compared with adjacent normal thyroid tissues. Lower UNC5D expression was significantly associated with aggressive tumor behaviors, such as lymph node metastasis and BRAF mutation. Overexpression of UNC5D significantly suppressed malignant cell behaviors, including cell proliferation and migration, as well as tumor growth in vivo. Conclusions: These findings suggest a potential tumor suppressor role of UNC5D in PTC progression; and provide insight into potential clinical relevance for the prognosis of PTC.

6.
J Clin Endocrinol Metab ; 102(2): 652-660, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27809695

RESUMO

Context: Graves disease (GD) is a common autoimmune disease triggered by genetic predisposition and environmental factors. However, the mechanisms of interaction between genetic and environmental factors contributing to the development of GD remain unknown. Objective: We aimed to identify GD susceptibility variants and genes on Xq21.1 locus and interpret the contribution of interaction between genetic predisposition on Xq21.1 and environmental factors to GD. Design: We performed refining study on Xq21.1 in a 2-stage study and carried out expression quantitative trait locus analysis of the best association signal with GD. Setting and Participants: A total of 4316 GD patients and 4374 sex-matched controls were collected from the Chinese Han population by cooperation with multiple hospitals. Results: We identified that rs3827440 or its linkage single nucleotide polymorphisms (SNPs) were probably the causal variant in the Xq21.1 locus, with the most substantial association with GD in our combined cohorts (P = 2.45 × 10-15). The genotypes of rs3827440 were correlated with the expression of ITM2A in monocytes and peripheral blood mononuclear cells (PBMCs) from healthy volunteers. Notably, the expression of ITM2A in monocytes after lipopolysaccharide (LPS) and interferon-γ (INF-γ) stimulation showed substantial difference among the volunteers that carried different genotypes of rs3827440 (P = 9.40 × 10-7 and P = 1.26 × 10-5 for 24 hours' LPS and INF-γ stimulation, respectively). Moreover, ITM2A expression was significantly decreased in PBMCs from untreated GD patients than that from controls. Conclusion: The results suggest that ITM2A might be a susceptibility gene for GD in the Xq21.1 locus, and environmental factors, such as viral and bacterial infections, probably contribute to GD pathogenesis by interacting with the risk SNP rs3827440 mediating the regulation of ITM2A expression.


Assuntos
Infecções Bacterianas/complicações , Interação Gene-Ambiente , Doença de Graves/etiologia , Doença de Graves/genética , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/genética , Viroses/complicações , China , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Graves/sangue , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
7.
Int J Ophthalmol ; 8(3): 448-52, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26085989

RESUMO

AIM: To investigate the expression and role of nuclear factor κB (NF-κB) in diabetic retinopathy (DR) and its relationship with neovascularization and retinal cell apoptosis. METHODS: A total of 80 male Wistar rats were randomly assigned to control (4, 8, 12 and 16wk, n=10 in each group) and diabetes mellitus (DM) groups (4, 8, 12 and 16wk, n=10 in each group). A diabetic rat model was established by intraperitoneal injection of streptozotocin (60 mg/kg). After 4, 8, 12 and 16wk, rats were sacrificed. Retinal layers and retinal neovascularization growth were stained with hematoxylin-eosin and examined under light microscopy. Cell apoptosis in the retina was detected by TdT-mediated dUTP nick end labeling, and NF-κB distribution and expression in the retina was determined using immunohistochemistry. RESULTS: DM model success rate up to 100%. Diabetes model at each time point after the experimental groupcompared with the control group, the blood glucose was significantly increased, decreased body weight, each time point showed significant differences compared with the control group (P<0.01). After 12wk other pathological changes in the retina of diabetic rats were observed; after 16wk, neovascularization were observed. After 1mo, retinal cell apoptosis was observed. Compared with the control group, NF-κB expression in the DM group significantly increased with disease duration. CONCLUSION: With the prolonging of DM progression, the expression NF-κB increases. NF-κB may be related to retinal cell apoptosis and neovascularization.

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