Complex Association Analysis of Graves Disease Using a Set of Polymorphic Markers (original) (raw)
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Genetic Determinants of Graves Disease
Molecular Genetics and Metabolism, 2000
Basedow-Graves disease is an autoimmune thyroid syndrome. Genetic factors contribute to the pathogenesis of Graves disease, and current findings confirm that a number of genes may be involved in the development of autoimmune thyrotoxicosis. At present three loci, namely human leukocyte antigen (HLA, 6p21.3), cytotoxic T-lymphocyte-associated esterase-4 (CTLA4, 2q33), and thyroid-stimulating hormone receptor (TSHR, 14q31), are the only well-known genetic determinants for Graves disease. It is difficult to determine clearly the contribution of large multifunctional proteasome genes and transporter genes associated with antigen processing in the disorder, because of strong linkage disequilibrium between these genes and certain HLA alleles. Two recently discovered suspectibility loci, 20q11.2 and Xq21.33-q22, should be studied to find specific genes linked to Graves disease.
A CTLA‐4 gene polymorphism is associated with both Graves' disease and autoimmune hypothyroidism
Clinical Endocrinology, 1997
OBJECTIVEThe autoimmune thyroid diseases, Graves' disease and autoimmune hypothyroidism, result from a complex interaction between genetic, environmental and endogenous factors. The genetic loci conferring susceptibility remain unclear. A recent report has demonstrated an association between a microsatellite polymorphism of the CTLA‐4 gene (allele 106) on chromosome 2q33 and Graves' disease in Caucasian patients in the USA. The aim of the present study was to confirm this association in UK patients and to determine whether this polymorphism is also associated with autoimmune hypothyroidism.DESIGNAnalysis of Caucasian patients with autoimmune thyroid disease from a single clinic, compared to local Caucasian controls.PATIENTSWe studied 112 patients with Graves' disease, 44 with autoimmune hypothyroidism and 91 controls.MEASUREMENTSCTLA‐4 microsatellite gene polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and resolution of the product...
Effect of polymorphism on CTLA-4 gene on Graves' Disease
Annals of Tropical Medicine and Public Health, 2019
Background: Graves is one of autoimmune Thyroid Diseases. Moreover, more than 20 genes polymorphisms are associated with Graves's diseases. Although, the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) genes play an important role in immunity system function, strategies to enhance CTL4 polymorphism gene may be impact on increase Graves' disease. Recent research has revealed that the 49A/G polymorphism in exon 1 has a detrimental EFFECT ON this disease, results in a threonine-to-alanine conversion. Objectives: The study was carried out to investigate and affect allele polymorphism CTL4 gene in Graves' disease in AL-Najaf province. Methods: In our study, 73(48 females and 25 males) individuals who detected Autoimmune hyperthyroidism and twenty healthy as a control groups. All Graves patients were recruited from the hormonal unite at Al-Sadder Medical City, Najaf/Iraq. The control group participating in the study did not have any history of immune diseases and chronic diseases. The study was approved by the ethical committees of Al-Sadder Medical City. Genomic DNA was extracted then polymerase chain reaction fragment length polymorphism (PCR-RFLP) technique is used, follow by Sequence data of polymorphism. Results: Results of this study found that all samples were digested with restriction enzyme Fnu4HI in two fragments (99 and 63) bp. These results indicate that 49 A/G polymorphism GLT4 gene was detected in Graves patients and control. Conclusion: Contrary to expectations, this study did not find a significant difference between Graves patients and healthy individuals in the Najaf city population.
Archivum immunologiae et therapiae experimentalis
Graves' disease ((GD)is an autoimmune disease believed to be caused by a combination of environmental and genetic factors. The gene encoding cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)is one of the candidate genes for conferring susceptibility to thyroid autoimmunity. he aim of the study was to investigate the association between the exon 1 CTLA-4 gene polymorphism A(49)G and susceptibility to GD and Graves ' ophthalmopathy (GO)as well as its severity in a Polish population of the Lower Silesia region. We analyzed the A(49)G exon 1 CTLA-4 gene polymorphism in 99 unrelated Polish patients with GD, of whom 50 had clinically evident GO (NOSPECS class III and higher), and 154 matched healthy subjects from the Lower Silesia region. Genomic DNA was isolated from whole frozen blood using the NucleoSpin Blood kit. A/G transition was genotyped by polymerase chain reaction followed by labeling with the SnaPshot kit of PE Applied Biosystems and detected using an ABI PRISM 310 ...
Clinical Endocrinology, 2010
Objective Graves' disease (GD) is an organ-specific autoimmune disorder. Both immune-modulating genes and thyroid-specific genes are involved in its genetic pathogenesis. It remains unclear, however, how the interactions of various susceptibility genes contribute to the pathogenesis and clinical severity of the disease. The purpose of this study was to investigate the relationships between GD and single nucleotide polymorphisms (SNPs) from CTLA-4, PTPN22, PTPN12, FCRL3 (general autoimmunity genes regulating T and B cells) and the TSHR and Tg genes (diseasespecific genes). Furthermore, we evaluated the influences these SNPs have on the risk and severity of GD. Design and methods This cross-sectional clinical study was performed in 436 GD patients and 316 healthy, gender-matched individuals. Twenty-eight SNPs from CTLA-4, PTPN22, PTPN12, FCRL3, TSHR and Tg genes were genotyped and their associations with the risk and severity of GD were analysed. Results The CTLA-4 rs231779, Tg rs2069550 and PTPN22 rs3789604 SNPs were associated with GD, with additive risk effects present in rs231779 and rs2069550. The ACACC and ACGCT haplotypes, composed of five SNPs in the CTLA-4 gene (rs4553808, rs5472909, rs231775, rs231777 and rs231779), were protective and risk haplotypes respectively. The AA genotype of PTPN22 rs3789604 and AA genotype of FCRL3 rs7528684 were correlated with a reduced risk of GD, while the CC genotype of TSHR rs2239610 was associated with higher serum concentrations of FT4 and TRAb. Logistic analysis confirmed the contribution of CTLA-4 rs231779 to the development of GD. Conclusions These preliminary results demonstrate that the immune-regulatory gene CTLA-4 and the thyroid-specific gene Tg contribute to the risk of Graves' disease with additive effects, while PTPN22 rs3789604 and FCRL3 rs7528684 polymorphisms are protective against the disease. In addition, the TSHR rs2239610 SNP is related to the severity of Graves' disease.
A genome-wide association study identifies two new risk loci for Graves' disease
Nature Genetics, 2011
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 ,536 individuals with Graves' disease (cases) and ,56 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,50 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 × 0 −0 for rs935560) and an intergenic region at 4p4 (P combined = .08 × 0 −3 for rs68325)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p4, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.
2011
Graves' disease (GD) is an organ-specific heterogenous autoimmune disorder associated with T-lymphocyte abnormality affecting the thyroid, eyes and skin. GD is a multifactorial disease that develops as a result of complex interaction between genetic susceptibility genes and environmental factors. It has been suggested that the Cytotoxic T lymphocytes associated molecule-4 (CTLA-4) is a genetic susceptibility candidate for GD. The present study was focused on A/G polymorphism at position 49 in exon-1 of the CTLA-4 gene in 80 GD patients (GP) and 80 sex and age matched healthy individuals among South Indian (Madurai) population. Serum concentrations of thyroid hormone (T 4 , T 3 and TSH) were determined by using automated analyzer. The genomic DNA was isolated from the patient and control groups and genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis using Bbv1. Significant difference (P \ 0.001) was observed in the level of T 3 , T 4 and TSH in GD patients and healthy individuals. The results revealed the CTLA-4 gene G/G genotype to be 32 (40%) in patients and 26 (32.50%) in healthy individuals, A/G genotype to be 37 (46.25%) in patients and 25 (31.25%) in healthy individuals and A/A genotype to be 11 (13.75%) in patients and 29 (36.25%) in healthy individuals. The calculated odds ratio (OR) in individuals with mutant genotype (GG/AG) reveal 3.6 fold risk for GD (95% confidence interval = 1.6-7.8). The mutant ''G'' allele frequency was observed to be 0.63 in GD patients and 0.48 in healthy individuals. Thus the present study demonstrates an association between the CTLA-4 gene polymorphism and Graves' disease. Keywords CTLA-4 gene Á Gene polymorphism Á Susceptibility Á Heterogenous Á Autoimmune disorder Á Graves' disease
Exon1 Polymorphism of ctla-4 Gene in Iranian Patients with Graves' Disease
Autoimmunity, 2003
Polymorphisms in ctla-4 gene have been shown to be associated with the Graves' disease (GD) susceptibility in different populations in the world. This study was undertaken to disclose the probable association of exon-1 polymorphism of ctla-4 with GD in Iranian patients. A49G polymorphism was investigated in 90 patients and 90 age/sex matched normal healthy controls, using PCR-SSCP and PCR-RFLP methods. Frequencies of AA, AG and GG genotypes among patients were found to be 21 (23.3%), 49 (54.5%) and 20 (22.2%) while these frequencies among healthy controls were 30 (33.3%), 53 (58.9%) and 7(7.8%), respectively. A significant increase of GG genotype and G allele was observed in patients ( p ¼ 0:012 and p ¼ 0:025). In conclusion, consistent with the results of most other studies, the presence of a G allele in position 49 of ctla-4 exon-1 is associated with susceptibility to GD in Iranian population.
Clinical Endocrinology, 2003
OBJECTIVE Recent studies have shown that Graves' disease (GD) is linked to and associated with alleles of the cytotoxic T lymphocyte antigen-4 (CTLA4) locus. However, the true pathogenic polymorphism(s) at this locus remains uncertain. Moreover, the association studies of the promoter CTLA4(− − − − 318)C/ T polymorphism in white GD populations have produced conflicting results. Therefore, we have analysed three CTLA4 single nucleotide polymorphisms, including promoter CTLA4(− − − − 318)C/ T , exon 1 CTLA4(49)A /G and intron 1 CTLA4(1822)C/ T in our GD cohort from the UK. PATIENTS AND METHODS We studied 301 white patients with GD and 349 healthy ethnically matched local controls. Amongst GD probands, 129 had significant thyroid-associated orbitopathy (TAO; NOSPECS class III or worse). The CTLA4(− − − − 318)C/T , CTLA4(49)A/G and CTLA4(1822)C/ T polymorphisms were genotyped by using the restriction enzymes Mse I, Bst 71I and Hae III, respectively. RESULTS We found no association between GD and alleles of CTLA4(− − − − 318)C/ T. GD was found to be associated with the G allele of CTLA4(49)A /G