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Biomedical subjects

J A Franklyn

Publications and source records attributed to J A Franklyn.

At least 19 recordsLinked to original sources
PubMed2006

Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity.

Genetic instability (GI) is a hallmark feature of tumor development. Securin, also known as pituitary tumor transforming gene (PTTG), is a mitotic checkpoint protein which is highly expressed in numerous cancers, is associated with tumor invasiveness, and induces GI in thyroid cells. We used fluorescence inter-simple sequence repeat PCR to assess GI caused primarily by DNA breakage events in 19 colorectal tumors. GI values ranged significantly, with Dukes' stage C&D colorectal tumors exhibiting greater GI and higher securin expression than Dukes' stage A&B tumors. Consistent with these findings, we observed a dose-dependent increase in GI in HCT116 cells in response to securin overexpression, as well as in non-transformed human fibroblasts. As securin has been implicated in a novel DNA repair pathway in fission yeast, we investigated its potential role in chemotoxic DNA damage response pathways in mammalian cells, using host cell reactivation assays. Securin overexpression in HCT116 cells inhibited etoposide-induced double-stranded DNA damage repair activity, and repressed Ku heterodimer function. Additionally, we observed that securin and Ku70 showed a reciprocal cytosol-nuclear translocation in response to etoposide-induced dsDNA damage. Our data suggest that, by repressing Ku70 activity and inhibiting the non-homologous end-joining dsDNA repair pathway, securin may be a critical gene in the development of GI in colorectal cancer.

Animals↗
PubMed2006

Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype.

CONTEXT: Both genetic and environmental factors contribute to susceptibility to Graves' disease (GD) and Hashimoto's thyroiditis (HT), as well as disease manifestations. OBJECTIVE: The objective of the study was to define how endogenous/environmental factors contribute to variation in phenotype. DESIGN/SETTING: This was a multicenter cohort study. PATIENTS/OUTCOME MEASURES: We prospectively collected clinical/biochemical data as part of the protocol for a United Kingdom DNA collection for GD and HT. We investigated, in 2805 Caucasian subjects, whether age at diagnosis, gender, family history (FH), smoking history, and presence of goiter influenced disease manifestations. RESULTS: For 2405 subjects with GD, the presence of goiter was independently associated with disease severity (serum free T4 at diagnosis) (P < 0.001). Free T4 (P < 0.05) and current smoking (P < 0.001) were both independent predictors of the presence of ophthalmopathy. Approximately half of those with GD (47.4% of females, 40.0% of males) and HT (n = 400) (56.4% of females, 51.7% of males) reported a FH of thyroid dysfunction. In GD, a FH of hyperthyroidism in any relative was more frequent than hypothyroidism (30.1 vs. 24.4% in affected females, P < 0.001). In HT, a FH of hypothyroidism was more common than hyperthyroidism (42.1 vs. 22.8% in affected females, P < 0.001). For GD (P < 0.001) and HT (P < 0.05), a FH was more common in maternal than paternal relatives. The reporting of a parent with thyroid dysfunction (hyper or hypo) was associated with lower median age at diagnosis of both GD (mother with hyperthyroidism, P < 0.001) and HT (father with hypothyroidism, P < 0.05). In GD and HT, there was an inverse relationship between the number of relatives with thyroid dysfunction and age at diagnosis (P < 0.01). CONCLUSIONS: Marked associations among age at diagnosis, disease severity, goiter, ophthalmopathy, smoking, and FH provide evidence for interactions between genetic and environmental/endogenous factors; understanding these may allow preventive measures or better tailoring of therapies.

Adolescent↗
PubMed2006

Pituitary tumor transforming gene (PTTG) stimulates thyroid cell proliferation via a vascular endothelial growth factor/kinase insert domain receptor/inhibitor of DNA binding-3 autocrine pathway.

CONTEXT: Vascular endothelial growth factor (VEGF) exerts its biological effects by binding to the tyrosine kinase receptors VEGF receptor type 1 (VEGFR1/Flt-1) and VEGFR2 (Flk-1/KDR). Kinase insert domain receptor (KDR) is the critical receptor controlling proliferation and migration of endothelial cells and has been shown to be expressed in some nonendothelial cells. We recently reported that the proangiogenic pituitary tumor transforming gene (PTTG) stimulates VEGF and up-regulates inhibitor of DNA binding-3 (ID3), an important gene in VEGF-dependent angiogenesis. OBJECTIVE: Our objective was to test whether VEGF, ID3, and KDR confer a PTTG-mediated effect on thyroid cell growth. DESIGN: Gene expression, MAPK stimulation, and cell proliferation were assessed in follicular thyroid cancer FTC133 cells. Gene expression and clinical associations were determined in 21 normal and 38 tumorous thyroid specimens (nine follicular and 29 papillary). RESULTS: ID3 correlated with VEGF mRNA expression in our series of thyroid cancers, which also showed up-regulated KDR mRNA. Stimulation of FTC133 cells with exogenous VEGF enhanced ID3 expression, which could be abrogated by the KDR-specific inhibitor ZM323881, suggesting that VEGF regulation of ID3 is KDR dependent. PTTG significantly correlated with KDR mRNA expression in our thyroid cancer cohort and up-regulated KDR and VEGF expression in FTC133 cells. Finally, cells transfected with PTTG demonstrated increased cell proliferation and phosphorylation of MAPK, which was abrogated by ZM323881. CONCLUSIONS: We report the presence of a VEGF/KDR/ID3-dependent autocrine pathway in FTC133 thyroid cells. By up-regulating both VEGF and KDR expression, we propose a novel PTTG-mediated proliferative pathway that may be critical to thyroid cancer growth and progression.

Adenocarcinoma, Follicular↗
PubMed2006

Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration.

CONTEXT: Thyroid nodules and goiter are common, and fine-needle aspiration biopsy (FNAB) is the first investigation of choice in distinguishing benign from malignant disease. OBJECTIVE: The objective of the study was to assess whether simple clinical and biochemical parameters can predict the likelihood of thyroid malignancy in subjects undergoing FNAB. DESIGN: The design was a prospective cohort. SETTING: The study was conducted at a single secondary/tertiary care clinic. PARTICIPANTS: One thousand five hundred consecutive patients without overt thyroid dysfunction (1304 females and 196 males, mean age 47.8 yr) presenting with palpable thyroid enlargement between 1984 and 2002 were evaluated by FNAB of the thyroid. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES: Goiter type was assessed clinically and classified as diffuse in 183, multinodular in 456, or solitary nodule in 861 cases. Serum TSH concentration at presentation was measured in a sensitive assay in patients presenting after 1988 (n = 1183). The final cytological or histological diagnosis was determined after surgery (n = 553) or a minimum 2-yr clinical follow-up period (mean 9.5 yr, range 2-18 yr). RESULTS: The overall sensitivity and specificity of FNAB in predicting malignancy were 88 and 84%, respectively. The risk of diagnosis of malignancy rose in parallel with the serum TSH at presentation, with significant increases evident in patients with serum TSH greater than 0.9 mU/liter, compared with those with lower TSH. Binary logistic regression analysis revealed significantly increased adjusted odds ratios (AORs) for the diagnosis of malignancy in subjects with serum TSH 1.0-1.7 mU/liter, compared with TSH less than 0.4 mU/liter [AOR 2.72, 95% confidence interval (CI) 1.02-7.27, P = 0.046], with further increases evident in those with TSH 1.8-5.5 mU/liter (AOR 3.88, 95% CI 1.48-10.19, P = 0.006, compared with TSH < 0.4 mU/liter) and greater than 5.5 mU/liter (AOR 11.18, 95% CI 3.23-8.63, P < 0.001, compared with TSH < 0.4 mU/liter). Males (AOR 1.8, 95% CI 1.04-3.1, P = 0.04), younger patients (AOR 1.1, 95% CI 1.01-1.15, P = 0.025), and those with clinically solitary nodules (AOR 2.53, 95% CI 1.5-4.28, P = 0.001) were also at increased risk. Based on these findings, a formula to predict the risk of the diagnosis of thyroid malignancy in individual patients, taking into account their gender, age, goiter type determined clinically, and serum TSH, was calculated. CONCLUSIONS: The risk of malignancy in a thyroid nodule increases with serum TSH concentrations within the normal range. In addition to patient's gender, age, and goiter type, the serum TSH concentration at presentation is an independent predictor of the presence of thyroid malignancy. We propose that these simple clinical and biochemical factors can serve as an adjunct to FNAB in predicting risk of malignancy.

Adolescent↗
PubMed2006

Pituitary tumor-transforming gene regulates multiple downstream angiogenic genes in thyroid cancer.

CONTEXT: Pituitary tumor-transforming gene (PTTG) is a multifunctional protein involved in several tumorigenic mechanisms, including angiogenesis. PTTG has been shown to promote angiogenesis, a key rate-limiting step in tumor progression, by up-regulation of fibroblast growth factor-2 and vascular endothelial growth factor. OBJECTIVE: To investigate whether PTTG regulates other angiogenic genes in thyroid cells, we performed angiogenesis-specific cDNA arrays after PTTG transfection. Two of the genes [inhibitor of DNA binding-3 (ID3) and thrombospondin-1 (TSP-1)] which showed differential expression in primary thyroid cells were validated in vitro and in vivo. RESULTS: TSP-1 showed a 2.5-fold reduction and ID3 showed a 3.5-fold induction in expression in response to PTTG overexpression in vitro. Conversely, suppression of PTTG with small interfering RNA was associated with a 2-fold induction of TSP-1 and a 2.2-fold reduction in ID3 expression. When we examined TSP-1 and ID3 expression in 34 differentiated thyroid cancers, ID3 was significantly increased in tumors compared with normal thyroid tissue. Furthermore, ID3 expression was significantly higher in follicular thyroid tumors than in papillary tumors. Although mean TSP-1 expression was not altered in cancers compared with normal thyroids, we observed a significant independent association between TSP-1 expression and early tumor recurrence, with recurrent tumors demonstrating 4.2-fold lower TSP-1 expression than normal thyroid tissues. CONCLUSION: We have identified ID3 and TSP-1 as two new downstream targets of PTTG in thyroid cancer. We propose that PTTG may promote angiogenesis by regulating the expression of multiple genes with both pro- and antiangiogenic properties and may thus be a key gene in triggering the angiogenic switch in thyroid tumorigenesis.

Cell Line, Tumor↗
PubMed2006

Lack of association between serum TSH or free T4 and body mass index in euthyroid subjects.

BACKGROUND: There is ongoing debate regarding the influence of minor changes in thyroid status within the normal range and body mass index (BMI). Overt thyroid dysfunction is well recognized to affect weight, but the influence of minor perturbations of thyroid function remains unclear. AIM OF THE STUDY: To examine in euthyroid subjects the association of serum concentrations of TSH and free T4 within the normal range and BMI. To compare serum TSH and free T4 concentrations in nonobese and obese subjects. SUBJECTS AND METHODS: A cohort of 401 euthyroid subjects with normal serum TSH (361 females, 40 males, mean age 48.2 years) who had been referred to a Thyroid Clinic due to the presence of a thyroid nodule or goitre. Measurements of serum TSH and free T4 were recorded, together with BMI (calculated from weight and height). Associations between measures of TSH, free T4 and BMI were investigated. RESULTS: There was no association between either serum TSH or free T4 concentration when considered as a continuous variable and BMI, and no difference in BMI when subjects were categorized according to serum TSH or free T4. There was also no difference in serum TSH or free T4 between lean and obese euthyroid subjects. Evidence of thyroid autoimmunity indicated by the presence of antibodies to thyroid peroxidase was likewise not associated with a difference in BMI. CONCLUSION: This study provides no evidence for an association between thyroid status within the normal range and BMI.

Antibodies↗
PubMed2006

Association of the BTNL2 rs2076530 single nucleotide polymorphism with Graves' disease appears to be secondary to DRB1 exon 2 position beta74.

OBJECTIVE: The HLA region encodes numerous immune response genes, with the DR/DQ molecules consistently associated with autoimmune disease (AID). Recent studies in sarcoidosis have identified association of a single nucleotide polymorphism (SNP) rs2076530 within BTNL2, a potential T-cell inhibitor, independent of the known DRB1 association. The aim of this study was to investigate the association rs2076530 with disease in a large UK Caucasian Graves' disease (GD) dataset. DESIGN: A case control association study of the rs2076530 polymorphism. PATIENTS: Eight hundred sixty-four Graves' disease patients and 864 controls. MEASUREMENTS: Tests for association with disease. RESULTS: We detected association of rs2076530 within a large GD dataset [OR = 1.32 (95% CI = 1.14-1.52)], however, linkage disequilibrium (LD) analysis revealed association of rs2076530 to be secondary to the previously established DRB1 exon 2 encoded position beta74 effect although a rare haplotype effect, including both loci, cannot be excluded. CONCLUSIONS: BTNL2 may be a sarcoidosis-specific susceptibility loci, although only extensive examination of the whole HLA region in different inflammatory/AIDs will enable DR/DQ independent HLA effects to be determined.

Butyrophilins↗
PubMed2006

Use of Tag single nucleotide polymorphisms (SNPs) to screen PTPN21: no association with Graves' disease.

OBJECTIVE: The protein-tyrosine-phosphate nonreceptor 22 gene (PTPN22) has recently been identified as a susceptibility locus for a number of autoimmune diseases including Graves' disease (GD). PTPN21 is another member of the PTPN family and its gene PTPN21 maps to the first reported region of genetic linkage to GD, GD-1, on chromosome 14q31. The aim of this study was to determine whether PTPN21 is acting as a GD susceptibility locus in UK Caucasian subjects. DESIGN: A case control association study of seven Tag single nucleotide polymorphisms (SNPs) (rs1469602, rs8007288, rs1998670, rs11622270, rs2274736, rs2295136 and rs366476) selected to predict 51 un-genotyped polymorphisms present within PTPN21. PATIENTS: Unrelated Caucasian patients of UK origin with GD and ethnically and gender matched control subjects with no family history of autoimmune disease were recruited. In total, DNA was obtained from 768 GD patients and 768 control subjects. RESULTS: No association of any of the seven Tag SNPs was detected with GD. Preliminary evidence of association of rs2274736 was found with younger age of GD onset (0-30 years) (OR = 1. 48 [95% CI = 1.11-1.97]). No other correlations with clinical phenotype or previously established susceptibility loci were detected. CONCLUSIONS: Using a Tag SNP approach we screened PTPN21 as a susceptibility locus for GD and found no evidence for association with disease. Preliminary evidence for association of rs2274736 with younger age of GD onset requires replication in similar sized data sets to exclude a false positive result. Methods such as the Tag SNP approach significantly reduce the amount of genotyping required when screening candidate loci, including those within regions of chromosomal linkage.

Adolescent↗
PubMed2006

Monocarboxylate transporter 8 expression in the human placenta: the effects of severe intrauterine growth restriction.

Thyroid hormones (THs) are essential for normal fetal development, with even mild perturbation in maternal thyroid status in early pregnancy being associated with neurodevelopmental delay in children. Transplacental transfer of maternal THs is critical, with increasing evidence suggesting a role for 3,3',5-tri-iodothyronine (T3) in development and function of the placenta itself, as well as in development of the central nervous and other organ systems. Intrauterine growth restriction (IUGR) is associated with fetal hypothyroxinaemia, a factor that may contribute to neurodevelopmental delay. The recent description of monocarboxylate transporter 8 (MCT8) as a powerful and specific TH membrane transporter, and the association of MCT8 mutations with profound neurodevelopmental delay, led us to explore MCT8 expression in placenta. We describe the expression of MCT8 in normal human placenta throughout gestation, and in normal third-trimester placenta compared with that associated with IUGR using quantitative reverse transcriptase PCR. MCT8 mRNA was detected in placenta from early first trimester, with a significant increase with advancing gestation (P=0.007). In the early third trimester, MCT8 mRNA was increased in IUGR placenta compared with normal samples matched for gestational age (P<0.05), but there was no difference between IUGR and normal placenta in the late third trimester. Western immunoblotting findings in IUGR and normal placentae were in accord with mRNA data. MCT8 immunostaining was demonstrated in villous cytotrophoblast and syncytiotrophoblast as well as extravillous trophoblast cells from the first trimester onwards with increasingly widespread immunoreactivity seen with advancing gestation. In conclusion, expression of MCT8 in placenta from early gestation is compatible with an important role in TH transport during fetal development and a specific role in placental development. Altered expression in placenta associated with IUGR may reflect a compensatory mechanism attempting to increase T3 uptake by trophoblast cells.

Adult↗
PubMed2005

Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves' disease.

CONTEXT: Recently six DNA variants, two of which (M55V and 001Msp) are present in nuclear factor-kappaB inhibitors SUMO-4 and MAP3K7IP2 and four of which (fcrl3_3, fcrl3_4, fcrl3_5, and fcrl3_6) modulate nuclear factor-kappaB binding and production of the B cell surface molecule FCRL3, have been reported to be associated with a number of autoimmune diseases. OBJECTIVE: The aim of this study was to investigate the association of these polymorphisms with disease in a large UK Caucasian Graves' disease (GD) data set. DESIGN: The study was a case-control association study of six polymorphisms. SETTING: The study was conducted at a UK academic department of medicine. PATIENTS OR PARTICIPANTS: Study population included 1056 GD patients and 864 controls. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Tests for association with disease were measured. RESULTS: No association with disease was found for the M55V single-nucleotide polymorphism (SNP). Association was, however, found between GD and the 001Msp SNP [odds ratio (OR) 1.19 (95% confidence interval [CI]) 1.03-1.37], fcrl3_3 SNP [OR 1.17 (95% CI 1.02-1.34)], fcrl3_5 SNP [OR 1.18 (95% CI 1.04-1.35)], and fcrl3_6 SNP [OR 1.20 (95% CI 1.05-1.36)]. The 001Msp SNP was found to be associated with the presence of TSH receptor autoantibodies [OR 1.75 (95% CI 1.09-2.79)]. CONCLUSION: Functional evidence suggests that the 001Msp, fcrl3_3, fcrl3_5, and fcrl3_6 SNPs could cause changes in B cell signaling and activation pathways that could account for their association with GD. Further replication in independent data sets and fine mapping of the surrounding gene regions are needed to confirm the magnitude of the effect and location of the etiological variant(s) present within these gene regions.

Adaptor Proteins, Signal Transducing↗
PubMed2005

A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease.

CONTEXT: Autoimmune thyroid diseases (AITD), comprising Graves' disease and autoimmune hypothyroidism, are characterized by loss of immunological self-tolerance to thyroid antigens. These are complex diseases arising from a combination of genetic and environmental factors. An understanding of the genetic susceptibility factors for AITD could help to target treatments more effectively and identify people at risk for these conditions. OBJECTIVE: The objective of this study was to identify regions of genetic linkage to AITD that could potentially harbor genetic susceptibility factors for these conditions. DESIGN: The study design was a genome-wide screen performed on affected relative pairs with AITD. SETTING: Patients were recruited through hospital endocrinology clinics. PARTICIPANTS: Some 1119 Caucasian relative pairs affected with AITD (Graves' disease or autoimmune hypothyroidism) were recruited into the study. INTERVENTION: Blood samples were obtained from each participant for DNA analysis, and clinical questionnaires were completed. MAIN OUTCOME MEASURE: The study aimed to identify regions of genetic linkage to AITD. RESULTS: Three regions of suggestive linkage were obtained on chromosomes 18p11 (maximum LOD score, 2.5), 2q36 (maximum LOD score, 2.2), and 11p15 (maximum LOD score, 2.0). No linkage to human leukocyte antigen was found. CONCLUSIONS: The absence of significant evidence of linkage at any one locus in such a large dataset argues that genetic susceptibility to AITD reflects a number of loci, each with a modest effect. Linkage analysis may be limited in defining such loci, and large-scale association studies may prove to be more useful in identifying genetic susceptibility factors for AITD.

Chromosome Mapping↗
PubMed2005

Thyroid hormone in health and disease.

Thyroid disease is common, affecting around 2% of women and 0.2% of men in the UK. Our understanding of the effects of thyroid hormones under physiological circumstances, as well as in pathological conditions, has increased dramatically during the last two centuries and it has become clear that overt thyroid dysfunction is associated with significant morbidity and mortality. Both hypo-and hyperthyroidism and their treatments have been linked with increased risk from cardiovascular disease and the adverse effects of thyrotoxicosis in terms of osteoporosis risk are well established. Although the evidence suggests that successful treatment of overt thyroid dysfunction significantly improves overall survival, the issue of treating mild or subclinical hyper- and hypothyroidism remains controversial. Furthermore, the now well-established effects of thyroid hormones on neurodevelopment have sparked a whole new debate regarding the need to screen pregnant women for thyroid function abnormalities. This review describes the current evidence of the effects of thyroid hormone on the cardiovascular, skeletal and neurological systems, as well as the influence of thyroid diseases and their treatments on the development of malignancy. Furthermore we will describe some recent developments in our understanding of the relationship between thyroid status and health.

Atherosclerosis↗
PubMed2005

Thyroid hormones and fetal brain development.

Thyroid hormones are intricately involved in the developing fetal brain. The fetal central nervous system is sensitive to the maternal thyroid status. Critical amounts of maternal T3 and T4 must be transported across the placenta to the fetus to ensure the correct development of the brain throughout ontogeny. Severe mental retardation of the child can occur due to compromised iodine intake or thyroid disease. This has been reported in areas of the world with iodine insufficiency, New Guinea, and also in mother with thyroid complications such as hypothyroxinaemia and hyperthyroidism. The molecular control of thyroid hormones by deiodinases for the activation of thyroid hormones is critical to ensure the correct amount of active thyroid hormones are temporally supplied to the fetus. These hormones provide timing signals for the induction of programmes for differentiation and maturation at specific stages of development. Understanding these molecular mechanisms further will have profound implications in the clinical management of individuals affected by abnormal maternal of fetal thyroid status.

Animals↗
PubMed2004

The in vitro effects of triiodothyronine on epidermal growth factor-induced trophoblast function.

The development of the human placenta involves a complex process of tightly regulated proliferation and invasion by extravillous trophoblast into the uterine decidua. Inadequate placentation is a feature of intrauterine growth restriction and other gestational pathology. There is some evidence that T(3) plays a role in the regulation of these processes and that T(3) may act synergistically with epidermal growth factor (EGF). The aim of this study was to define the expression of thyroid hormone receptors in extravillous trophoblast, elucidate the effects of T(3) on both proliferation and differentiation of human trophoblast cells of varying origins, and define the potential interaction between EGF and T(3) on these processes. Using immunohistochemistry, specific thyroid hormone receptor isoforms were localized in extravillous trophoblast in first- and second-trimester placental bed biopsies, indicating potential sensitivity to T(3). In studies of human trophoblast-derived cell lines and primary cultures of cytotrophoblast cells in vitro, T(3) and EGF exerted an antiproliferative effect on an extravillous-like cell line (SGHPL-4) but stimulated proliferation in JEG-3 choriocarcinoma cells. EGF enhanced survival of nonproliferative term primary cytotrophoblast cells and significantly enhanced invasion of fibrin gels by SGHPL-4 cells, an effect attenuated by T(3). Both T(3) and EGF also significantly enhanced SGHPL-4 motility. These results suggest that EGF and T(3) may act synergistically to regulate both proliferation and differentiated function of human trophoblast.

Cell Division↗
PubMed2004

A systematic approach to the assessment of known TNF-alpha polymorphisms in Graves' disease.

Single-nucleotide polymorphisms (SNPs) within the tumour necrosis factor alpha (TNF-alpha) gene on chromosome 6p21.3 have been associated with many autoimmune diseases; however, results have been conflicting and accurate allele frequencies have never been established in a UK Caucasian population. The aim of this study was to assess the frequency of 22 known TNF-alpha SNPs in a UK Caucasian control population and investigate association of all polymorphisms with >5% minor allele frequency in a large case-control data set of patients with Graves' disease (GD). Eight of the 22 SNPs had minor allele frequencies >5% and were investigated further. The other 14 SNPs were present in the UK population at frequencies ranging from 0 to 4.7%. A significant increase of the A allele of the -238 SNP was seen in GD patients when compared with control subjects (9.6 vs 6.8%, respectively; P=0.003) and mirrored in the genotype distribution (P=0.009). Furthermore, association of the -238 SNP appears not to be due to linkage disequilibrium of the known HLA-DRB1(*)03 associations with GD. This study has established accurate allele frequencies of TNF-alpha SNPs in a UK population and provides preliminary evidence for association of the TNF-alpha gene with GD.

Case-Control Studies↗