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Simon H S Pearce

Publications and source records attributed to Simon H S Pearce.

14 recordsLinked to original sources
PubMed2007

Analysis of the Fc receptor-like-3 (FCRL3) locus in Caucasians with autoimmune disorders suggests a complex pattern of disease association.

CONTEXT: A four-marker haplotype in the 5' region of the Fc receptor-like 3 gene (markers FCRL3_3 to FCRL3_6) has been identified recently as contributing to rheumatoid arthritis (RA) susceptibility in the Japanese population. The promoter FCRL3_3*C allele also showed significant association with autoimmune thyroid disease and systemic lupus erythematosus. These findings raise the possibility that this locus may influence autoimmune disease susceptibility across many populations. PATIENTS AND DESIGN: We analyzed the same four 5' FCRL3 single nucleotide polymorphism markers, together with three additional exonic single nucleotide polymorphisms in the FCRL3 gene, in cohorts of white Caucasians with Graves' disease (n = 625), type 1 diabetes (n = 279), autoimmune Addison's disease (AAD; n = 200), and RA (n = 769). Healthy controls from the United Kingdom (n = 490) and New Zealand (n = 593) were used. RESULTS: Six of the seven FCRL3 markers showed association with AAD (P = 0.005-0.0001), with maximum evidence at the FCRL3_3*T allele [P([corrected]) = 0.0008; odds ratio (OR), 1.61; 5-95% confidence intervals (CIs), 1.26-2.05]. The most common seven-marker FCRL3 haplotype (TGGGAAA) was also found to be significantly associated with AAD (P([corrected]) = 1.1 x 10(-4); OR, 1.71; 5-95% CIs, 1.33-2.18). There was nominal evidence for allelic association at the marker FCRL3_8 in Graves' disease (OR, 1.50; 5-95% CIs, 1.06-2.13) and at FCRL3_9 with RA (OR, 1.25; 5-95% CIs, 1.01-1.54). CONCLUSIONS: The FCRL3 haplotype that is associated with AAD in Caucasians appears to be protective for autoimmune diseases in the Japanese population, demonstrating that this haplotype is unlikely to contain a single primary etiological allele for autoimmunity. Our observations suggest that the susceptibility to autoimmunity at the FCRL3 locus is more complex than initially thought and may extend either side of the currently associated region to include the adjacent FCRL2 gene.

Adult↗
PubMed2006

Genetic progress towards the molecular basis of autoimmunity.

The past few years have seen the identification of PTPN22 and the confirmation of CTLA-4 as common autoimmune disease genes. Together with MHC and INS, these developments have increased the collection of confirmed susceptibility loci for autoimmunity. In this article, the latest developments related to these genes and to other recently studied candidate autoimmune susceptibility loci (PDCD1, FCRL3, SUMO4, CD25, PADI4 and SLC22A4) are reviewed. Collectively, these genes strongly indicate that aberrant inhibition of the signalling cascade initiated by activation of the T-cell receptor is involved in the aetiology of autoimmune disease. However, much basic genetic, molecular and clinical research is still needed to help us fully understand the underlying mechanisms of autoimmunity and how these translate into prognosis or therapy.

Animals↗
PubMed2006

What is the evidence behind the evidence-base? The premature death of block-replace antithyroid drug regimens for Graves' disease.

Block-replace and titration antithyroid drug regimens both give similar rates of medium- to long-term remission of hyperthyroid Graves' disease. Recent meta-analysis, however, has suggested that titration regimens may be preferable owing to a higher rate of adverse events seen in the block-replace arms of published comparative studies. This article critically re-evaluates the evidence upon which these meta-analyses were based. We suggest that there is little objective evidence that is pertinent to current clinical practice to separate block-replace from titration antithyroid drug regimens and that both remain satisfactory approaches to the medical management of hyperthyroid Graves' disease.

Antithyroid Agents↗
PubMed2006

Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population.

Regulatory T lymphocytes play a crucial role in modulating potentially self-reactive clones, and dysfunction of this cell type contributes to autoimmune disease. FOXP3 is a critical determinant of CD(4+)CD(25+)T regulatory (T(reg)) cell development and function. The aim of this study was to investigate whether genetic polymorphisms at the FOXP3 locus predispose to autoimmune endocrinopathies. Five single nucleotide polymorphisms (SNPs) and two microsatellite polymorphisms were genotyped in our Caucasian cohorts of 633 unrelated Graves' disease (GD) subjects, 104 autoimmune Addison's disease (AAD) subjects and 528 healthy controls. SNP genotyping was performed by either restriction enzyme digestion or by primer-extension-MALDI-TOF (matrix-assisted laser desorption/ionisation time-of-flight) assay. Microsatellites were analysed using fluorescent PCR. Case-control analysis was performed using chi(2) testing on contingency tables for allele frequency. Haplotype analysis was performed using the UNPHASED package. No evidence for disease association was found with any of the seven polymorphisms in either of the GD or AAD subjects as compared with controls (P = 0.26-0.94). Haplotype analysis found a weak evidence for the association of a minor haplotype with GD; this was not significant when corrected for multiple testing. This study has found no robust evidence that FOXP3 gene polymorphism contributes to the susceptibility to GD or AAD in the UK population.

Addison Disease↗
PubMed2005

No association of the codon 55 methionine to valine polymorphism in the SUMO4 gene with Graves' disease.

OBJECTIVE: A functional polymorphism at codon 55 of the small ubiquitin-like modifier-4 (SUMO4) gene (methionine to valine; M55V) has recently been associated with type 1 diabetes mellitus (T1D). We aimed to establish whether this locus also contributes towards the genetic susceptibility to Graves' disease (GD) and autoimmune Addison's disease. DESIGN: A case-control analysis was performed using genomic DNA samples from 595 unrelated white GD subjects, 104 white autoimmune Addison's disease subjects and 467 healthy white control subjects. The SUMO4 M55V single nucleotide polymorphism (SNP) was genotyped using polymerase chain reaction (PCR) amplification followed by digestion with the restriction enzyme MseI. RESULTS: There was no association of the SUMO4 M55V alleles with either GD, thyroid-associated orbitopathy or autoimmune Addison's disease when compared to controls; P = 0.28, 0.46 and 0.91, respectively, by chi2 testing. CONCLUSION: We cannot confirm a generalized role for SUMO4 in autoimmune endocrinopathy. The SUMO4 codon 55 methionine to valine polymorphism may be exclusively associated with susceptibility to T1D, or the effect of the locus in GD and Addison's disease may be much less than that found in T1D patients.

Addison Disease↗
PubMed2004

Role of the CD40 locus in Graves' disease.

The genetic basis for Graves' disease remains largely unknown, but significant linkage to microsatellite markers on 20q11 suggests that this region harbors a susceptibility gene. One obvious candidate gene at this 20q11 locus is CD40, which encodes a B-cell-surface receptor that is involved in T-cell to B-cell signaling and is implicated in control of T-cell autoreactivity. In addition, an allele of a single nucleotide polymorphism (SNP) in the Kozak consensus sequence of the 5' untranslated region of CD40 exon 1 has been reported to show modest evidence for association with Graves' disease. We have investigated the role of this 5' untranslated region (5' UTR) in Graves' disease susceptibility in our cohort of 451 unrelated white subjects with Graves' disease and 446 healthy controls. The CD40 5'UTR SNP (C --> T, position -1) was polymerase chain reaction (PCR)amplified and genotyped using the restriction enzyme NcoI. The frequency of the C allele was 74.8% in Graves' probands compared to 75.1% in controls (not significant [NS]). We find no evidence to support allelic association with Graves' disease at this CD40 SNP, despite the adequate power of the study. We are unable to confirm a role for CD40 in Graves' disease pathogenesis in our U.K. population, however, further studies involving larger patient cohorts and a saturated SNP marker map are required to resolve this issue.

5' Untranslated Regions↗
PubMed2004

Spontaneous reporting of adverse reactions to carbimazole and propylthiouracil in the UK.

OBJECTIVE: To determine the frequency and spectrum of serious adverse drug reactions (ADRs) to thionamide antithyroid drugs. DESIGN AND METHODS: Data spontaneously reported to the UK-wide pharmacovigilance agency, The Committee on Safety of Medicines (Yellow Card Scheme), between 1963 and 2003 were analysed to determine the spectrum and relative frequency of ADRs to carbimazole and propylthiouracil. Representative data on the number of dispensed prescriptions were available from 1981, and were used as a denominator to estimate relative reporting rates of ADRs attributed to the drugs. RESULTS: Between 1981 and 2003 there were 5.23 million prescriptions for thionamide drugs in England and Scotland, 94% of which were for carbimazole. Neutrophil dyscrasia (agranulocytosis and neutropenia) accounted for 49% of all fatalities attributed to these medications. The median time reported for the appearance of neutrophil dyscrasia was 30 days of treatment, but there was a wide range (7-875 days). Neutrophil dyscrasia was more frequently fatal in subjects over 65 years of age; 13.8%vs. 1.2% of fatal reports in younger subjects [odds ratio (OR) 12.90; 5-95% confidence intervals (CI) 1.45-114.92]. Since 1981, reports of most ADRs, including neutrophil dyscrasia, were made significantly more frequently per propylthiouracil prescription dispensed than per carbimazole prescription. CONCLUSION: Detailed data about ADRs to these compounds, and their patient demography, based on a large number of reports are described. Neutrophil dyscrasia is the commonest life-threatening ADR to thionamides. The excess of ADR reports for propylthiouracil compared to carbimazole could reflect genuine differences in toxicity between the compounds, the relative unfamiliarity of UK physicians with propylthiouracil, or the higher use of propylthiouracil in certain patient groups.

Adolescent↗
PubMed2003

Disordered calcium crystal handling in antisense CLC-5-treated collecting duct cells.

Dent's disease, an X-linked tubulopathy secondary to defects in chloride channel CLC-5, is characterised by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and renal stones. Mechanisms leading to nephrocalcinosis are unknown. Using a murine collecting duct cell line (mIMCD-3), we confirm endogenous expression of mCLC-5. During transfection of antisense CLC-5, we observe a reduction in CLC-5 protein expression that correlates with a reduction in the number of acidic endosomal compartments, as determined by quantitative analysis of confocal microscope images using LysoTracker Red. Using wheat germ agglutinin-lectin as an endocytic marker, an arrest of endocytosis is observed in antisense CLC-5 treated cells. Exposure of the cell surface to calcium oxalate crystals results in crystal agglomeration in a minority of sense CLC-5 transfectants (45%) and all antisense CLC-5 transfectants. We conclude that expression of CLC-5 in mIMCD-3 cells allows acidification of endosomes and endocytosis, and that disruption of CLC-5 expression causes abnormal crystal agglomeration.

Animals↗
PubMed2003

Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome.

The immunodysregulation, polyendocrinopathy, enteropathy syndrome (IPEX), is a rare disorder of immune regulation resulting in multiple autoimmune disorders, which demonstrates X-linked recessive inheritance. The disease gene, FOXP3, was identified in 2001, and several mutations within this gene have since been described in patients with IPEX. We used linkage analysis, mutational screening of the FOXP3 gene, human leukocyte antigen typing, and analysis of X-chromosome inactivation to investigate 2 kindreds (21 subjects in total) with 4 male infants (3 now deceased) and 1 girl affected by IPEX. In 1 family a novel FOXP3 mutation was identified in the proband, with a single base deletion at codon 76 of exon 2, leading to a frameshift, which predicted a truncated protein product (108 residues vs. 431 in wild type). In the second family, the FOXP3 locus was excluded by recombination, and mutational analysis of the gene was negative. The affected girl from this family was shown to have human leukocyte antigen DR2 and DR6 alleles and random X-chromosome inactivation in peripheral blood mononuclear cells. Our analysis has elucidated the molecular basis of IPEX in one family and has, for the first time, provided evidence for an autosomal locus, suggesting genetic heterogeneity in this syndrome.

Base Sequence↗
PubMed2002

Medical therapy of macroprolactinomas in males: I. Prevalence of hypopituitarism at diagnosis. II. Proportion of cases exhibiting recovery of pituitary function.

Hyperprolactinaemia frequently causes secondary hypogonadism through central suppression of gonadotropin secretion. Macroprolactinomas (> 1 cm diameter) are more common in males and may additionally cause more generalised hypopituitarism. Recovery of the thyrotropic and/or corticotropic axes is well described following selective adenomectomy, but remains poorly defined in relation to medical (dopamine-agonist) therapy of macroprolactinomas. We therefore performed a retrospective examination of case records of male patients who had received medical therapy alone for macroprolactinoma between 1980-2001 (n = 35) and in whom tumor shrinkage was documented by interval pituitary imaging (reported throughout by a single neuroradiologist). Mean prolactin level at baseline was 59,932 mU/L (median 31,400; range 3,215-332,000); mean period of follow up was 4.2 years (median 2.6; range: 1.0-15). Defects of the following axes were evident at diagnosis: LH/FSH-testosterone (n = 27; 77%), TSH-T4 (n = 14; 41%-not including one case with pre-existing 1 degress hypothyroidism), ACTH-cortisol (n = 8; 23%). Overall, 14 men (40%) were deficient in 1 axis, seven (20%) in 2 axes and seven (20%) in 3 axes. Growth hormone secretory status was not systematically evaluated. In all but 6 patients, prolactin levels fell to normal or near-normal levels (mean 764 mU/L; median 260; range: < 10-4,833). Of the patients in whom adequate reassessment had been performed, thyrotroph function recovered in 4/9, corticotroph function in 4/6 and gonadotroph function in 16/26 cases. In four cases (11%) previously described, development of visual impairment as a result of the chiasmal traction syndrome necessitated a dose reduction in medical therapy to allow a degree of controlled tumor re-expansion. The prevalence at diagnosis of TSH and ACTH deficiency in men with macroprolactinomas was 41% and 23%, respectively. Among eight patients with insufficiency of TSH and/or ACTH secretion who underwent complete interval reassessment over several years of treatment, recovery of at least one axis occurred in six cases (75%). This study highlights the importance of screening ACTH- and/or TSH-deficient men during dopamine agonist therapy in order to identify cases where hypopituitarism has resolved.

Adrenocorticotropic Hormone↗
PubMed2002

Clinical disorders of extracellular calcium-sensing and the molecular biology of the calcium-sensing receptor.

The calcium-sensing receptor is a G protein-coupled receptor that has a key role in extracellular calcium homeostasis, regulating the secretion of parathyroid hormone and the reabsorption of urinary calcium appropriate to the prevailing calcaemic environment. Molecular abnormalities of the calcium-sensing receptor are responsible for three clinical disorders, familial benign hypocalciuric hypercalcaemia, neonatal severe hyperparathyroidism and autosomal dominant hypocalcaemia with hypercalciuria. In the future, therapeutic compounds that modulate calcium-sensing receptor function may have a role in the medical management of hyperparathyroidism (calcimimetic drugs) and osteoporosis (calcilytic drugs).

Calcium↗