Prophylactic oral bisphosphonate therapy in duchenne muscular dystrophy.

INTRODUCTION: We assessed prophylactic use of bisphosphonate (BP) in Duchenne muscular dystrophy (DMD) patients on glucocorticoid (GC) therapy. METHODS: Fifty-two DMD patients on daily GC were offered BP (oral risedronate). Patients were reviewed for tolerability, side effects, bone pain, and fracture frequency. Bone mineral density (BMD) was determined by annual dual energy X-ray absorptiometry. BP-treated patients were compared with 15 BP-naïve patients (untreated cohort). RESULTS: Side effects occurred in 9 patients. Thirty-six patients continued BP therapy for over 12 months (mean, 3.6 years). Five treated patients reported bone pain. Three treated patients suffered a vertebral fracture, significantly less than in the untreated cohort (5/15). Lumbar spine adjusted BMD Z-scores remained unchanged in treated patients and were significantly greater than in the untreated cohort. CONCLUSIONS: Prophylactic oral risedronate therapy was tolerated by most DMD patients. It appears to maintain BMD and may reduce fracture rate in DMD patients on GC. Muscle Nerve 54: 79-85, 2016.

FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity.

Naturally occurring variation in gene copy number is increasingly recognized as a heritable source of susceptibility to genetically complex diseases. Here we report strong association between FCGR3B copy number and risk of systemic lupus erythematosus (P = 2.7 x 10(-8)), microscopic polyangiitis (P = 2.9 x 10(-4)) and Wegener's granulomatosis in two independent cohorts from the UK (P = 3 x 10(-3)) and France (P = 1.1 x 10(-4)). We did not observe this association in the organ-specific Graves' disease or Addison's disease. Our findings suggest that low FCGR3B copy number, and in particular complete FCGR3B deficiency, has a key role in the development of systemic autoimmunity.

Testosterone Treatment of Pubertal Delay in Duchenne Muscular Dystrophy.

BACKGROUND: The outlook for adolescents with Duchenne muscular dystrophy (DMD) has improved greatly as a result of corticosteroid use, but treatment will compromise growth and delay puberty. Whether exogenous testosterone can promote growth, development, and skeletal health is unclear. METHODS: We collected data retrospectively on growth and pubertal response in 14 adolescents with DMD who were treated with testosterone between 2008 and 2014. RESULTS: A total of 14 boys were treated at a median age of 14.5 years. Eight have finished treatment after a mean age of 3.1 years and the feedback from families was generally positive. The mean testicular volume pretreatment was 2.4 and 3.9 mL posttreatment. The mean baseline testosterone concentrations were < 1.0 and 5.4 nmol/L postintervention. Median height velocity increased from 0.45 cm/y before treatment to 3.6 cm/y after the treatment. The mean height gain was 14.2 cm. CONCLUSIONS: A broad range of testosterone preparations was used. Testosterone was generally well-liked, but side effects were experienced by some patients and the pubertal growth increment appears to be compromised. Few subjects had adult endogenous testosterone levels posttreatment. Controlled studies are required to determine the most appropriate treatment regimen and the precise impact of testosterone on key outcomes, such as muscle function and bone integrity. Clinicians will then be better placed to advise families about likely benefits and risks.

The CCP, Campaign Governance and COVID-19: Evidence from Shanghai.

This paper examines Shanghai's grassroots COVID-19 management as a lens to explore the role of local Chinese Communist Party (CCP) organisations in public policy implementation in China. We bring together literature on the Party-state relationship with literature on 'routine' and 'mobilizational' governance to construct a framework that conceptualises the CCP as the central actor in implementing public policy through campaigns. We distinguish 9 governance techniques deployed by the CCP in grassroots COVID management, which we illustrate with evidence from 37 semi-structured interviews conducted in summer 2021 with secretaries and directors from local Residents' Committees, government officials mobilised to assist with pandemic management, representatives from property management companies and Party-Mass Service Centres, as well as volunteers and residents. We demonstrate that, although Party-led policy implementation elicits comprehensive compliance, it places significant pressure on the system of grassroots governance.

Large-vessel vasculitis.

Large-vessel vasculitis (LVV) manifests as inflammation of the aorta and its major branches and is the most common primary vasculitis in adults. LVV comprises two distinct conditions, giant cell arteritis and Takayasu arteritis, although the phenotypic spectrum of primary LVV is complex. Non-specific symptoms often predominate and so patients with LVV present to a range of health-care providers and settings. Rapid diagnosis, specialist referral and early treatment are key to good patient outcomes. Unfortunately, disease relapse remains common and chronic vascular complications are a source of considerable morbidity. Although accurate monitoring of disease activity is challenging, progress in vascular imaging techniques and the measurement of laboratory biomarkers may facilitate better matching of treatment intensity with disease activity. Further, advances in our understanding of disease pathophysiology have paved the way for novel biologic treatments that target important mediators of disease in both giant cell arteritis and Takayasu arteritis. This work has highlighted the substantial heterogeneity present within LVV and the importance of an individualized therapeutic approach. Future work will focus on understanding the mechanisms of persisting vascular inflammation, which will inform the development of increasingly sophisticated imaging technologies. Together, these will enable better disease prognostication, limit treatment-associated adverse effects, and facilitate targeted development and use of novel therapies.

Specificity of depression following an acute coronary syndrome to an adverse outcome extends over five years.

Many studies have demonstrated that depression is associated with a worse cardiovascular outcome and increased risk of death in those experiencing an acute coronary syndrome (ACS). Recent studies have suggested, however, that any association is strongly influenced by the timing of the depression, with post-ACS depression providing the greatest risk. Establishing any timing impact should assist etiological clarification. We initially recruited 489 subjects hospitalized for an ACS, assessed lifetime and current depression, and then - at 1 and 12 months - assessed subsequent depression. Subjects were followed for up to 5 years to assess cardiovascular outcome and the impact of depression at differing time points, with three defined poor outcome categories (i.e. cardiac admission and/or cardiac rehospitalization). While outcome was associated with a number of non-depression variables, a poor outcome was most clearly associated with depressive episodes emerging at the time of the ACS but with some risk affected by episodes that commenced prior to the ACS and being persistent. Neither lifetime depressive episodes nor transient depressive episodes occurring around the baseline ACS event appeared to provide any risk. Study findings indicate that any differential deleterious impact of post-ACS depression has both short-term and longer-term outcomes, and, by implicating the centrality of post-ACS depression, should assist studies seeking to identify causal explanations.

The impact of differing anxiety disorders on outcome following an acute coronary syndrome: time to start worrying?

BACKGROUND: Both depression and anxiety have been implicated as influencing survival following an acute coronary syndrome (ACS). Studies evaluating the contribution of anxiety have produced varying results, perhaps reflecting the use of dimensional self-report measures of state anxiety and failure to control for co-morbid depression. We sought to assess the impact of anxiety on outcome in ACS patients using DSM-IV diagnoses, in addition to self-report measures, controlling for effects of concurrent depressive diagnosis as well as medical and socio-demographic variables. METHODS: Some 489 patients hospitalized with an ACS were assessed for lifetime and current DSM-IV anxiety disorders using both Composite International Diagnostic Interview (CIDI) decisions and such decisions complemented by clinical judgments of impairment. Patients were re-interviewed over the next 12 months to assess cardiac outcome (ACS readmission and cardiac mortality). RESULTS: Univariate analyses revealed a trend for those with a lifetime history of agoraphobia to experience poorer cardiac outcome and for those with a lifetime diagnosis of generalized anxiety disorder (GAD) to experience a superior cardiac outcome. After controlling for post-ACS depression and key medical and demographic covariates, agoraphobia was a significant predictor of poorer cardiac outcome while the trend for those with a history of GAD to experience a superior cardiac outcome remained. CONCLUSIONS: Any impact of "anxiety" on post-ACS outcome appears to be influenced by the clinical sub-type. The seemingly paradoxical finding that GAD might improve outcome may reflect "apprehensive worrying" being constructive, by improving self-management of the individual's cardiac problems.

Omega-3 deficiency associated with perinatal depression: case control study.

Women are depleted of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during the perinatal period due to fetal diversion. An association has been shown between lowered n-3 PUFAs and depression in general. We therefore hypothesise that women with lower n-3 PUFA levels are at greater risk of depression during pregnancy. Sixteen depressed and 22 non-depressed women were recruited during the third trimester and fasting bloods were taken for plasma fatty acid analysis. High docosahexaenoic acid (DHA), high total n-3 and a low n-6:n-3 ratio were associated with significantly lower odds of depression. After adjustment for parity, age and education level, those with high DHA still had significantly lower odds of being depressed. Those with high total n-3 and a low n-6:n-3 ratio were also at significantly reduced risk of depression, although the magnitude of the difference was reduced. Study results quantified women with lower omega-3 PUFA levels as being six times more likely to be depressed antenatally, compared to women who had higher omega-3 PUFA levels. The prophylactic benefits of supplementation either prenatally or during pregnancy require close study to assess whether omega-3 PUFAs play a role in the prevention of perinatal depression.

Discordance for X-linked hypophosphataemic rickets in identical twin girls.

BACKGROUND: We report monozygotic twin girls with a family history consistent with X-linked hypophosphataemic rickets (XLH). One twin had a skeletal and biochemical phenotype consistent with XLH, whilst the second twin appeared normal. Complete non-penetrance in XLH has not been previously reported and our aim was to explore potential reasons for this. METHODS: Serum and urine biochemistry were analysed at regular intervals. Microsatellite analysis was performed to confirm monozygosity and bi-parental inheritance of the X chromosome. The X chromosome inactivation pattern was studied in peripheral blood. Exons of the paternal PHEX and FGF23 genes were sequenced. RESULTS: Biochemistry was persistently abnormal in the slow-growing twin 1 and normal in twin 2 who has grown normally. Maximal tubular phosphate reabsorption was 0.68 mmol/l in twin 1 and 1.64 mmol/l in twin 2 at 10.8 years of age (normal 1.15-2.58 mmol/l). Microsatellite analysis confirmed monozygosity and the X chromosome inactivation pattern was random. These studies also excluded uniparental isodisomy. The exon sequence of paternal PHEX and FGF23 genes was normal. CONCLUSIONS: Discordant X inactivation is a well-recognised phenomenon in identical twins, and we suspect that non-random expression of the normal PHEX gene in critical tissues is the most likely explanation for non-penetrance.

Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1.

Background Type I pseudohypoaldosteronism (PHA1) is a rare condition characterised by profound salt wasting, hyperkalaemia and metabolic acidosis due to renal tubular resistance to aldosterone (PHA1a) or defective sodium epithelial channels (PHA1b or systemic PHA). Our aim was to review the clinical presentation related to the genotype in patients with PHA1. Methods A questionnaire-based cross-sectional survey was undertaken through the British Society of Paediatric Endocrinology and Diabetes (BSPED) examining the clinical presentation and management of patients with genetically confirmed PHA1. We also reviewed previously reported patients where genotypic and phenotypic information were reported. Results Genetic confirmation was made in 12 patients with PHA1; four had PHA1a, including one novel mutation in NR3C2; eight had PHA1b, including three with novel mutations in SCNN1A and one novel mutation in SCNN1B. It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile. Patients presenting with missense mutations of SCNN1A and SCNN1B had a less marked rise in serum aldosterone suggesting preservation in sodium epithelial channel function. Conclusions We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b. Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA. There were no obvious genotype-phenotype correlations between mutations on the same gene in our cohort and others, although a lower serum aldosterone may suggest a missense mutation in SCNN1 in patients with PHA1b.

The role of fatty acids in the development and treatment of mood disorders.

PURPOSE OF REVIEW: There is increasing evidence from epidemiological, case-control and randomized clinical trials for a link between omega-3 deficiency and the development of mood disorders. This article examines recent evidence for this association. RECENT FINDINGS: During the past year our understanding of the effect of omega-3 depletion on the structure and function of the brain has been furthered by research examining human brain tissue and by studies utilizing animal models of depression. Human and animal research has also provided further evidence for omega-3 affecting mood via its anti-inflammatory effects. Previous clinical trials indicated that omega-3 can be effective as an adjunctive treatment for those with treatment-resistant depression. More recent clinical trial data indicate that omega-3 may also be an effective monotherapy for childhood depression and for depressed mood in patients who engage in recurrent self-harm. The recent clinical trial data regarding omega-3 as a treatment for bipolar disorder are inconclusive, however, and clinical trials in postnatal depression are still lacking. SUMMARY: This article reviews the most important recent papers in this burgeoning and interesting research area.

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.

Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves' disease susceptibility.

CONTEXT: A recent large-scale analysis of nonsynonymous coding polymorphisms showed strong evidence that an alanine to threonine amino acid change at codon 946 of the interferon-induced helicase (IFIH1) gene (SNP ID rs1990760) was associated with type 1 diabetes. Previous investigations have also demonstrated that an intronic polymorphism (termed PD1.3; SNP ID rs11568821) in the programmed cell death (PDCD1) gene was associated with systemic lupus erythematosus and rheumatoid arthritis. OBJECTIVE: We sought to replicate these genetic associations in Graves' disease and autoimmune Addison's disease patient cohorts. PATIENTS AND METHODS: A total of 602 Graves' disease subjects, 214 Addison's disease subjects, and 446 healthy controls were genotyped for the IFIH1 and PDCD1 single-nucleotide polymorphisms using mass spectrometer analysis of primer extension products (Sequenom). RESULTS: The alanine-carrying allele at the IFIH1 codon 946 polymorphism was present in 796 of 1204 (66%) Graves' disease patient alleles compared with 508 of 892 (57%) control subject alleles [odds ratio 1.47 (5-95% confidence interval, 1.23-1.76); P = 1.9 x 10(-5)]. In contrast, there was no association of alleles at this marker in autoimmune Addison's disease. Neither was there evidence for association in either patient cohort at the PD1.3 polymorphism. CONCLUSIONS: We confirm a significant contribution of the Ala946Thr IFIH1 polymorphism to organ-specific autoimmune diseases, extending the range of conditions associated with this variant to include Graves' disease. This polymorphism may also contribute to several other autoimmune disorders.

Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience.

CONTEXT: Primary adrenal failure is a life-threatening condition that can be caused by a range of etiologies, including autoimmune, metabolic, and developmental disorders. The nuclear receptors DAX1 (NR0B1) and steroidogenic factor-1 (SF1/Ad4BP, NR5A1) play an important role in adrenal development and function, and mutations in these transcription factors have been found in patients with adrenal hypoplasia. OBJECTIVE: Our objective was to investigate the prevalence of DAX1 and SF1 mutations in children and adults with primary adrenal failure of unknown etiology (i.e. not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease). PATIENTS: One hundred seventeen patients were included. Eighty-eight individuals presented in infancy or childhood with adrenal hypoplasia or primary adrenal failure of unknown etiology (n = 64 46,XY phenotypic males; n = 17 46,XY gonadal dysgenesis/impaired androgenization; n = 7 46,XX females). Twenty-nine individuals presented in adulthood with Addison's disease of unknown etiology. METHODS: Mutational analysis of DAX1 (NR0B1) (including exon 2alpha/1A) and SF1 (NR5A1) was done by direct sequencing. RESULTS: DAX1 mutations were found in 58% (37 of 64) of 46,XY phenotypic boys referred with adrenal hypoplasia and in all boys (eight of eight) with hypogonadotropic hypogonadism and a family history suggestive of adrenal failure in males. SF1 mutations causing adrenal failure were found in only two patients with 46,XY gonadal dysgenesis. No DAX1 or SF1 mutations were identified in the adult-onset group. CONCLUSIONS: DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys. SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.

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.

Left-sided breast cancer loco-regional radiotherapy with deep inspiration breath-hold: Does volumetric-modulated arc radiotherapy reduce heart dose further compared with tangential intensity-modulated radiotherapy?

INTRODUCTION: Left-sided breast cancer radiotherapy has been associated with an increase in cardiac mortality. This study investigated the potential heart-sparing effect of volumetric-modulated arc radiotherapy (VMAT). We compared VMAT to tangential intensity-modulated radiotherapy (t-IMRT) in the loco-regional treatment of left-sided breast cancer, including internal mammary nodal irradiation, based on deep inspiration breath-hold (DIBH) and free-breathing (FB). METHODS: Radiotherapy for 15 patients was re-planned. Four plans were compared: t-IMRT-DIBH; VMAT-DIBH; t-IMRT-FB; VMAT-FB. Prescribed dose was 50 Gy in 25 fractions. T-IMRT plans were generated using tangentially orientated fields. VMAT plans were generated using two partial arcs (average arc 190°). RESULTS: Mean heart dose (MHD) was 5 ± 2.4 Gy, 5.7 ± 1.4 Gy, 9.7 ± 3.3 Gy and 8.1 ± 2.0 Gy for t-IMRT-DIBH, VMAT-DIBH, IMRT-FB and VMAT-FB respectively. The difference in MHD between IMRT-DIBH and VMAT-DIBH was not significant (P = 0.14). VMAT-DIBH significantly spared the volume of heart irradiated to doses of 20 Gy and above (p < 0.05), however, resulted in a significantly higher V5 Gy (P < 0.001), compared to t-IMRT-DIBH. VMAT-DIBH resulted in higher combined lung mean (11 ± 0.8 Gy vs. 8.8 ± 1.1 Gy, P < 0.001) and higher contralateral breast mean dose (5 ± 1 Gy vs. 1.6 ± 1.2 Gy, P < 0.001) compared with t-IMRT-DIBH. CONCLUSIONS: On average, there was no significant difference in MHD between VMAT-DIBH and t-IMRT-DIBH. However, VMAT-DIBH was found to benefit a select group of patients. For patients in whom the MHD was >6.3 Gy with t-IMRT-DIBH, the use of VMAT-DIBH resulted in a benefit in reducing the MHD.

Clinical equipoise: Protons and the child with craniopharyngioma.

INTRODUCTION: Childhood craniopharyngioma is a complex condition to manage. Survival figures are high but the potential for long-term morbidity is great. There is much debate regarding the best management for these tumours with increasing interest in the use of proton beam therapy. We have therefore reviewed our radiotherapy (RT) practice at Westmead Hospital and the literature regarding the use of protons for these children. METHODS: Three children have received fractionated stereotactic RT for craniopharyngioma at Westmead Hospital since 2007. Each RT plan was reviewed and additional organs at risk were contoured to enable comparison with published proton data. RESULTS: Planning target volume coverage was similar with all modalities: with the conformity index ranging from 0.70 to 0.78 in our patients compared with 0.50-0.84 in the published data. RT dose to temporal lobes, hippocampi and whole brain was also similar with protons and photons. Proton beam therapy may give lower dose to the Circle of Willis than stereotactic RT. CONCLUSION: Currently there is no clear evidence that proton beam therapy will improve survival or reduce morbidity for children with craniopharyngioma. However, proton therapy has the potential to reduce RT dose to the Circle of Willis, which may reduce the risk of future cerebrovascular complications. We propose that more resources should be allocated to ensuring these patients are managed by experienced multidisciplinary teams through the continuum from diagnosis to long-term follow-up.

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.

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.