PubMed Health⌕ Search

Biomedical subjects

John P Walsh

Publications and source records attributed to John P Walsh.

At least 19 recordsLinked to original sources
PubMed2025

Genome topology analysis and transcriptomics of human osteoclasts reveals enhancer-promoter interactions at loci for bone traits and diseases.

Genome-wide association studies (GWAS) relevant to osteoporosis have identified hundreds of loci; however, understanding how these variants influence the phenotype is complicated because most reside in non-coding DNA sequence that serves as transcriptional enhancers and repressors. To advance knowledge on these regulatory elements in osteoclasts (OCs), we performed Micro-C analysis, which informs on the genome topology of these cells and integrated the results with transcriptome and GWAS data to further define loci linked to BMD. Using blood cells isolated from 4 healthy participants aged 31-61 yr, we cultured OC in vitro and generated a Micro-C chromatin conformation capture dataset. We characterized chromatin loops (CLs) in OC from among more than 69 million chromatin interactions identified in the genome. Of the CL identified in OC, >16 000 were unique compared to precursor cells. When sentinel single nucleotide polymorphisms from osteoporosis and bone-related GWAS and those in linkage disequilibrium at r 2 > 0.6 were mapped to CL for OC, 12 588 of these variants were observed within chromatin contact regions. Notable in differential gene ontology enrichment analyses of the topology data for OC and precursors were pathways regulating pluripotency of stem cells, Wnt signaling, nucleotide-binding oligomerization domain (NOD)-like receptor signaling and chemokine signaling. These data, in combination with other 3D genome architecture and epigenetic data (eg, histone modifications and chromatin accessibility), will be useful in modeling to predict genome-wide, which enhancers regulate which genes in OC. This data will therefore also be informative for resolving GWAS hits. In conclusion, we have generated a high-resolution genome topology dataset for human OC and have used this to identify CLs relevant to studies of the genetics of osteoporosis. This data will serve as a powerful resource to inform future functional studies of OC biology.

BMD↗
PubMed2024

Epigenome-wide Association Study Shows Differential DNA Methylation of MDC1, KLF9, and CUTA in Autoimmune Thyroid Disease.

CONTEXT: Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto disease (HD), which often run in the same family. AITD etiology is incompletely understood: Genetic factors may account for up to 75% of phenotypic variance, whereas epigenetic effects (including DNA methylation [DNAm]) may contribute to the remaining variance (eg, why some individuals develop GD and others HD). OBJECTIVE: This work aimed to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) comparing GD to HD. METHODS: Whole-blood DNAm was measured across the genome using the Infinium MethylationEPIC array in 32 Australian patients with GD and 30 with HD (discovery cohort) and 32 Danish patients with GD and 32 with HD (replication cohort). Linear mixed models were used to test for differences in quantile-normalized &#x3b2; values of DNAm between GD and HD and data were later meta-analyzed. Comb-p software was used to identify DMRs. RESULTS: We identified epigenome-wide significant differences (P < 9E-8) and replicated (P < .05) 2 DMPs between GD and HD (cg06315208 within MDC1 and cg00049440 within KLF9). We identified and replicated a DMR within CUTA (5 CpGs at 6p21.32). We also identified 64 DMPs and 137 DMRs in the meta-analysis. CONCLUSION: Our study reveals differences in DNAm between GD and HD, which may help explain why some people develop GD and others HD and provide a link to environmental risk factors. Additional research is needed to advance understanding of the role of DNAm in AITD and investigate its prognostic and therapeutic potential.

Humans↗
PubMed2006

Erectile dysfunction predicts generalised cardiovascular disease: evidence from a case-control study.

AIMS: To determine whether idiopathic erectile dysfunction, in the absence of overt cardiovascular disease or cardiovascular risk factors, is associated with vascular or autonomic dysfunction. METHODS: We studied 49 men with ED (without known cardiovascular risk factors or disease) and 50 age-matched controls, aged 40-70 years. Macrovascular endothelial function was examined by brachial artery ultrasonography and microvascular function by venous occlusion plethysmography. Blood pressure measurement and electrocardiography were performed lying and standing, and the 30:15 RR ratio calculated. RESULTS: Body mass index, testosterone, fasting lipids and glucose did not differ significantly between groups. Standing pulse pressure was higher (50+/-1mm Hg versus 43+/-2mm Hg, p<0.004) and 30:15 RR ratio lower (0.97+/-0.01 versus 1.01+/-0.01, p<0.02) in the ED group. Flow-mediated dilatation of the brachial artery was not significantly different between groups. Flow debt repayment during forearm reactive hyperaemia was lower in the ED group (7.2+/-0.7 ml versus 9.5+/-0.8 ml per 100ml, p<0.02) than in controls. CONCLUSIONS: Men with idiopathic ED have evidence of endothelial dysfunction in forearm resistance vessels, increased pulse pressure and impaired heart rate variability. This supports the concept that erectile dysfunction is a predictor of cardiovascular dysfunction and a precursor of clinical cardiovascular disease.

Adult↗
PubMed2006

Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a double-blind, randomized clinical trial.

CONTEXT: In patients with primary hypothyroidism, anecdotal evidence suggests that well-being is optimized by fine adjustment of T(4) dosage, aiming for a serum TSH concentration in the lower reference range. This has not been tested in a clinical trial. OBJECTIVE: Our objective was to test whether adjustment of T(4) dosage aiming for a serum TSH concentration less than 2 mU/liter improves well-being compared with a serum TSH concentration in the upper reference range. DESIGN: We conducted a double-blind, randomized clinical trial with a crossover design. PARTICIPANTS: Fifty-six subjects (52 females) with primary hypothyroidism taking T(4) (>/=100 microg/d) with baseline serum TSH 0.1-4.8 mU/liter participated. INTERVENTIONS: Each subject received three T(4) doses (low, middle, and high in 25-microg increments) in random order. OUTCOME MEASURES: Outcome measures included visual analog scales assessing well-being (the primary endpoint) and hypothyroid symptoms, quality of life instruments (General Health Questionnaire 28, Short Form 36, and Thyroid Symptom Questionnaire), cognitive function tests, and treatment preference. RESULTS: Mean (+/- sem) serum TSH concentrations were 2.8 +/- 0.4, 1.0 +/- 0.2, and 0.3 +/- 0.1 mU/liter for the three treatments. There were no significant treatment effects on any of the instruments assessing well-being, symptoms, quality of life, or cognitive function and no significant treatment preference. CONCLUSIONS: Small changes in T(4) dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life, despite the expected changes in serum TSH and markers of thyroid hormone action. These data do not support the suggestion that the target TSH range for the treatment of primary hypothyroidism should differ from the general laboratory range.

Adult↗
PubMed2006

Are Australian children iodine deficient? Results of the Australian National Iodine Nutrition Study.

OBJECTIVE: To document the population iodine nutritional status in Australian schoolchildren. DESIGN AND SETTING: Cross-sectional survey of schoolchildren aged 8-10 years, based on a one-stage random cluster sample drawn from all Year 4 school classes in government and non-government schools in the five mainland Australian states of New South Wales, Victoria, South Australia, Western Australia and Queensland. The study was conducted between July 2003 and December 2004. PARTICIPANTS: 1709 students from 88 schools (881 boys and 828 girls), representing 85% of the estimated target number of students. The class participation rate was 65%. MAIN OUTCOME MEASURES: (i) Urinary iodine excretion (UIE) levels (compared with the criteria for the severity of iodine deficiency of the World Health Organization/International Council for the Control of Iodine Deficiency Disorders: iodine replete, UIE > or = 100 microg/L; mild iodine deficiency, UIE 50-99 microg/L; moderate iodine deficiency, UIE 20-49 microg/L; severe iodine deficiency, UIE < 20 microg/L); (ii) Thyroid volumes measured by ultrasound (compared with new international reference values). RESULTS: Overall, children in mainland Australia are borderline iodine deficient, with a national median UIE of 104 microg/L. On a state basis, NSW and Victorian children are mildly iodine deficient, with median UIE levels of 89 microg/L and 73.5 microg/L, respectively. South Australian children are borderline iodine deficient, with a median UIE of 101 microg/L. Both Queensland and Western Australian children are iodine sufficient, with median UIE levels of 136.5 microg/L and 142.5 microg/L, respectively. Thyroid volumes in Australian schoolchildren are marginally increased compared with international normative data obtained from children living in iodine sufficient countries. There was no significant association between UIE and thyroid volume. CONCLUSION: Our results confirm the existence of inadequate iodine intake in the Australian population, and we call for the urgent implementation of mandatory iodisation of all edible salt in Australia.

Age Factors↗
PubMed2006

Investigations of thyroid hormones and antibodies based on a community health survey: the Busselton thyroid study.

OBJECTIVE: Overt or subclinical thyroid dysfunction is common within the community, yet the significance of subtle anomalies in thyroid function tests remains contentious. The aims of this study were to: (a) establish reference intervals for serum-free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid antibodies (antithyroperoxidase, TPOAb and antithyroglobulin, TgAb) in the Busselton community of south-western Western Australia; and (b) determine the prevalence of thyroid hormone anomalies in this community. SUBJECTS AND DESIGN: In 1981, 2115 adults residing in Busselton participated in a cross-sectional health survey that involved blood collection and a questionnaire on lifestyle and general health history. MEASUREMENTS: Serum samples were analysed for FT4, TSH, TPOAb and TgAb by immunochemiluminescent assays. RESULTS: Based on standard statistical approaches and using guidelines recommended by the National Academy of Clinical Biochemistry (NACB), reference intervals were derived for each analyte: 9-23 pmol/l for FT4, 0.4-4.0 mIU/l (TSH), < 35 KIU/l (TPOAb) and < 55 KIU/l (TgAb). The prevalence of elevated thyroid antibodies was 12.4% among subjects without a history of thyroid disease and is more common in women than in men. Elevated thyroid antibody levels were observed at both extremes of TSH abnormality, but were more commonly increased when TSH levels were above 4.0 mIU/l (63% subjects) than for those with TSH levels 0.4-4.0 mIU/l (7.8% subjects). CONCLUSIONS: This study establishes the prevalence of antibodies to thyroperoxidase and thyroglobulin in a community-based sample and reference intervals for free T4 and TSH. When the NACB decision limits are applied to older men or women, there is a markedly increased number with 'elevated' autoantibody levels compared to sex- and age-specific reference intervals.

Adolescent↗
PubMed2006

Novel mutations in the calcium-sensing receptor gene associated with biochemical and functional differences in familial hypocalciuric hypercalcaemia.

OBJECTIVE: Heterozygous inactivating mutations of the calcium-sensing receptor (CaR) gene cause familial hypocalciuric hypercalcaemia (FHH), a generally benign disorder characterized by mild to moderate PTH-dependent hypercalcaemia. We aimed to identify the causative CaR mutations in three families with FHH and examine the correlation between type of mutation and biochemical and/or functional phenotypes. PATIENTS, DESIGN AND MEASUREMENTS: The CaR gene from FHH family members was assessed for mutations by direct DNA sequencing and mutations were confirmed by restriction enzyme analysis. Functional studies on two missense mutations were conducted by introducing them by site-directed mutagenesis into the CaR cloned into a mammalian expression vector, and assessing calcium responsiveness using an inositol phosphate (IP) assay in HEK293 cells. Biochemical data from patients heterozygous for each type of mutant were correlated with functionality. RESULTS: Two novel nonsense mutations (R25stop and K323stop) and one novel missense mutation (G778D) were identified. The G778D mutant receptor and another mutation identified in an earlier study (L174R) demonstrated a complete lack of Ca2+ responsiveness using the IP assay. When cotransfected with wild-type receptor, the mutant receptors demonstrated a dominant-negative effect on wild-type receptor response, with L174R having a more pronounced effect than G778D. Significantly more severe hypercalcaemia and a trend towards higher PTH levels were observed in patients heterozygous for CaR mutants with a stronger dominant-negative effect. CONCLUSIONS: Naturally occurring CaR mutations with differences in dominant-negative effect on wild-type receptor demonstrate differences in biochemical severity in FHH.

Animals↗
PubMed2006

Subclinical thyroid dysfunction and blood pressure: a community-based study.

OBJECTIVE: Overt hypothyroidism and hyperthyroidism are associated with hypertension, but it is uncertain whether the same is true of subclinical hypothyroidism and hyperthyroidism. DESIGN, SUBJECTS AND MEASUREMENTS: Cross-sectional study of 2033 participants (aged 17-89 years) in the Busselton Thyroid Study who did not have a history of thyroid disease. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and the prevalence of hypertension (defined as SBP >or=140 mmHg, DBP >or=90 mmHg or on treatment for hypertension) in subjects with thyroid dysfunction and euthyroid subjects were compared using linear regression models. Subjects with treated hypertension (N = 299) were excluded from analyses of SBP and DBP but included in analyses of hypertension prevalence. RESULTS: Mean SBP, DBP and the prevalence of hypertension did not differ significantly between subjects with subclinical hypothyroidism (N = 105) and euthyroid subjects (N = 1859), nor did they differ between subjects with serum TSH concentrations in the upper reference range (2.0-4.0 mU/l; N = 418) and those with TSH concentrations in the lower reference range (0.4-2.0 mU/l; N = 1441). The prevalence of hypertension was higher in subjects with subclinical hyperthyroidism than euthyroid subjects (prevalence odds ratio 2.8, 95% confidence interval 1.3-6.0 adjusted for age, age(2) and sex), but this was based on a small number of subjects with subclinical hyperthyroidism (N = 35). CONCLUSIONS: Subclinical hypothyroidism is not associated with hypertension. The observed association between subclinical hyperthyroidism and hypertension requires confirmation in a larger sample.

Adolescent↗
PubMed2006

Urine free cortisol analysis by automated immunoassay and high-performance liquid chromatography for the investigation of Cushing's syndrome.

BACKGROUND: We compared a widely used immunoassay method for urine free corticoids with a high-performance liquid chromatography (HPLC) method for the investigation of Cushing's syndrome. METHODS: Urine free corticoid analysis using an Immulite:2000 automated immunoassay analyser and urine free cortisol analysis by a specific HPLC method on 39 patients with an elevated baseline immunoassay 24 h urine free corticoid result who were referred from 2000 to 2004. RESULTS: Reference ranges for urine free corticoids by immunoassay and for urine free cortisol by HPLC were <900 and <170 nmol/day, respectively. Of the 39 patients with an elevated immunoassay urine free corticoid result, Cushing's syndrome was surgically proven in 22 patients, giving a positive predictive value of 56%. Cushing's syndrome was excluded in 12 of the remaining 17 patients by applying the specific HPLC method and at least one of the following: a clinical evaluation which was not suggestive or adequate suppression of plasma cortisol following dexamethasone. Urine free cortisol analysis by HPLC gave a positive predictive value of 81% for Cushing's syndrome. CONCLUSIONS: Although immunoassay has a low specificity for urine cortisol, it is a widely available test which serves as a valid initial investigation of Cushing's syndrome.

Adolescent↗
PubMed2006

A novel mutation (K378X) in the sequestosome 1 gene associated with increased NF-kappaB signaling and Paget's disease of bone with a severe phenotype.

UNLABELLED: Sequestosome 1/p62 (p62) mutations are associated with PDB; however, there are limited data regarding functional consequences. We report a novel mutation in exon 7 (K378X) in a patient with polyostotic Paget's disease of bone. p62 mutants increased NF-kappaB activation and significantly potentiated osteoclast formation and bone resorption in human primary cell cultures. INTRODUCTION: Sequestosome 1/p62 (p62) mutations are associated with Paget's disease of bone (PDB); however, there are limited data regarding functional consequences. One report has linked the common P392L mutation in the p62 ubiquitin binding associated (UBA) domain with increases in NF-kappaB activity, a transcription factor essential for osteoclastogenesis. To further clarify the functional impact of p62 mutations associated with PDB, we assessed the effect of p62 mutation (a novel mutation: K378X, and previously reported mutations: P392L and E396X) on RANK-induced NF-kappaB activation and compared this with the effect of wildtype p62. In addition, we studied the effect of p62 mutation on osteoclast formation and bone resorption. MATERIALS AND METHODS: We performed co-transfection experiments with expression plasmids for p62 (wildtype or mutated) and RANK and an NF-kappaB luciferase reporter gene. Luciferase activities were recorded after addition of luciferin to cellular lysates. RAW(264.7) cells stably expressing enhanced green fluorescent protein (EGFP)-tagged p62 (wildtype, K378X, or P392L) or EGFP alone were assessed for changes in cell proliferation. Additionally, these cells were stimulated with RANKL to produce osteoclast-like cells (OLCs). Primary human monocytes collected from the K378X-affected patient and a control subject were stimulated to form OLCs and bone resorption data were obtained. RESULTS: The novel mutation introduces a premature stop codon in place of Lys-378 and thereby eliminates the entire p62 UBA domain; this and two additional natural mutations (P392L, E396X) increased NF-kappaB activation compared with wildtype p62. Wildtype p62 consistently inhibited NF-kappaB activation compared with empty vector. UBA mutations (K378X and P392L) significantly increased the number of OLCs formed in response to RANKL and also the number of nuclei of the OLCs. K378X-affected human monocytes formed more OLCs with more nuclei and increased bone resorption compared with control monocytes. CONCLUSIONS: Our data show that mutation of the p62 UBA domain results in increased activation of NF-kappaB and osteoclast formation and function compared with wildtype p62. These results may partially explain the mechanism by which p62 mutation contributes to the pathogenesis of PDB.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Subclinical thyroid dysfunction as a risk factor for cardiovascular disease.

BACKGROUND: There have been few large epidemiological studies examining the association between thyroid dysfunction and cardiovascular disease. In particular, it is uncertain if subclinical hypothyroidism is a risk factor for cardiovascular disease. METHODS: Serum thyrotropin and free thyroxine concentrations were measured in 2108 archived serum samples from a 1981 community health survey in Busselton, Western Australia (Busselton Health Study). In a cross-sectional study, we examined the prevalence of coronary heart disease in subjects with and without subclinical thyroid dysfunction. In a longitudinal study, we examined the risk of cardiovascular mortality and coronary heart disease events (fatal and nonfatal combined) to the end of 2001 (excluding subjects who had coronary heart disease at baseline). RESULTS: In the cross-sectional analysis, subjects with subclinical hypothyroidism (n = 119) had a significantly higher prevalence of coronary heart disease than euthyroid subjects (n = 1906) (age- and sex-adjusted prevalence odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = .04). In the longitudinal analysis of subjects with subclinical hypothyroidism (n = 101), there were 21 cardiovascular deaths observed compared with 9.5 expected (age- and sex-adjusted hazard ratio, 1.5; 95% confidence interval, 1.0-2.4; P = .08) and 33 coronary heart disease events observed compared with 14.7 expected (age- and sex-adjusted hazard ratio, 1.7; 95% confidence interval, 1.2-2.4; P < .01). The increased risk of coronary heart disease events remained significant after further adjustment for standard cardiovascular risk factors. Subjects with subclinical hyperthyroidism (n = 39) had no adverse outcomes. CONCLUSION: Subclinical hypothyroidism may be an independent risk factor for coronary heart disease.

Adolescent↗
PubMed2005

Evaluation of the role of Valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone.

Paget's disease of bone (PDB) is a common metabolic bone disease of late onset with a strong genetic component. Rarely, PDB can occur as part of a syndrome in which the disease is accompanied by inclusion body myopathy and frontotemporal dementia (inclusion body myopathy, Paget's disease and frontotemporal dementia, IBMPFD). Recently, IBMPFD has been shown to be caused by mutations in Valosin-containing Protein (VCP), which is required for the proteasomal degradation of phosphorylated IkappaB-alpha, a necessary step in the activation of the transcription factor NF-kappaB. Here, we evaluated the role of VCP in the pathogenesis of typical PDB. We conducted mutation screening of VCP in 44 kindreds with familial Paget's disease recruited mainly through clinic referrals in the UK, Australia and New Zealand. We also performed an association study of VCP haplotypes in patients with PDB who did not have a family history of the disease (sporadic PDB). No mutations were found in VCP in three PDB families where there was evidence of allele sharing between affected subjects in the VCP critical region on chromosome 9p13. We failed to detect disease-associated mutations in any of the three exons previously reported to contain IBMPFD mutations in a further 41 PDB families. We found no evidence of allelic association between common VCP haplotypes in a case-control study of 179 sporadic PDB patients and 172 age- and sex-matched controls. Genetic variation in VCP does not appear to be a common cause of familial or sporadic PDB in the absence of myopathy and dementia.

Adenosine Triphosphatases↗
PubMed2005

Parity and the risk of autoimmune thyroid disease: a community-based study.

CONTEXT: Recent studies have suggested that fetal microchimerism (transplacental passage of fetal cells followed by engraftment into maternal tissues) may play a role in the pathogenesis of autoimmune thyroid disease. If that is true, then parity should be a risk factor for autoimmune thyroid disease. OBJECTIVE: The objective of this study was to examine parity as a risk factor for autoimmune thyroid disease. DESIGN, SETTING, AND PARTICIPANTS: TSH, thyroid peroxidase antibody, and thyroglobulin antibody concentrations were measured on archived sera from 1045 female participants in a 1981 community health survey in Busselton, Western Australia. OUTCOME MEASURES: Odds ratios (ORs) for positive thyroid antibodies (increased concentration of either antibody) or thyroid dysfunction (abnormal serum TSH) were used. RESULTS: After adjustment for age, women who had previously been pregnant did not have a significantly increased risk of positive thyroid antibodies [OR, 1.20; 95% confidence interval (CI), 0.74-1.97; P = 0.46], raised TSH (OR, 0.93; 95% CI, 0.46-1.87; P = 0.84), or reduced TSH (OR, 0.87; 95% CI, 0.33-2.30; P = 0.79) compared with women who had never been pregnant. For each additional pregnancy, the OR was 1.02 (95% CI, 0.94-1.11; P = 0.57) for positive antibodies, 1.02 (95% CI, 0.91-1.14; P = 0.67) for raised TSH, and 1.03 (95% CI, 0.87-1.22; P = 0.73) for reduced TSH. Analysis using number of live births gave similar results. The results were similar in younger and older women. CONCLUSIONS: Parity is not a risk factor for thyroid autoimmunity or thyroid dysfunction. These data do not support a key pathogenic role for fetal microchimerism in chronic autoimmune thyroid disease.

Adult↗
PubMed2005

Polycystic ovarian syndrome: marked differences between endocrinologists and gynaecologists in diagnosis and management.

BACKGROUND: Women with polycystic ovarian syndrome (PCOS) commonly consult endocrinologists or gynaecologists and it is not known whether these specialty groups differ in their approach to management. OBJECTIVE: To compare the investigation, diagnosis and treatment practices of endocrinologists and gynaecologists who treat PCOS. DESIGN AND SETTING: A mailed questionnaire containing a hypothetical patient's case history with varying presentations--oligomenorrhoea, hirsutism, infertility and obesity--was sent to Australian clinical endocrinologists and gynaecologists in teaching hospitals and private practice. RESULTS: Evaluable responses were obtained from 138 endocrinologists and 172 gynaecologists. The two specialty groups differed in their choice of essential diagnostic criteria and investigations. Endocrinologists regarded androgenization (81%) and menstrual irregularity (70%) as essential diagnostic criteria, whereas gynaecologists required polycystic ovaries (61%), androgenization (59%), menstrual irregularity (47%) and an elevated LH/FSH ratio (47%) (all P-values < 0.001). In investigation, gynaecologists were more likely to request ovarian ultrasound (91%vs. 44%, P < 0.001) and endocrinologists more likely to measure adrenal androgens (80%vs. 58%, P < 0.001) and lipids (67%vs. 34%, P < 0.001). Gynaecologists were less likely to assess glucose homeostasis but more likely to use a glucose tolerance test to do so. Diet and exercise were chosen by most respondents as first-line treatment for all presentations. However, endocrinologists were more likely to use insulin sensitizers, particularly metformin, for these indications. In particular, for infertility, endocrinologists favoured metformin treatment whereas gynaecologists recommended clomiphene. CONCLUSIONS: There is a lack of consensus between endocrinologists and gynaecologists in the definition, diagnosis and treatment of PCOS. As a consequence, women may receive a different diagnosis or treatment depending on the type of specialist consulted.

Australia↗
PubMed2005

Thyroid dysfunction and serum lipids: a community-based study.

OBJECTIVE: It is uncertain whether subclinical hypothyroidism (SCH) is associated with hypercholesterolaemia, particularly in subjects with SCH and serum TSH < or = 10 mU/l. DESIGN, PATIENTS AND MEASUREMENTS: Cross-sectional study of 2108 participants in a 1981 community health survey in Busselton, Western Australia. Serum total cholesterol and triglycerides were measured in all subjects and high density lipoprotein cholesterol (HDL-C) measured (and low density lipoprotein cholesterol (LDL-C) calculated) in a subgroup of 631 subjects at the time of the survey. In 2001, TSH and free T4 concentrations were measured on archived sera stored at -70 degrees C. Serum lipid concentrations in subjects with thyroid dysfunction and euthyroid subjects were compared using linear regression models. RESULTS: In the group as a whole, serum total cholesterol was higher in subjects with SCH (N = 119) than in euthyroid subjects (N = 1906) (mean +/- SD 6.3 +/- 1.3 mmol/l vs. 5.8 +/- 1.2 mmol/l, P < 0.001 unadjusted, P = 0.061 adjusted for age, age(2) and sex). Serum total cholesterol was similarly elevated in subjects with SCH and TSH < or = 10 mU/l (N = 89) (6.3 +/- 1.3 mmol/l, P < 0.001 unadjusted, P = 0.055 adjusted for age, age(2) and sex). In the subgroup analysis, LDL-C was higher in subjects with SCH (N = 30) than in euthyroid subjects (N = 580) (4.1 +/- 1.2 mmol/l vs. 3.5 +/- 1.0 mmol/l, P < 0.01 unadjusted, P = 0.024 adjusted for age, age(2) and sex). LDL-C was significantly increased in subjects with SCH and TSH < or = 10 mU/l (N = 23) (4.3 +/- 1.3 mmol/l, P < 0.001 unadjusted, P = 0.002 adjusted for age, age(2) and sex). CONCLUSION: SCH is associated with increased serum LDL-C concentrations, which is significant after adjustment for age, age(2) and sex.

Adolescent↗
PubMed2004

Ubiquitin-associated domain mutations of SQSTM1 in Paget's disease of bone: evidence for a founder effect in patients of British descent.

UNLABELLED: Mutations in the UBA domain of SQSTM1 are a common cause of Paget's disease of bone. Here we show that the most common disease-causing mutation (P392L) is carried on a shared haplotype, consistent with a founder effect and a common ancestral origin. INTRODUCTION: Paget's disease of bone (PDB) is a common condition with a strong genetic component. Mutations affecting the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1) have recently been shown to be an important cause of PDB. The most common mutation results in a proline to leucine amino acid change at codon 392 (P392L), and evidence has been presented to suggest that there may be a recurrent mutation rather than a founder mutation on an ancestral chromosome. Because marked geographical differences exist in the prevalence of PDB, we have investigated the frequency of SQSTM1 mutations in different populations and looked for a founder effect on chromosomes bearing SQSTM1 UBA domain mutations. MATERIALS AND METHODS: We conducted mutation screening of SQSTM1 and performed haplotype analysis using the PHASE software program in 83 kindreds with familial PDB, recruited mainly through clinic referrals in the United Kingdom, Australia, and New Zealand. Similar studies were conducted in 311 individuals with PDB who did not have a family history and 375 age- and sex-matched controls from the United Kingdom. RESULTS: The proportion of patients with familial PDB who had SQSTM1 UBA domain mutations varied somewhat between referral centers from 7.1% (Sydney, Australia) to 50% (Perth, Australia), but the difference between centers was not statistically significant. Haplotype analysis in 311 British patients with PDB who did not have a family history and 375 age- and sex-matched British controls showed that two common haplotypes accounted for about 90% of alleles at the SQSTM1 locus, as defined by common single nucleotide polymorphisms (SNPs) in exon 6 (C916T, G976A) and the 3'UTR (C2503T, T2687G). These were H1 (916T-976A-2503C-2687T) and H2 (916C-976G-2503T-2687G). There was no significant difference in haplotype distribution in PDB cases and controls, but the P392L mutation was found on the H2 haplotype in 25/27 cases (93%), which is significantly more often than expected given the allele frequencies in the normal population (odds ratio, 13.2; 95% CI, 3.1-56.4; p < 0.0001). Similar findings were observed in familial PDB, where 12/13 (92%) of P392L mutations were carried on H2 (odds ratio 17.2; 95% CI, 2.2-138; p = 0.001). CONCLUSIONS: These results provide strong evidence for a founder effect of the SQSTM1 P392L mutation in PDB patients of British descent, irrespective of family history. Our results imply that these individuals share a common ancestor and that the true rate of de novo mutations may be lower than previously suspected.

3' Untranslated Regions↗