Thyroid hormones have important roles in growth, development and control of metabolism, and their dysregulation can lead to disease.
Objectives
To identify genes contributing to hyperthyrotropinaemia.
Design, setting, participants
Linkage and association analyses using 1258 individuals from three Alpine villages.
Outcome measures
The study applied two different upper limits of the reference range (URR) for serum thyroid stimulating hormone (TSH) values (TSH ≥4.6 mU/l and TSH >3.0 mU/l), along with normal or low fT4 (free thyroxine) values or thyroid medical treatment to define two groups of individuals for analysis: one hyperthyrotropinaemic or high-TSH (H-TSH) (TSH ≥4.6 mU/l) group; and a larger group (TSH >3.0 mU/l) called hyperthyrotropinaemic and upper reference range TSH (H+URR-TSH).
Results
Non-parametric genome-wide linkage analysis was performed on pedigrees generated from the two groups. Linkage analysis in the H+URR-TSH group revealed a significant peak on chromosome 3q28-q29 (LOD 3.34) and a suggestive linkage peak on chromosome 6q26-27 (LOD 2.66). Analysis in the smaller hyperthyrotropinaemic (H-TSH) group supported linkage to chromosome 6q26-27. Single SNP and gene based SNP association analyses under the linkage peaks identified the PDE10A and DACT2 genes as candidates at the chromosome 6 locus.
Conclusions
PDE10A or DACT2 were identified as candidate genes contributing to hyperthyrotropinaemia (and possibly hypothyroidism) in this sample. Studies in additional populations support association of variants at this locus with TSH values, especially in the PDE10A gene. Genetic linkage in families with hyperthyrotropinaemia suggests the presence of functional variants that contribute to pathological disruption of the hypothalamus–pituitary–thyroid axis.
To the Editor: Oxidative stress is a possible mechanism to explain the toxic effects of particulate matter (PM). Conceptually, PM oxidative burden is an appealing exposure metric because it captures a biological process thought to be responsible for PM-induced airway inflammation. However, few epidemiologic studies have examined this exposure metric, and results have been inconsistent.1 Direct measurement of PM oxidative properties could improve the ability to estimate PM effects and enhance the understanding of its mechanism of action, potentially leading to targeted public health strategies aimed at removing the most toxic PM components. We previously reported adverse effects of PM10 (mean aerodynamic diameter <10 μm) mass on asthma and chronic obstructive pulmonary disease (COPD) exacerbations, increased by low antioxidant status (vitamin C) and variation in antioxidant genes.2 Here, we investigate the effects of PM10 oxidative properties on respiratory exacerbations. We conducted a bi-directional case-crossover study in patients admitted to the hospital for asthma/COPD exacerbation, comparing PM10 oxidative potential (OP) on the admission day with that on 14 days before/after (controls). PM10 was collected using a high-volume sampler located near the hospital, and oxidative potential was measured as depletion of three antioxidants (ascorbic acid, AA; glutathione, GSH; uric acid, UA) in a synthetic respiratory tract lining fluid model. The oxidative potential effects were estimated using conditional logistic regressions for paired data, adjusting for PM10 mass, temperature, and humidity. Effect modification by vitamin C serum levels was also assessed. Details on study methods are provided in the eAppendix (https://links.lww.com/EDE/A776). The analyses included 160 exacerbations in 151 patients with data available from at least one case and one control filter. Patients' characteristics are presented in eTable 1; https://links.lww.com/EDE/A776. With the exception of a high positive correlation between OPAA and OPGSH (r = 0.69), there was no substantial correlation between the three oxidative potential readings and PM10 mass. PM10 oxidative potentials showed no association with asthma/COPD admissions, with similarly negative results after adjustment for PM10 mass (Table) and when stratifying by vitamin C serum levels (eTable 2; https://links.lww.com/EDE/A776).TABLE: Associationa of Asthma/COPD Exacerbations with a Unit Increase in OP m−3 for Each Antioxidant (n = 160 Exacerbations; n = 156 Filters)Our findings suggest that intrinsic oxidative properties are not driving the adverse effect of PM10 effects on respiratory exacerbations.2 PM10 effects could be due instead to indirect oxidative effects mediated by host reactions through cellular activation,1,3 such as that resulting in an influx of activated inflammatory cells to the lung, which cannot be captured by our particles' oxidative potential measurement method based on oxidation reactions in an acellular respiratory tract lining fluid model. The association between particles' oxidative potential and respiratory outcomes was evaluated in three recent epidemiologic panel studies.4–6 Only one of these studies found a positive association of outdoor PM2.5 oxidative potential, but not mass, with airway inflammation in 45 asthmatic children.6 The other two, using a semi-experimental design in 31 volunteers exposed to various levels of ambient PM, found no association of either PM mass or oxidative potential with lung function and exhaled nitric oxide4 or acute nasal airway inflammation.5 Although 85% of the patients in our study lived around the Chelsea and Westminster Hospital where PM10 was sampled,2 the use of monitoring sites to derive individual exposure is problematic due to temporal and spatial variation in PM oxidative properties, with higher oxidative potential in proximity to traffic.7,8 PM personal-sampling methods are more accurate but are not an option in a case-crossover design. Also, we measured the oxidative potential of PM10, and smaller particles may have different oxidative properties. However, previous measurements in London showed greater oxidative potential for PM10, suggesting an enrichment of redox-active components in the coarse fraction.7 Further studies with larger sample sizes, more accurate measurements of exposure (such as personal sampling), sampling several PM fractions, and comparing assays to measure oxidative potential are needed to establish the exact mechanism of PM oxidative potential on respiratory exacerbations. Cristina Canova Department of Molecular Medicine University of Padova Padova, Italy Imperial College London, United Kingdom [email protected]; [email protected] Cosetta Minelli Imperial College London, United Kingdom Christina Dunster Frank Kelly King's College London, United Kingdom Pallav L. Shah NHLI, Imperial College London, United Kingdom Chelsea and Westminster Hospital London, United Kingdom Cielito Caneja Chelsea and Westminster Hospital London, United Kingdom Michael K. Tumilty Peter Burney Imperial College London, United Kingdom
Introduction: A usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA) related Interstitial Lung Disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors. Methods: We used two-sample bidirectional Mendelian Randomisation (MR) to investigate the causal effects of RA on UIP and of UIP on RA, using variants from genome-wide association studies of RA (separately for seropositive and seronegative RA) and of IPF as genetic instruments. We conducted inverse-variance-weighted fixed-effect MR as a primary analysis and undertook sensitivity analyses to assess potential violations of the key MR assumption of no (horizontal) pleiotropy. Results: Seropositive RA showed a protective effect on IPF (Odds Ratio, OR = 0·93; 95% Confidence Interval, CI: 0·87-0·99; P=0·032), but this might result from bias due to the definition of IPF in the IPF GWAS. On the other hand, the MR in the other direction showed a strongly significant causal effect of IPF on seropositive RA (OR = 1·06, 95% CI: 1·04-1·08, P=1·22x10-11). Conclusion: Our findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between IPF and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The causal effect of IPF on seropositive RA suggests that patho-mechanisms involved in the development of UIP may promote RA.
Exposure to the complex metal-rich aerosol produced by arc welding is putatively linked to obstructive lung disease in welders through a mechanism of oxidative stress. Given that published studies have been mainly conducted by means of cross-sectional surveys, this research aims systematically to review these; we have previously published a similar review of (the many fewer) longitudinal studies on welders’ lung function decline.
Methods
Medline, Embase and Web of Science were searched up to July 2013 by combining two blocks for exposure (welding fume) and outcomes (FEV1, FVC, FEV1/FVC%, asthma, acute and chronic bronchitis, dyspnoea and wheezing) both containing free text keywords and MeSH terms. Double data extraction was performed independently. To explore possible causes of heterogeneity a subgroup analysis was undertaken to account for country income level, participants’ smoking status and welders’ age.
Results
Fifty-six cross-sectional studies were identified and 40 were included in the review. Of these, 35 were included in a meta-analysis; lung function was measured in 22 studies and symptoms in 30 studies. Compared with non-welders, welding was associated with a statistically significant reduction in FEV1 (SMD= -0.34; 95% CI, -0.57, -0.12; I2=92%) and FEV1/FVC% (SMD= -0.51; 95% CI, -0.94, -0.08; I2=96%). The substantial heterogeneity in both outcomes was explored further but no subgroup analyses explained it. FVC reduction with welding exposure was not statistically significant and highly heterogeneous. Welding was associated with asthma (OR=1.65, 95% CI, 1.14, 2.37; I2=0%), acute bronchitis (OR=1.61, 95% CI, 1.15, 2.27; I2=11%), chronic bronchitis after excluding a large study1 (1.92, 95% CI, 1.50, 2.46; I2=40%), dyspnoea in medium/low income countries (OR=3.54, 95% CI, 1.96, 5.08; I2=0%) and wheezing among non-smokers (OR=9.06, 95% CI, 3.75, 21.9; I2=0%). All risk estimates for symptoms were higher in medium/low income countries.
Conclusions
Welding fume exposure has a negative effect on the respiratory health of workers, possibly leading to obstructive lung disease and increasing the risk of respiratory symptoms particularly in medium/low income countries.
Reference
Groth M, Lyngenbo O. Respiratory symptoms in Danish welders. Scand J Soc Med, 1989;17(4):p. 271–6
Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma.
Exposure to welding fume increases the risk of pneumococcal infection; whether such susceptibility extends to other respiratory infections is unclear. We report findings from a survey and from medical consultation data for workers in a large shipyard in the Middle East.Between January 2013 and December 2013, we collected cross-sectional information from 529 male workers variously exposed to welding fume. Adjusted ORs for respiratory symptoms (cough, phlegm, wheezing, shortness of breath and 'chest illness') were estimated using multivariable logistic regression. Subsequently, we examined consultation records from 2000 to 2011 for 15 954 workers who had 103 840 consultations for respiratory infections; the associations between respiratory infections and levels of welding exposure were estimated using a count regression model with a negative binomial distribution.13% of surveyed workers reported respiratory symptoms with a higher prevalence in winter, particularly among welders. The adjusted OR in welders versus other manual labourers was 1.72 (95% CI 1.02 to 3.01) overall and 2.31 (1.05 to 5.10) in winter months; no effect was observed in summer. The risk of consultation for respiratory infections was higher in welders than in manual labourers, with an adjusted incidence rate ratio of 1.45 (1.59 to 1.83) overall, 1.47 (1.42 to 1.52) in winter and 1.33 (1.23 to 1.44) in summer (interaction, p<0.001).The observation that respiratory symptoms and consultations for respiratory infection in welders are more common in winter may indicate an enhanced vulnerability to a broad range of infections. If confirmed, this would have important implications for the occupational healthcare of a very large, global workforce.
Background: Asthma is among the most common chronic conditions in childhood. We aimed to develop and validate a simple and robust model to predict asthma at 8 years of age. Methods: The data come from 3 UK cohorts in the STELAR consortium. We studied 1,145 children from Ashford and Aberdeen and externally validated the predictive model using data on 348 children from Manchester. Information on characteristics of the children, family related factors and asthma-like symptoms were collected at recruitment and at 1 and 2 or 3 years of age. We defined asthma at age 8 by the presence of at least two of the following: (1) current wheeze; (2) asthma treatment; (3) a doctor9s diagnosis of asthma. We developed a predictive model using the Least Absolute Shrinkage and Selection Operator method (LASSO) and assessed predictive performance by discrimination and calibration measures. Results: Current asthma was present in 117 (22.5%), 119 (21%) and 80 (21.5%) children living in Ashford, Aberdeen and Manchester, respectively.The final model included 20 predictors such as gender, maternal history of hay-fever or eczema, parental history of asthma, older sibling(s), domestic crowding; a doctor9s diagnosis of eczema, current wheeze and antibiotic use, each before the age of 3. Predictive accuracy in the external validation was 0.83, the area under the receiver operating characteristic curve was 0.65 and positive and negative predictive values were 0.81 and 0.83. Conclusion: After validation, our LASSO model demonstrated good discrimination ability for asthma; its predictive performance compares favorably with that from previous tools, such as the API and PIAMA, due to increased specificity and higher positive predictive value.
Background: Chronic Obstructive Pulmonary Disease (COPD) moved from fourth to third commonest cause of death in the world between 1990 and 2010, but little is known of what is driving this change. COPD has been associated with age, poverty and smoking.
Methods: We compared COPD mortality among those aged 40 years and older in 1990 and 2010, using data from the Global Burden of Disease programme. Mortality in 2010 was standardised to the 1990 population to quantify the difference in mortality rates attributable to changes in population. Regional COPD mortality rates for 1990 and 2010 were regressed against age, sex, gross national income/capita and an index of cumulative smoking exposure. Finally, we estimated the percentage of change in COPD mortality risk attributable to changes in age distribution, gross national income and smoking index.
Findings: Total deaths over the age of 40 years fell slightly from 2,995,058 in 1990 to 2,837,877 in 2010, though the number would have risen to 5,231,916 if the age-sex specific rates had remained constant. Changes in smoking led to a small increase in age-sex specific rates, but the main association with the changes in age-sex specific COPD mortality rates was a change in gross national income.
Interpretation: The main drivers of changes in COPD mortality between 1990 and 2010 are changes in age distribution, associated with increased deaths, and improving economic conditions, associated with reduced COPD mortality rates.
Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10−11) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
Rationale: The extent to which current asthma is a predictor of post-bronchodilator airflow obstruction (post-BD AO) in middle-age is not well defined. Aim: To develop a risk prediction model for post-BD AO (post-BD FEV1/FVC<LLN) in middle-aged Australians, and to compare individualized predictions in non-smokers which vary by asthma, age-of-onset and 10-year wheeze status. Methods: Predictor data (smoking, asthma, symptoms, sex, job-type) were from the Tasmanian Longitudinal Health Study (TAHS) cohort at age 41-45 years. Post-BD spirometry/ wheeze status were assessed at age 51-55 years. The model was developed using randomForest®Results: Of n=2,338, 12.9% had current asthma at mean age 43, while 7.3% had wheeze and 4.6% had post-BD AO at age 53. The model’s area under the receiver operator characteristic curve was 80% (95%PI:79–81%), sensitivity 78% (84/107 actual cases) and specificity 66% giving a 98% negative and 10% positive predictive value. For example, a female non-smoking cleaner who reported childhood asthma and wheeze at age 43 had a 10-year predicted probability for post-BD AO of 6.1% if she also reported wheeze at age 53 (predicted occurrence of 1 in 16). The risk was slightly less (5.6%) if wheeze at age 53 was absent. The same pattern was seen for adult-onset asthma (5.7% and 5.2% respectively). Risks were 1.4% for non-asthma and 2.4% for remitted asthma. Conclusion: Our 10-year prediction model has good discriminatory ability but many of those identified did not have lung function consistent with COPD, partly due to a low prevalence in this middle-aged population. For middle-aged non-smokers, the predictions suggest a low-moderate risk for current asthma.
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