Novartis and Pfizer.

Accurately determining the distribution of rare variants is an important goal of human genetics, but resequencing of a sample large enough for this purpose has been unfeasible until now. Here, we applied Sanger sequencing of genomic PCR amplicons to resequence the diabetes-associated genes KCNJ11 and HHEX in 13,715 people (10,422 European Americans and 3,293 African Americans) and validated amplicons potentially harbouring rare variants using 454 pyrosequencing. We observed far more variation (expected variant-site count ∼578) than would have been predicted on the basis of earlier surveys, which could only capture the distribution of common variants. By comparison with earlier estimates based on common variants, our model shows a clear genetic signal of accelerating population growth, suggesting that humanity harbours a myriad of rare, deleterious variants, and that disease risk and the burden of disease in contemporary populations may be heavily influenced by the distribution of rare variants.

Rationale: Recent U.S. data suggest an increased risk of work-related asthma among health care workers, yet only a few specific determinants have been elucidated. Objectives: To evaluate associations of asthma prevalence with occupational exposures in a cross-sectional survey of health care professionals. Methods: A detailed questionnaire was mailed to a random sample (n ϭ 5,600) of all Texas physicians, nurses, respiratory therapists, and occupational therapists with active licenses in 2003. Information on asthma symptoms and nonoccupational asthma risk factors obtained from the questionnaire was linked to occupational exposures derived through an industry-specific job-exposure matrix. Measurements: There were two a priori defined outcomes: (1 ) physiciandiagnosed asthma with onset after entry into health care ("reported asthma") and (2 ) "bronchial hyperresponsiveness-related symptoms," defined through an 8-item symptom-based predictor. Conclusions:The contribution of occupational exposures to asthma in health care professionals is not trivial, meriting both implementation of appropriate controls and further study.

Background: Previous studies have described increased occurrence of asthma among healthcare workers, but to our knowledge there are no validated survey questionnaires with which to study this occupational group. Aims: To develop, validate, and refine a new survey instrument on asthma for use in epidemiological studies of healthcare workers. Methods: An initial draft questionnaire, designed by a multidisciplinary team, used previously validated questions where possible; the occupational exposure section was developed by updating health services specific chemical lists through hospital walk-through surveys and review of material safety data sheets. A cross-sectional validation study was conducted in 118 non-smoking subjects, who also underwent bronchial challenge testing, an interview with an industrial hygienist, and measurement of specific IgE antibodies to common aeroallergens. Results: The final version consisted of 43 main questions in four sections. Time to completion of the questionnaire ranged from 13 to 25 minutes. Test-retest reliability of asthma and allergy items ranged from 75% to 94%, and internal consistency for these items was excellent (Cronbach's a > 0.86). Against methacholine challenge, an eight item combination of asthma related symptoms had a sensitivity of 71% and specificity of 70%; against a physician diagnosis of asthma, this same combination showed a sensitivity of 79% and specificity of 98%. Agreement between self-reported exposures and industrial hygienist review was similar to previous studies and only moderate, indicating the need to incorporate more reliable methods of exposure assessment. Against the aerollergen panel, the best combinations of sensitivity and specificity were obtained for a history of allergies to dust, dust mite, and animals. Conclusions: Initial evaluation of this new questionnaire indicates good validity and reliability, and further field testing and cross-validation in a larger healthcare worker population is in progress. The need for development of more reliable occupational exposure assessment methods that go beyond self-report is underscored.

No abstract

To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.

Background Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk. Methods Three-hundred-forty-one lung cancer cases and 752 volunteer controls age 21–89 years participated in a structured interview, standardized CT scan and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than -950 Hounsfield Units on the inspiratory scan (HUI) and percent voxels less than -856 HU on expiratory scan (HUE). Results The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared to those without, regardless of assessment method, however, in multivariable modeling, only percent voxels < -856 HUE as a continuous measure of air trapping (OR=1.04; 95% CI (1.03, 1.06)) and FEV1/FVC < 0.70 (OR=1.71; 95% CI (1.21, 2.41)) were independent predictors of lung cancer risk. Nearly 10% of lung cancer cases were negative on all objective measures of COPD. Conclusion Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplemental measures at the time of screening for lung cancer. Impact Quantitative measures of air trapping based on imaging provide additional information for the identification of high risk groups who might benefit the most from lung cancer screening.

Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.