Dataset Information

Association of Forced Vital Capacity with the Developmental Gene NCOR2.

ABSTRACT: BACKGROUND:Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. METHODS:Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p<0.002; 0.05/25), with a nominal p-value considered as suggestive evidence. For SNPs with evidence of replication, effects on the expression levels of nearby genes in lung tissue were tested in 1,111 lung samples (Lung eQTL consortium), with further functional investigation performed using public epigenomic profiling data (ENCODE). RESULTS:NCOR2-rs12708369 showed strong replication in children (p = 0.0002), with replication unavailable in adults due to low imputation quality. This intronic variant is in a strong transcriptional enhancer element in lung fibroblasts, but its eQTL effects could not be tested due to low imputation quality in the eQTL dataset. SERPINE2-rs6754561 replicated at nominal level in both adults (p = 0.036) and children (p = 0.045), while WNT16-rs2707469 replicated at nominal level only in adults (p = 0.026). The eQTL analyses showed association of WNT16-rs2707469 with expression levels of the nearby gene CPED1. We found no statistically significant eQTL effects for SERPINE2-rs6754561. CONCLUSIONS:We have identified a new gene, NCOR2, in the retinoic acid signalling pathway pointing to a role of vitamin A metabolism in the regulation of FVC. Our findings also support SERPINE2, a COPD gene with weak previous evidence of association with FVC, and suggest WNT16 as a further promising candidate.

SUBMITTER: Minelli C

PROVIDER: S-EPMC4737618 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Association of Forced Vital Capacity with the Developmental Gene NCOR2.

Minelli Cosetta C Dean Charlotte H CH Hind Matthew M Alves Alexessander Couto AC Amaral André F S AF Siroux Valerie V Huikari Ville V Soler Artigas María M Evans David M DM Loth Daan W DW Bossé Yohan Y Postma Dirkje S DS Sin Don D Thompson John J Demenais Florence F Henderson John J Bouzigon Emmanuelle E Jarvis Deborah D Järvelin Marjo-Riitta MR Burney Peter P

PloS one 20160202 2

<h4>Background</h4>Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on l ...[more]

PMID: 26836265

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Project description:RationaleBlack Africans have reduced FVC compared with white persons, but the prevalence and determinants of reduced values are not well understood.ObjectivesTo evaluate the prevalence and factors leading to reduced FVC in a Nigerian population and to examine current theories regarding the determinants of this difference.MethodsWe studied the ventilatory function of 883 adults aged 40 years or older participating in the Burden of Obstructive Lung Disease Study in Ile-Ife, Nigeria. Respondents completed pre- and post-bronchodilator spirometry test and provided information on their smoking history, respiratory symptoms, risk factors, and diagnoses, including anthropometric details. We used standard categories to define body mass index as either underweight, normal, overweight, or obese. We defined reduced FVC as a post-bronchodilator FVC below the lower limit of normal using National Health and Nutrition Examination Survey (NHANES) equations, Global Lung Function Initiative 2012 equations, and local reference equations based on nonsmoking study participants without a respiratory diagnosis. We fit multivariate linear regression models to FVC as a continuous measure, adjusting for age, sex, height, and other confounders.ResultsThe prevalence of reduced FVC was 70.4% for men and 72.8% for women when using NHANES values for white Americans, 17.8% for men and 14.4% for women using NHANES equations for African Americans, and 15.5% for men and 20.5% for women using the Global Lung Function Initiative 2012 equations. Using the equations derived from nonsmoking respondents in the survey without a respiratory diagnosis, the prevalence of reduced FVC was less than 4% for both men and women. FVC was lower in participants who had less than 7 years of education (FVC, -96 ml; 95% confidence interval [CI], -172 to -19), were underweight (FVC, -269 ml; 95% CI, -464 to -73), were overweight (FVC, -132 ml; 95% CI, -219 to -46), and were obese (FVC, -222 ml; 95% CI, -332 to -112).ConclusionsThere is a wide variation in the prevalence of reduced FVC based on the reference standard used. This variation is not satisfactorily explained by factors thought to affect FVC within individual populations. However, the prevalence strongly associates with both education level and body mass index in this population, regardless of the specific standard used.

Project description:BackgroundThe assumption that the assessment of forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)) does not provide additional information in asthmatic children with normal FEV(1) percent predicted has not been adequately tested.ObjectiveWe sought to determine whether the measurement of FEF(25-75) percent predicted offers advantages over FEV(1) percent predicted and FEV(1)/forced vital capacity (FVC) percent predicted for the evaluation of childhood asthma.MethodsThis is a secondary analysis of data from the Pediatric Asthma Controller Trial and the Characterizing the Response to a Leukotriene Receptor Antagonist and Inhaled Corticosteroid trials. Pearson correlation coefficients, Pearson partial correlation coefficients, canonical correlations, and receiver operating characteristic (ROC) curves were constructed.ResultsAmong 437 children with normal FEV(1) percent predicted, FEF(25-75) percent predicted, and FEV(1)/FVC percent predicted were (1) positively correlated with log(2) methacholine PC(20), (2) positively correlated with morning and evening peak expiratory flow percent predicted, and (3) negatively correlated with log(10) fraction of exhaled nitric oxide and bronchodilator responsiveness. Pearson partial correlations and canonical correlations indicated that FEF(25-75) percent predicted was better correlated with bronchodilator responsiveness and log(2) methacholine PC(20) than were FEV(1) percent predicted or FEV(1)/FVC percent predicted. In the ROC curve analysis, FEF(25-75) at 65% of predicted value had a 90% sensitivity and a 67% specificity for detecting a 20% increase in FEV(1) after albuterol inhalation.ConclusionFEF(25-75) percent predicted was well correlated with bronchodilator responsiveness in asthmatic children with normal FEV(1). FEF(25-75) percent predicted should be evaluated in clinical studies of asthma in children and might be of use in predicting the presence of clinically relevant reversible airflow obstruction.

Project description:Purpose: Poor forced vital capacity (FVC) effort has been considered to be the main reason for FVC reduction by the ATS/ERS guideline; however, this has rarely been mentioned in previous studies. The present study aims to determine whether reduced FVC in asthmatic children is correlated to poor FVC effort. Methods: A total of 209 asthmatic children within 5-13 years old were included and divided into reduced FVC ("restricted," n = 66) and typical obstruction group ("obstructed," n = 143). Forced expiratory flows before and after bronchodilation were recorded in asthmatic children. The differences in clinical characteristics, spirometric results, FVC effort, and bronchodilator response were compared between two groups. Exhalation time (ET) was divided into effective ET (ETe) and plateau ET (ETp) by the start point of exhalation plateau on the time-volume curve. FVC effort was assessed by ET, ETp, and back extrapolated volume (EV)/FVC (%). Results: Asthmatic children in the restricted group had significantly higher slow vital capacity (SVC)/FVC (%), higher EV/FVC (%), shorter ET, shorter ETe, and longer ETp, when compared with those with obstructed. In the obstructed group, ET (r = 0.201, P = 0.016) and ETe (r = 0.496, P < 0.001) positively correlated with FVC, and ETp (r = -0.224, P = 0.007) negatively correlated with FVC. In the restricted group, FVC positively correlated with ETe (r = 0.350, P = 0.004) but not ET and ETp. FVC z-score significantly correlated with total IgE (n = 51, r = -0.349, P = 0.012) and with FEF25-75% z-score (n = 66, r = 0.531, P < 0.001) in the restricted group. The further logistic regression revealed that the risk of restricted increased by 1.12 (95% CI, 1.04-1.22, P = 0.005) with every 1% increase in %ΔFVC. In subjects with restricted and bronchodilation tests, %ΔFVC was significantly associated with FeNO (n = 29, r = 0.386, P = 0.039), FEF25-75% z-score (n = 29, r = -0.472, P = 0.010), and SVC/FVC (%) (n = 19, r = 0.477, P = 0.039) but not with EV/FVC (%), ET, ETe, or ETp (P > 0.05). Conclusion: These findings suggested that "poor FVC effort" does not account for the FVC reduction in asthmatic children. Short ET and high SVC/FVC (%) are characteristics of reduced FVC.

Dataset Information

Association of Forced Vital Capacity with the Developmental Gene NCOR2.

Publications

Association of Forced Vital Capacity with the Developmental Gene NCOR2.

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