Dataset Information

Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers.

ABSTRACT:

Rationale

Previous studies of chronic obstructive pulmonary disease (COPD) have suggested that genetic factors play an important role in the development of disease. However, single-nucleotide polymorphisms that are associated with COPD in genome-wide association studies have been shown to account for only a small percentage of the genetic variance in phenotypes of COPD, such as spirometry and imaging variables. These phenotypes are highly predictive of disease, and family studies have shown that spirometric phenotypes are heritable.

Objectives

To assess the heritability and coheritability of four major COPD-related phenotypes (measurements of FEV1, FEV1/FVC, percent emphysema, and percent gas trapping), and COPD affection status in smokers of non-Hispanic white and African American descent using a population design.

Methods

Single-nucleotide polymorphisms from genome-wide association studies chips were used to calculate the relatedness of pairs of individuals and a mixed model was adopted to estimate genetic variance and covariance.

Measurements and main results

In the non-Hispanic whites, estimated heritabilities of FEV1 and FEV1/FVC were both about 37%, consistent with estimates in the literature from family-based studies. For chest computed tomography scan phenotypes, estimated heritabilities were both close to 25%. Heritability of COPD affection status was estimated as 37.7% in both populations.

Conclusions

This study suggests that a large portion of the genetic risk of COPD is yet to be discovered and gives rationale for additional genetic studies of COPD. The estimates of coheritability (genetic covariance) for pairs of the phenotypes suggest considerable overlap of causal genetic loci.

SUBMITTER: Zhou JJ

PROVIDER: S-EPMC3826281 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers.

Zhou Jin J JJ Cho Michael H MH Castaldi Peter J PJ Hersh Craig P CP Silverman Edwin K EK Laird Nan M NM

American journal of respiratory and critical care medicine 20131001 8

<h4>Rationale</h4>Previous studies of chronic obstructive pulmonary disease (COPD) have suggested that genetic factors play an important role in the development of disease. However, single-nucleotide polymorphisms that are associated with COPD in genome-wide association studies have been shown to account for only a small percentage of the genetic variance in phenotypes of COPD, such as spirometry and imaging variables. These phenotypes are highly predictive of disease, and family studies have sh ...[more]

PMID: 23972146

Similar Datasets

Project description:RationaleSleep disturbance frequently affects patients with chronic obstructive pulmonary disease (COPD), and is associated with reduced quality of life and poorer outcomes. Data indicate that smokers with preserved pulmonary function have clinical symptoms similar to those meeting spirometric criteria for COPD, but little is known about the driving factors for sleep disturbance in this population of emerging interest.ObjectivesTo compare the magnitude and correlates of sleep disturbance between smokers with preserved pulmonary function and those with airflow obstruction.MethodsUsing cross-sectional data from the COPD Outcomes-Based Network for Clinical Effectiveness and Research Translation multicenter registry, we identified participants clinically identified as having COPD with a smoking history of at least 20 pack-years and either preserved pulmonary function or airflow obstruction. We quantified sleep disturbance by T-score measured in the sleep disturbance domain of the Patient-Reported Outcomes Information System questionnaire, and defined a minimum important difference as a T-score difference of two points. We performed univariate and multivariable linear regression to evaluate correlates within each group.ResultsWe identified 100 smokers with preserved pulmonary function and 476 with airflow obstruction. The sleep disturbance T-score was 4.1 points greater among individuals with preserved pulmonary function (95% confidence interval [CI], 2.0-6.3). In adjusted analyses, depression symptom T-score was associated with sleep disturbance in both groups (airflow obstruction: β, 0.61 points; 95% CI, 0.27-0.94; preserved pulmonary function: β, 0.25 points; 95% CI, 0.12-0.38). Of note, lower percent predicted FEV1 was associated with greater sleep disturbance among those with preserved pulmonary function (β, -0.19 points; 95% CI, -0.31 to -0.07), whereas higher FEV1 was associated with greater sleep disturbance among individuals with airflow obstruction (β, 0.06 points; 95% CI, 0.01-0.10).ConclusionsAmong smokers with clinically identified COPD, the severity of sleep disturbance is greater among those with preserved pulmonary function compared with those with airflow obstruction. Nonrespiratory symptoms, such as depression, were associated with sleep disturbance in both groups, whereas the relationship of sleep disturbance with FEV1 differed.

Project description:RationaleGenome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood.ObjectivesTo identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations.MethodsThe relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN).Measurements and main resultsThe CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10⁻⁴), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10⁻⁴ and 4.8 × 10⁻⁵), and airflow obstruction (P = 0.004 and 1.8 × 10⁻⁵) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV₁. The HHIP locus was not associated with smoking intensity but was associated with FEV₁/FVC (P = 1.9 × 10⁻⁴ and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function.ConclusionsThe CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.

Project description:The development of chronic obstructive pulmonary disease, upon exposure to tobacco smoke, is the cumulative effect of defects in several genes. With the aim of understanding the genetic structure that is characteristic of our patient population, we selected forty two single nucleotide polymorphisms of twenty genes based on previous studies and genotyped a total of 382 samples, which included 236 patients and 146 controls using Sequenom MassARRAY system. Allele frequencies of rs2276109 (MMP12) and rs1800925 (IL13) differed significantly between patients and controls (p = 0.013 and 0.044 respectively). Genotype analysis showed association of rs2276109 (MMP12) under additive and dominant models (p = 0.017, p = 0.012 respectively), rs1800925 (IL13) under additive model (p = 0.047) and under recessive model, rs1695 (GSTP1; p = 0.034), rs729631, rs975278, rs7583463 (SERPINE2; p = 0.024, 0.024 and 0.012 respectively), rs2568494, rs10851906 (IREB2; p = 0.026 and 0.041 respectively) and rs7671167 (FAM13A; p = 0.029). The minor alleles of rs1695 (G), rs7671167 (T), rs729631 (G), rs975278 (A) and rs7583463 (A) showed significant negative association whereas those of rs2276109 (G), rs2568494 (A), rs10851906 (G) and rs1800469 (T; TGF-β) showed significant positive association with lung function under different genetic models. Haplotypes carrying A allele of rs2276109, G allele of rs1695 showed negative correlation with lung function. Haplotypes carrying major alleles of rs7671167 (C) of FAM13A and rs729631 (C), rs975278 (G), rs7583463 (C) of SERPINE2 had protective effect on lung function. Haplotypes of IREB2 carrying major alleles of rs2568494 (G), rs2656069 (A), rs10851906 (A), rs965604 (C) and minor alleles of rs1964678 (T), rs12593229 (T) showed negative correlation with lung function. In conclusion, our study replicated the results of most of the previous studies. However, the positive correlation between the minor alleles of rs2568494 (A) and rs10851906 (G) of IREB2 and lung function needs further investigation.

Dataset Information

Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets