Loci Identified by Genome-wide Association Studies Influence Different Disease-related Phenotypes in Chronic Obstructive Pulmonary Disease

Abstract

Rationale: Genome-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. Objectives: To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations. Methods: The relationship between these three loci and COPDrelated 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 Results: The CHRNA3/5 locus was significantly associated with pack-years of smoking (P 5 0.002 and 3 3 10 24 ), emphysema assessed by a radiologist using high-resolution computed tomography (P 5 2 3 10 24 and 4.8 3 10 25 ), and airflow obstruction (P 5 0.004 and 1.8 3 10 25 ) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV 1 . The HHIP locus was not associated with smoking intensity but was associated with FEV 1 /FVC (P 5 1.9 3 10 24 and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P 5 0.007) and with both retrospectively (P 5 0.015) and prospectively (P 5 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function. Conclusions: The 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.Keywords: COPD exacerbations; nicotine addiction; high-resolution CT; genetic association analysis; emphysema Chronic obstructive pulmonary disease (COPD) is a common condition that is intimately linked with cigarette smoking and is predicted to be the third leading cause of mortality and the fifth leading cause of morbidity in the world by the year 2020 (1). COPD is characterized by the presence of airflow limitation resulting from airway inflammation and remodelling or lung parenchymal destruction with emphysema. Although COPD severity is typically determined by spirometric measures (2), there is extensive heterogeneity in the amount of emphysema, degree of functional impairment, and frequency of exacerbations among patients with COPD with the same level of airflow obstruction (3). COPD can be associated with systemic manifestations, such as cachexia, which can effectively result in impaired functional capacity, worsening dyspnea, reduced health-related quality of life, and increased mortality (4).Familial aggregation studies suggest ...

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

“…These findings were consistent with the results reported in the GWAS. [5][6][7][8] We found that the SNP rs8034191 near CHRNA3/5 locus was significantly associated with pack-years of smoking in the same direction as reported by the GWAS conducted by Pillai et al 7 in COPD cases. The same SNP rs8034191 has also been found to be associated with heavier smoking behaviors by Stevens et al 17 However, in a recent replication casecontrol study in polish population, the same SNP was not associated with pack-years of smoking in COPD cases.…”

“…[5][6][7]11 Genomic DNA was extracted from blood using the commercially extraction kit (Tiangen Biotech Co., Ltd, Beijing, China) according to the manufacturer's instructions. Genotyping was carried out commercially by BGI (Shenzhen, China) using Sequenom's iPLEX SNP genotyping protocol developed for measurement with the MassARRAY mass spectrometer (Sequenom, San Diego, CA, USA).…”

“…5,11,14 Previous GWAS also revealed significant associations between SNPs in this region and COPD-related phenotypes, such as lung function, smoking behavior and emphysema. [7][8][9][10] It was reported that association analysis of quantitative traits can increase power in comparison with qualitative phenotypes and FEV 1 is an important COPD intermediate phenotype that provides a quantitative assessment of COPD severity, we analyzed FEV 1 % predicted and FEV 1 /FVC in our COPD patients who have a wide range of pulmonary function. Using an additive genetic model, four SNPs in IREB2 (rs1964678, rs12593229, rs965604, rs13180) were associated with FEV 1 % predicted and three SNPs in CHRNA3/5 locus (rs16969968, rs8034191, rs1051730) were both associated with FEV 1 % predicted and FEV 1 /FVC after adjusting for age, gender, BMI, pack-years and current smoking status.…”

Genetics of Complex Airway Disease

“…By contrast, HHIP was associated with systemic components of COPD and with the frequency of COPD exacerbations, and FAM13A was associated with lung function (24). Examination of the HHIP locus in a case-control study of current or former smokers with COPD, lung cancer, or normal lung function showed a shared susceptibility between lung cancer and COPD that may be mediated through the epithelial response to smoking (25).…”

Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future

“…60 They used the family-based ICGN cohort as a replication population. They found that the CHRNA3/5 locus was associated with pack years, emphysema and airflow obstruction.…”