Genomewide Linkage Analysis of Quantitative Spirometric Phenotypes in Severe Early-Onset Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction; airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC). To identify genetic determinants of quantitative spirometric phenotypes, an autosomal 10-cM genomewide scan of short tandem repeat (STR) polymorphic markers was performed in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. Multipoint variance-component linkage analysis (using SOLAR) was performed for quantitative phenotypes, including FEV(1), FVC, and FEV(1)/FVC. In the initial genomewide scan, significant evidence for linkage to FEV(1)/FVC was demonstrated on chromosome 2q (LOD score 4.12 at 222 cM). Suggestive evidence was found for linkage to FEV(1)/FVC on chromosomes 1 (LOD score 1.92 at 120 cM) and 17 (LOD score 2.03 at 67 cM) and to FVC on chromosome 1 (LOD score 2.05 at 13 cM). The highest LOD score for FEV(1) in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on chromosome 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV(1) (LOD score 2.43 at 37 cM) to this region was demonstrated. These observations provide both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions. The significant linkage of FEV(1)/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis.

Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections

“…Furthermore, in recent genomewide scans for COPD, the MBL2 gene locus (10q11) was not among chromosomal regions strongly linked to lung function measurements in middle-aged individuals of the Framingham cohort 22 or families with severe, earlyonset COPD probands. 23 On the other hand, this does not entirely exclude a role for MBL2 in the development of COPD later in life, as is more commonly seen clinically. We have not excluded the possibility that the rare B/B genotype could still be associated with COPD susceptibility, due to greater impairment of host defence, in which case a much larger sample size than ours would be required, and primers that avoid the potential misclassification of A/B and B/B individuals should be employed.…”

Prevalence of COPD in Primary Care Clinics: Correlation with Non-Respiratory Diseases

“…In particular, the patients with liver diseases had a significantly higher prevalence of COPD when the odds ratio was adjusted by the amount of smoking and age. (18,19), lung growth (20), gender (21,22), socioeconomic status (23) and nutrition (24). Furthermore, recently, it has been reported that systemic inflammation could be involved in the pathogenesis of COPD (5)(6)(7), and that COPD patients are at increased risk for several comorbidities including myocardial infarction, osteoporosis, depression and diabetes (1).…”

Scores of asthma and asthma severity reveal new regions of linkage in EGEA study families

“…Since FEV1 (% pred) was studied in only four asthma genome screens, linkage scans conducted for lung function phenotypes in families with early-onset chronic obstructive pulmonary disease (COPD) and from the general population were considered [24]. Among the three linkage signals detected for FEV1, 1p36 was reported to be linked to asthma in two scans [22,25] and 6q14 to eosinophils in one scan [26], whereas linkage to 2q36 was observed for atopy phenotypes in two asthma scans [18,21,22] and for lung function phenotypes in asthmatic families [19] and early-onset COPD families [27,28]. Regarding this latter result, longitudinal studies have shown that asthma is associated with accelerated lung function decline and is a risk factor for COPD [29].…”