The SERPINE2 gene is associated with chronic obstructive pulmonary disease in two large populations.

Chronic obstructive pulmonary disease (COPD) is a complex disease influenced by multiple genes and environmental factors. A region on chromosome 2q has been shown to be linked to COPD. A positional candidate gene from the chromosome 2q region SERPINE2 (Serpin peptidase inhibitor, clade E [nexin, plasminogen activator inhibitor type 1], member 2), was previously evaluated as a susceptibility gene for COPD in two association studies, but the results were contradictory.To identify the relationship between SERPINE2 polymorphisms and COPD-related phenotypes using family-based and case-control association studies.In the present study, we genotyped 25 single nucleotide polymorphisms (SNPs) from SERPINE2 and analyzed qualitative and quantitative COPD phenotypes in 635 pedigrees with 1,910 individuals and an independent case-control population that included 973 COPD cases and 956 control subjects. The family data were analyzed using family-based association tests. The case-control data were analyzed using logistic regression and linear models.Six SNPs demonstrated significant associations with COPD phenotypes in the family-based association analysis (0.001

Polymorphisms in the superoxide dismutase-3 gene are associated with emphysema in COPD

Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes. We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1), and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n = 389) and smoking controls from the Normative Aging Study (NAS, n = 472). We examined whether the single nucleotide polymorphisms (SNPs) were associated with COPD status, lung function variables, and quantitative computed tomography (CT) measurements of emphysema and airway wall thickness. Furthermore, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n = 3061) and the Boston Early-Onset COPD Study (EOCOPD, n = 949). In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p = .029 and p = .0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p = .048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations. In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies

Genome-wide Association Study Identifies BICD1 as a Susceptibility Gene for Emphysema

Rationale: Chronic obstructive pulmonary disease (COPD), characterized by airflow limitation, is a disorder with high phenotypic and genetic heterogeneity. Pulmonary emphysema is a major but variable component of COPD; familial data suggest that different components of COPD, such as emphysema, may be influenced by specific genetic factors

Quantitative linkage genome scan for atopy in a large collection of Caucasian families

Quantitative phenotypes correlated with a complex disorder offer increased power to detect linkage in comparison to affected-unaffected classifications. Asthma is a complex disorder characterized by periods of bronchial obstruction and increased bronchial hyper reactivity. In childhood and early adulthood, asthma is frequently associated also with quantitative measures of atopy. Genome wide quantitative multipoint linkage analysis was conducted for serum IgE levels and percentage of positive skin prick test (SPT(per)) using three large groups of families originally ascertained for asthma. In this report, 438 and 429 asthma families were informative for linkage using IgE and SPT(per) which represents 690 independent families. Suggestive linkage (LOD > or = 2) was found on chromosomes 1, 3, and 8q with maximum LODs of 2.34 (IgE), 2.03 (SPT(per)), and 2.25 (IgE) near markers D1S1653, D3S2322-D3S1764, and D8S2324, respectively. The results from chromosomes 1 and 3 replicate previous reports of linkage. We also replicate linkage to 5q with peak LODs of 1.96 (SPT(per)) and 1.77 (IgE) at or near marker D5S1480. Our results provide further evidence implicating chromosomes 1, 3, and 5q. The current report represents one of the biggest genome scans so far reported for asthma related phenotypes. This study also demonstrates the utility of increased sample sizes and quantitative phenotypes in linkage analysis of complex disorders

Genome-Wide Association Analysis of Body Mass in Chronic Obstructive Pulmonary Disease

Rationale: Cachexia, whether assessed by body mass index (BMI) or fat free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD) and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among COPD patients suggests a role for genetic susceptibility. Objective: To determine genetic susceptibility loci involved in the development of low body mass and fat free mass index in COPD subjects Methods: A genome-wide association study of BMI was conducted in three independent cohorts of European descent with GOLD Stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE, n=1734), Norway-Bergen cohort (n=851), and a subset of subjects from the National Emphysema Treatment Trial (NETT, n=365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). Measurements and Main Results: In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity associated (FTO) gene, and BMI (p = 4.97 x 10-7) and FFMI (p = 1.19 x 10-7). We replicated the association in a fourth, independent cohort consisting of 502 COPD subjects from COPDGene (p = 6 x 10-3). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume in the first second (FEV1), varied significantly by FTO genotype. Conclusions: Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD