The ß(2)-adrenergic receptor (ADRB2) is an important regulator of airway smooth muscle tone. We tested the hypothesis that three functional polymorphisms in the ADRB2 gene (Thr164Ile, Gly16Arg and Gln27Glu) are associated with reduced lung function, asthma or chronic obstructive pulmonary disease (COPD). We first genotyped 8,971 individuals from the Copenhagen City Heart Study for all three polymorphisms. To validate our findings, we genotyped an additional 53,777 individuals from the Copenhagen General Population Study for the Thr164Ile polymorphism. We identified 60,910 Thr164Ile noncarriers, 1,822 heterozygotes and 16 homozygotes. In the Copenhagen City Heart Study, the Thr164Ile genotype was associated with reduced forced expiratory volume in 1 s (FEV(1)) % predicted (trend p = 0.01) and FEV(1)/forced vital capacity (FVC) (p = 0.001): Thr164Ile heterozygotes had 3% and 2% reduced FEV(1) % pred and FEV(1)/FVC, respectively, compared with noncarriers. The odds ratio for COPD in Thr164Ile heterozygotes was 1.46 (95% CI 1.05-2.02). In the Copenhagen General Population Study, the Thr164 genotype associated with reduced FEV(1) % pred (p = 0.04) and FEV(1)/FVC (p
BACKGROUND: Carriers of cystic fibrosis intron-8 5T alleles with high exon-9 skipping could have increased annual lung function decline and increased risk for asthma or chronic obstructive pulmonary disease (COPD). METHODS: We genotyped 9131 individuals from the adult Danish population for cystic fibrosis 5T, 7T, 9T, and F508del alleles, and examined associations between 11 different genotype combinations, and annual FEV1 decline and risk of asthma or COPD. RESULTS: 5T heterozygotes vs. 7T homozygous controls had no increase in annual FEV1 decline, self-reported asthma, spirometry-defined COPD, or incidence of hospitalization from asthma or COPD. In 5T/7T heterozygotes vs. 7T homozygous controls we had 90% power to detect an increase in FEV1 decline of 8 ml, an odds ratio for self-reported asthma and spirometry-defined COPD of 1.9 and 1.7, and a hazard ratio for asthma and COPD hospitalization of 1.8 and 1.6, respectively. Both 5T homozygotes identified in the study showed evidence of asthma, while none of four 5T/F508del compound heterozygotes had severe pulmonary disease. 7T/9T individuals had annual decline in FEV1 of 19 ml compared with 21 ml in 7T homozygous controls (t-test: P = 0.03). 6.7% of 7T homozygotes without an F508del allele in the cystic fibrosis transmembrane conductance regulator gene reported asthma vs. 11% of 7T/9T individuals with an F508del allele (chi2: P = 0.01) and 40% of 7T homozygotes with an F508del allele (P = 0.04). 7T homozygotes with vs. without an F508del allele also had higher incidence of asthma hospitalization (log-rank: P = 0.003); unadjusted and adjusted equivalent hazard ratios for asthma hospitalization were 11 (95%CI: 1.5-78) and 6.3 (0.84-47) in 7T homozygotes with vs. without an F508del allele. CONCLUSION: Polythymidine 5T heterozygosity is not associated with pulmonary dysfunction or disease in the adult Caucasian population. Furthermore, our results support that F508del heterozygosity is associated with increased asthma risk independently of the 5T allele.
Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted and FEV1/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive disabling condition, for which tobacco smoking, environmental pollution, inherited alpha-antitrypsin deficiency and their interactions are predisposing factors. We carried out a family study on COPD in order to address the role of heritable and environmental risk factors at a population level. METHODS: In a nationwide study on familial risks for COPD the Multigeneration Register on 0-72-year-old subjects was linked to the Hospital Discharge Register from years 1987 to 2004. Standardised incidence ratios (SIRs) were calculated for affected singleton siblings, twins and spouses by comparing them with those whose siblings or spouses had no hospitalisation for COPD. RESULTS: More than 14 300 hospitalised cases and 604 affected siblings were identified. The familial SIR for obstructive chronic bronchitis was 4.65, which was higher for those diagnosed at young age but independent of sex or the age differences between the siblings. When both siblings were diagnosed with obstructive chronic bronchitis or emphysema the SIRs were 4.45 and 14.22, respectively. The SIR for obstructive chronic bronchitis in 24 twin pairs was 11.87. The SIR for spouses was about 1.6. CONCLUSIONS: The much higher risk for siblings of patients with COPD than the risk for spouses suggests that heritable effects underlie familial susceptibility to this disease. For the rare familial emphysema, alpha-antitrypsin deficiency may be an important cause. To what extent it also contributes to familial obstructive chronic bronchitis remains to be established. The anticipated gene-environment interactions with sufficient sample size need to be accommodated in future aetiological studies on COPD.
Familial clustering of chronic obstructive pulmonary disease (COPD) is well established, but the familial risk of COPD has not been determined among adoptees. The aim was to determine whether the familial transmission of COPD is related to disease in biological and/or adoptive parents.
Historic cohort study.
80,214 (50% females).
The Swedish Multi-Generation Register was used to follow all Swedish-born adoptees born in 1932-2004 (n=80,214) between 1 January 1964 and 31 December 2010 for COPD (n=1978). The risk of COPD was estimated in adoptees with at least one biological parent with COPD but no adoptive parent with COPD (n=162) compared with adoptees without a biological or adoptive parent with COPD. The risk of COPD was also determined in adoptees with at least one adoptive parent but no biological parent with COPD (n=110), and in adoptees with both affected biological and adoptive parents (n=162).
COPD in adoptees.
Adoptees with COPD in at least one biological parent but no adoptive parent were more likely to have COPD than adoptees without a biological or adoptive parent with COPD (standardised incidence ratio, SIR=1.98 (95% CI 1.69 to 2.31)). The familial SIR for adoptees with both a biological parent and an adoptive parent with COPD was 1.68 (95% CI 1.39 to 2.00). Adoptees with at least one adoptive parent with COPD but no biological parent with COPD were not at an increased risk of COPD (SIR=1.12 (95% CI 0.92 to 1.35)).
The findings of the study show that the familial transmission of COPD is associated with COPD in biological but not adoptive parents, suggesting that genetic or early life factors are important in the familial transmission of COPD.
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Chronic obstructive pulmonary disease (COPD) is a complex disease influenced by multiple genetic and environmental factors. This short communication gives a description of the preliminary genetic results from a case-control study in Bergen, Norway.
A large case-control study in Bergen in 2003-2005 with 6365 invited subjects generated 1954 cases or controls. The overall attendance of invited subjects was 60%, but causes of non-attendance varied considerably among different sources of recruitment.
In this case-control study, the candidate gene SERPINE2 on chromosome 2q has demonstrated significant association to COPD. However, only weak or lacking associations have so far been observed for the other candidate genes examined.
These findings provide support for SERPINE2 as a COPD susceptibility gene in the Norwegian population.