Genetic association between human chitinases and lung function in COPD.

Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.

Associations of IL6 polymorphisms with lung function decline and COPD.

BACKGROUND: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. METHODS: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV(1)) over 5 years and baseline FEV(1) at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). RESULTS: In the LHS, three IL6 SNPs were associated with decline in FEV(1) (0.023< or =p< or =0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01< or =p< or =0.04 in additive genetic models). CONCLUSION: The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV(1) and susceptibility to COPD in smokers.

Association of genetic variations in the CSF2 and CSF3 genes with lung function in smoking-induced COPD.

Granulocyte-macrophage colony-stimulating factor (CSF), also known as CSF2, and granulocyte CSF, also known as CSF3, are important survival and proliferation factors for neutrophils and macrophages. The objective of the present study was to determine whether single nucleotide polymorphisms (SNPs) of CSF2 and CSF3 are associated with lung function in smoking-induced chronic obstructive pulmonary disease. In total, five SNPs of CSF2 and CSF3 were studied in 587 non-Hispanic white subjects with the fastest (n = 281) or the slowest (n = 306) decline of lung function selected from among continuous smokers in the National Heart, Lung, and Blood Institute Lung Health Study (LHS). These SNPs were also studied in 1,074 non-Hispanic white subjects with the lowest (n = 536) or the highest (n = 538) baseline lung function at the beginning of the LHS. An increase in the number of CSF3 -1719T alleles was significantly associated with protection against low lung function (odds ratio 0.73, 95% confidence interval 0.56-0.95), and was still significant after adjustment for multiple comparisons. There was also a significant association of a CSF3 haplotype with baseline levels of forced expiratory volume in one second. No association was found for CSF2 SNPs and lung function, nor was there evidence of epistasis. In conclusion, genetic variation in colony-stimulating factor 3 is associated with cross-sectionally measured lung function in smokers.

Polymorphisms of interleukin-10 and its receptor and lung function in COPD.

Interleukin (IL)-10 is a type-2 T-helper cell cytokine with a broad spectrum of anti-inflammatory actions. Inflammation plays an important role in the pathogenesis of chronic obstructive pulmonary disease. It was hypothesised that single nucleotide polymorphisms (SNPs) of the genes encoding IL-10 (IL10) and the alpha subunit of its receptor (IL10RA) are associated with changes in, or value of, forced expiratory volume in one second (FEV1) in smoking-induced chronic obstructive pulmonary disease. In total, eleven SNPs of IL10 and IL10RA were studied in 586 White subjects, selected from continuous smokers followed for 5 yrs in the Lung Health Study, who showed the fastest (n=280) and slowest (n=306) decline in FEV1. These 11 SNPs were also studied in 1,072 participants exhibiting the lowest (n=538) and highest (n=534) baseline FEV1 at the beginning of the Lung Health Study. No association was found in the primary analyses. Although a subgroup analysis showed that the IL-10 3368A allele was associated with a fast decline in FEV1, the association did not pass correction for multiple comparisons. No gene-gene interaction of IL10 with IL10RA was found. There was no association of polymorphisms of the genes encoding interleukin-10 and the alpha subunit of its receptor with the rate of decline in, or value of, forced expiratory volume in one second in smoking-induced chronic obstructive pulmonary disease.

Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers.

Genetic variants in the tumour necrosis factor (TNF) gene have been investigated in chronic obstructive pulmonary disease (COPD). However, there are many instances of nonreplication of these associations due to insufficient power or other factors. In this study, a large number of subjects were examined to elucidate whether genetic variations of TNF and/or lymphotoxin A (LTA), which is clustered with TNF, are associated with variations in lung function among smokers. The present authors designed two nested case-control studies in the National Heart, Lung, and Blood Institute Lung Health Study (LHS), which enrolled 5,887 smokers. The first design included continuous smokers who had the fastest (n = 279) and the slowest (n = 304) decline of lung function during the 5-yr follow-up period, and the second included the subjects who had the lowest (n = 533) and the highest (n = 532) post-bronchodilator % predicted forced expiratory volume in one second at the start of the LHS. Within the TNF and LTA region, 10 tagging single-nucleotide polymorphisms were selected and genotyped. Unlike the previous associations between TNF-308 and COPD in Asians, the current study found no association between either of the two phenotypes and the LTA and TNF polymorphisms. In conclusion, these results support the findings of previous studies in late-onset chronic obstructive pulmonary disease in Caucasian populations.

Predicting episodes of poor asthma control in treated patients with asthma.

BACKGROUND: Asthma exacerbations are dangerous, expensive, and difficult to anticipate. OBJECTIVE: To characterize patients with asthma who had asthma episodes and exacerbations during 4 weeks of observation. METHODS: A total of 2032 volunteers with asthma (age, 3-64 years; 62% female subjects) were studied over two 2-week intervals after flu vaccine and placebo. Baseline data, including several asthma questionnaires, were analyzed for prediction of subsequent asthma events as recorded on diaries detailing peak flow, medication use, and health care use. RESULTS: During 28 days of diary collection, 43.2% of participants had at least 1 episode of poor asthma control. Most episodes were characterized by increased use of rescue medications or reductions in peak flow, but nearly 15% of participants had exacerbations characterized by use of systemic corticosteroids, unscheduled health care visits, or both. Episode frequency was highest in children <10 years of age. Additional risk factors were smoking, African American ethnicity, low lung function, and past history of severe asthma. The best predictors were symptom questionnaires, and a simple questionnaire concerning the preceding 2 weeks worked as well as more complex questionnaires or those reflecting longer periods. In regression analyses, questionnaire results, smoking, lung function, ethnicity, and asthma history all were associated with asthma episodes in people older than 10 years, whereas only asthma history was predictive in those <10 years. CONCLUSION: Symptom questionnaires are predictive of subsequent asthma episodes in people older than age 10 years, but not in younger people. CLINICAL IMPLICATIONS: Simple assessments may be helpful in identifying patients most at risk for future asthma episodes.

Mortality in COPD: Role of comorbidities.

Chronic obstructive pulmonary disease (COPD) represents an increasing burden throughout the world. COPD-related mortality is probably underestimated because of the difficulties associated with identifying the precise cause of death. Respiratory failure is considered the major cause of death in advanced COPD. Comorbidities such as cardiovascular disease and lung cancer are also major causes and, in mild-to-moderate COPD, are the leading causes of mortality. The links between COPD and these conditions are not fully understood. However, a link through the inflammation pathway has been suggested, as persistent low-grade pulmonary and systemic inflammation, both known risk factors for cardiovascular disease and cancer, are present in COPD independent of cigarette smoking. Lung-specific measurements, such as forced expiratory volume in one second (FEV(1)), predict mortality in COPD and in the general population. However, composite tools, such as health-status measurements (e.g. St George's Respiratory Questionnaire) and the BODE index, which incorporates Body mass index, lung function (airflow Obstruction), Dyspnoea and Exercise capacity, predict mortality better than FEV(1) alone. These multidimensional tools may be more valuable because, unlike predictive approaches based on single parameters, they can reflect the range of comorbidities and the complexity of underlying mechanisms associated with COPD. The current paper reviews the role of comorbidities in chronic obstructive pulmonary disease mortality, the putative underlying pathogenic link between chronic obstructive pulmonary disease and comorbid conditions (i.e. inflammation), and the tools used to predict chronic obstructive pulmonary disease mortality.

C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease.

BACKGROUND: Although C-reactive protein (CRP) levels are increased in chronic obstructive pulmonary disease (COPD), it is not certain whether they are associated with adverse clinical outcomes. METHODS: Serum CRP levels were measured in 4803 participants in the Lung Health Study with mild to moderate COPD. The risk of all-cause and disease specific causes of mortality was determined as well as cardiovascular event rates, adjusting for important covariates such as age, sex, cigarette smoking, and lung function. Cardiovascular events were defined as death from coronary heart disease or stroke, or non-fatal myocardial infarction or stroke requiring admission to hospital. RESULTS: CRP levels were associated with all-cause, cardiovascular, and cancer specific causes of mortality. Individuals in the highest quintile of CRP had a relative risk (RR) for all-cause mortality of 1.79 (95% confidence interval (CI) 1.25 to 2.56) compared with those in the lowest quintile of CRP. For cardiovascular events and cancer deaths the corresponding RRs were 1.51 (95% CI 1.20 to 1.90) and 1.85 (95% CI 1.10 to 3.13), respectively. CRP levels were also associated with an accelerated decline in forced expiratory volume in 1 second (p < 0.001). The discriminative property of CRP was greatest during the first year of measurement and decayed over time. Comparing the highest and lowest CRP quintiles, the RR was 4.03 (95% CI 1.23 to 13.21) for 1 year mortality, 3.30 (95% CI 1.38 to 7.86) for 2 year mortality, and 1.82 (95% CI 1.22 to 2.68) for > or =5 year mortality. CONCLUSIONS: CRP measurements provide incremental prognostic information beyond that achieved by traditional markers of prognosis in patients with mild to moderate COPD, and may enable more accurate detection of patients at a high risk of mortality.

Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease.

BACKGROUND: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. METHODS: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. RESULTS: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93). CONCLUSIONS: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years.

Bronchodilator response in the lung health study over 11 yrs.

Long-term changes in bronchodilator response in people with mild chronic obstructive pulmonary disease were assessed in this study. Changes in forced expiratory volume in one second (FEV1) in response to isoproterenol was measured in 4,194 participants in the Lung Health Study annually for 5 yrs, and again 11 yrs after study entry. Responses were quantitated in terms of mL (absolute), as per cent of the pre-bronchodilator value (relative), and as a per cent of the predicted normal value (% predicted). At baseline, the mean pre-bronchodilator FEV1 was 75.4% predicted, and responses were small. Relative and percentage predicted responses were similar in males and females; and correlated positively with methacholine reactivity, and negatively with smoking intensity and age. Baseline bronchodilator responses did not correlate with subsequent decline in FEV1. There was a substantial increase in response over the first year of the study, largely due to smoking cessation, with larger increases in those who stopped smoking. After the first year absolute responses changed little in those who maintained smoking cessation, but increased in those who did not. Mean relative and percentage predicted responses increased in all participants throughout the study. There was substantial annual variability of absolute response, and it was poorly reproducible in individual participants. In conclusion, smoking cessation increased bronchodilator response, and response did not predict the rate of decline of forced expiratory volume in one second.

Autopneumonectomy with compensatory lung growth.

A 23-year-old female immigrant from Ethiopia presented with a history of hemoptysis and an abnormal chest x-ray. A computed tomography scan showed that her left lung was greatly shrunken and her right lung was very large but structurally normal. She had a history of multiple respiratory infections as a young child but had been well since the age of five years. Her lung function was within normal limits except for an increased residual volume. It is very likely that her left lung was destroyed early in childhood and that her right lung underwent compensatory growth. She did not show airways obstruction, which is usually seen when compensatory lung growth occurs after surgical removal of lung tissue; this may indicate that, in those cases, the surgery compromised airway function.

Lack of association of group specific component haplotypes with lung function in smokers.

BACKGROUND: Airway inflammation may affect the decrease in lung function that occurs in response to cigarette smoke, and is an important pathological feature in chronic obstructive pulmonary disease (COPD). Group specific component (GC) can act as an inflammatory mediator and may therefore have important influences on the inflammatory reaction in the airway. Several reports have described associations between GC haplotypes and COPD but these remain controversial. In addition, most of these studies were based on a small number of subjects. METHODS: We have studied the contribution of GC haplotypes to the level of lung function in a large cohort of smokers with high or low lung function (mean FEV(1) % predicted 91.8 and 62.6, respectively). The frequency of the three major GC haplotypes (1S, 1F and 2) was investigated in 537 individuals with high lung function and 533 with low lung function. RESULTS: No significant difference was found in the frequency of any GC haplotype between the high and low lung function groups. There was also no significant difference between the groups in genotype frequency of the two single nucleotide polymorphisms that underlie the haplotypes. CONCLUSION: The GC haplotype does not contribute to reduced lung function in this cohort of smokers.

Polymorphisms in the beta2 adrenergic receptor and bronchodilator response, bronchial hyperresponsiveness, and rate of decline in lung function in smokers.

BACKGROUND: Non-specific bronchial hyperresponsiveness (NSBH) is a known predictor of accelerated rate of decline in lung function in smokers. Polymorphisms of the beta(2) adrenergic receptor (ADRB2) have previously been associated with NSBH and bronchodilator response (BDR) in asthmatics. Based on these associations, we hypothesised that ADRB2 polymorphisms would be associated with NSBH and BDR as well as an accelerated rate of decline in lung function among smokers. METHODS: The prevalence of two ADRB2 polymorphisms, Arg16-->Gly and Gln27-->Glu, was examined in 587 smokers chosen from the NHLBI Lung Health Study for having the fastest (n=282) and slowest (n=305) 5 year rate of decline in forced expiratory volume in 1 second (FEV(1); mean DeltaFEV(1) -4.14 and +1.08% predicted/year, respectively). RESULTS: Contrary to our hypothesis, no ADRB2 allele or haplotype was associated with NSBH, BDR, or rate of decline in lung function. However, there was a significant negative association between heterozygosity at position 27 and a fast decline in lung function (adjusted odds ratio 0.56, 95% CI 0.40 to 0.78, p=0.0007). CONCLUSIONS: Heterozygosity at position 27 may be protective against an accelerated rate of decline in lung function. The polymorphism at position 16 does not contribute to the rate of decline in lung function, measures of NSBH, or BDR in smokers.

Association of IL-1beta and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers.

BACKGROUND: There is increasing evidence that the cytokine network is central to the immunopathology of inflammatory airway diseases. The interleukin 1 (IL-1) receptor antagonist (IL-1RN) is a naturally occurring anti-inflammatory agent that binds to the IL-1 receptor but does not possess agonist activity. Each of the genes of the IL-1 locus on chromosome 2q14 is polymorphic. The IL1RN gene contains an 86 bp tandem repeat and allele 2 of this polymorphism has been associated with various inflammatory diseases. The IL-1beta (IL1B) gene contains a promoter polymorphism (C-511T) that has been associated with inflammatory diseases and is in linkage disequilibrium with the IL1RN polymorphism. METHODS: We investigated whether polymorphisms in the IL1B and IL1RN genes were associated with rate of decline of lung function. Genotypes were determined in 284 smokers with a rapid decline in lung function and 306 smokers with no decline in lung function. RESULTS: None of the genotypes was associated with the rate of decline of lung function. However, the distribution of IL1B/IL1RN haplotypes was different between smokers with a rapid decline in lung function and those with no decline in lung function (p=0.0005). CONCLUSION: These results suggest that IL1B/IL1RN haplotypes play a role in the rate of decline in lung function in smokers.

Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study.

We analyzed Lung Health Study (LHS) data to assess the effect of self-reported lower respiratory illnesses resulting in physician visits (LRI) on lung function. Participants were 5,887 smokers aged 35-60 yr, FEV(1)/FVC < 0.70 and FEV(1) of 55-90% predicted. Two-thirds were randomized into an intensive smoking cessation program (SI); one-third were advised only to stop smoking (UC). For 5 yr participants had annual spirometry and questioning regarding LRI. SI had greater rates of smoking cessation than usual care (UC) with fewer LRI (p = 0.0008). Sustained quitters had fewer LRI than continuing smokers (p = 0.0003). In the year LRI occurred, FEV(1) did not change in sustained quitters, but decreased significantly in smokers (p = 0.0001) with some recovery the following year if no LRI occurred. Over 5 yr, LRI had a significant effect on rate of decline of FEV(1) only in smokers. In smokers averaging one LRI/yr over 5 yr there were additional declines in FEV(1) of 7 ml /yr (p = 0.001). Smokers with more than one LRI/yr had greater declines. Chronic bronchitis was associated with increased frequencies of LRI, but did not affect their influence on lung function. Smoking and LRI had an interactive effect on FEV(1) in people with mild COPD, and in smokers frequent LRI may influence the long-term course of the disease.

Susceptibility genes for rapid decline of lung function in the lung health study.

The genes that contribute to the genetic susceptibility to chronic obstructive pulmonary disease (COPD) remain largely unknown. We hypothesized that widely divergent rates of decline in lung function in smokers would be a robust phenotype for detection of genes that contribute to COPD severity. We selected 283 rapid decliners (deltaFEV1 = -154 +/- 3 ml/yr) and 308 nondecliners (deltaFEV1 = +15 +/- 2 ml/yr) from among smokers followed for 5 yr in the NHLBI Lung Health Study. Rapid decline of FEV1 was associated with the MZ genotype of the alpha1-antitrypsin gene (odds ratio [OR] = 2.8, p = 0.03). This association was stronger for a combination of a family history of COPD with MZ (OR = 9.7, p = 0.03). These data suggest that the MZ genotype results in an increased rate of decline in lung function and interacts with other familial factors. Haplotype frequencies of the microsomal epoxide hydrolase (mEH) gene were significantly different between rapid decliners and nondecliners (p = 0.03). A combination of a family history of COPD with homozygosity for the His113/His139 mEH haplotype was also associated with rapid decline of lung function (OR = 4.9, p = 0.04). The alpha1-antitrypsin S and 3' polymorphisms, vitamin D-binding protein isoforms, and tumor necrosis factor (TNF-alpha G-308A and TNF-beta A252G) polymorphisms were not associated with rate of decline of lung function.