Familial Aggregation of Severe, Early-Onset COPD: Candidate Gene Approaches

Early life events can affect health in later life. We hypothesised that low lung function (FEV₁ <80% predicted) in early adulthood (25–40 years) is associated with higher prevalence and earlier incidence of respiratory, cardiovascular, and metabolic abnormalities, and premature death.

In this cohort analysis, we tested this hypothesis using data from the Framingham Offspring Cohort (FOC) and validated our observations in CARDIA (an independent cohort) and GenIII (which includes the direct descendants of FOC participants). These were three general population cohorts that included men and women, who were regularly and prospectively followed up to collect extensive clinical, physiological, biological, and imaging information. Main outcomes were prevalence (in early adulthood) and incidence (during follow-up) of comorbidity, and all-cause mortality. χ² test, unpaired t test, Fisher's exact test, and Cox proportional hazards models were used for data analysis. Differential dropout rates during follow-up were regarded as a potential source of bias.

We found that 111 (10%) of 1161 participants in FOC, 338 (13%) of 2648 participants in CARDIA, and 71 (4%) of 1912 participants in GenIII had FEV₁ of less than 80% predicted at the age of 25–40 years. These individuals also had higher prevalence of respiratory, cardiovascular, and metabolic abnormalities in early adulthood; higher and earlier (about a decade) incidence of comorbidities during follow-up (39 years vs 47 years in FOC; 30 years vs 37 years in CARDIA, p<0·0001); and higher all-cause mortality than individuals with normal lung function in early adulthood (in FOC, hazard ratio 2·3 [95% CI 1·4–3·7], p=0·001), which was independent of, but additive with, cumulative smoking exposure. In GenIII, we observed that individuals with at least one parent stratified as having low lung function in early adulthood in FOC (n=115) had lower FEV₁ in early adulthood (10% had FEV₁ of less than 80% predicted; this proportion was 3% in those with both parents classified as normal in FOC [n=248]; p<0·0001); and early adulthood FEV₁ of GenIII participants was related (R²=0·28, p<0·0001) to FOC parents' average FEV₁ in early adulthood.

Low peak lung function in early adulthood is common in the general population and could identify a group of individuals at risk of early comorbidities and premature death.

Fondo de Investigacion Sanitaria, Sociedad Española de Neumologia y Cirurgia Torácica, Formació Personal Investigador, Agencia de Gestió d'Ajuts de Recerca 2016, and AstraZeneca Foundation Young Researcher Award.

The risk factors for acute episodes of respiratory disease in current and former smokers who do not have COPD are unknown.

Eight thousand two hundred forty-six non-Hispanic white and black current and former smokers in the Genetic Epidemiology of COPD (COPDGene) cohort had longitudinal follow-up (LFU) every 6 months to determine acute respiratory episodes requiring antibiotics or systemic corticosteroids, an ED visit, or hospitalization. Negative binomial regression was used to determine the factors associated with acute respiratory episodes. A Cox proportional hazards model was used to determine adjusted hazard ratios (HRs) for time to first episode and an acute episode of respiratory disease risk score.

At enrollment, 4,442 subjects did not have COPD, 658 had mild COPD, and 3,146 had moderate or worse COPD. Nine thousand three hundred three acute episodes of respiratory disease and 2,707 hospitalizations were reported in LFU (3,044 acute episodes of respiratory disease and 827 hospitalizations in those without COPD). Major predictors included acute episodes of respiratory disease in year prior to enrollment (HR, 1.20; 95% CI, 1.15-1.24 per exacerbation), airflow obstruction (HR, 0.94; 95% CI, 0.91-0.96 per 10% change in % predicted FEV₁), and poor health-related quality of life (HR, 1.07; 95% CI, 1.06-1.08 for each 4-unit increase in St. George's Respiratory Questionnaire score). Risks were similar for those with and without COPD.

Although acute episode of respiratory disease rates are higher in subjects with COPD, risk factors are similar, and at a population level, there are more episodes in smokers without COPD.

Air pollutants have, and continue to be, major contributing factors to chronic diseases and mortality, subsequently impacting public health. Chronic diseases include: chronic obstructive pulmonary diseases (COPD), cardiovascular diseases (CVD), asthma, and cancer. Byproducts of oxidative stress found in air pollutants are common initiators or promoters of the damage produced in such chronic diseases. Such air pollutants include: ozone, sulfur oxides, carbon monoxide, nitrogen oxides, and particulate matter. Interaction between oxidative stress byproducts and certain genes within our population may modulate the expression of specific chronic diseases. In this brief review we attempt to provide some insight into what we currently know about the health problems associated with various air pollutants and their relationship in promoting chronic diseases through changes in oxidative stress and modulation of gene expression. Such insight eventually may direct the means for effective public health prevention and treatment of diseases associated with air pollution and treatment of diseases associated with air pollution.

Weight loss occurs frequently in patients with chronic obstructive pulmonary disease (COPD). Although the precise cellular mechanisms underlying weight loss in COPD are unclear, this is a clinically relevant phenomenon because it contributes to limit the exercise capacity of these patients and, therefore, it jeopardizes their quality of life. More importantly, it is a negative prognostic factor that is independent of the degree of lung function impairment present. Thus, weight loss in COPD constitutes a new therapeutic target. This article reviews the mechanisms and potential consequences of weight loss in COPD and highlights areas that needed future research. It is hoped that a better understanding of its pathogenesis may eventually contribute to the development of new therapeutic strategies that contribute to improve the well-being and/or long-term prognosis of patients suffering from this devastating disease and, potentially, from others characterized also by unexplained weight loss.

Clinical asthma is very widely assumed to be the net result of excessive inflammation driven by aberrant T-helper-2 (Th2) immunity that leads to inflamed, remodelled airways and then functional derangement that, in turn, causes symptoms. This notion of disease is actually poorly supported by data, and there are substantial discrepancies and very poor correlation between inflammation, damage, functional impairment, and degree of symptoms. Furthermore, this problem is compounded by the poor understanding of the heterogeneity of clinical disease. Failure to recognise and discover the underlying mechanisms of these major variants or endotypes of asthma is, arguably, the major intellectual limitation to progress at present. Fortunately, both clinical research and animal models are very well suited to dissecting the cellular and molecular basis of disease endotypes. This approach is already suggesting entirely novel pathways to disease—eg, alternative macrophage specification, steroid refractory innate immunity, the interleukin-17–regulatory T-cell axis, epidermal growth factor receptor co-amplification, and Th2-mimicking but non-T-cell, interleukins 18 and 33 dependent processes that can offer unexpected therapeutic opportunities for specific patient endotypes.