Thorarinn Gislason

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 × 10−14, 5.4 × 10−10, 8.6 × 10−17, 1.2 × 10−10 and 6.5 × 10−19, respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 × 10−12) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 × 10−6, 2.2 × 10−5 and 2.4 × 10−4, respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 × 10−8) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Risk factors for rehospitalisation in COPD: role of health status, anxiety and depression

The aim of the present study was to analyse the risk of rehospitalisation in patients with chronic obstructive pulmonary disease and associated risk factors. This prospective study included 416 patients from a university hospital in each of the five Nordic countries. Data included demographic information, spirometry, comorbidity and 12 month follow-up for 406 patients. The hospital anxiety and depression scale and St. Georges Respiratory Questionnaire (SGRQ) were applied to all patients. The number of patients that had a re-admission within 12 months was 246 (60.6%). Patients that had a re-admission had lower lung function and health status. A low forced expiratory volume in one second (FEV1) and health status were independent predictors for re-admission. Hazard ratio (HR; 95% CI) was 0.82 (0.74–0.90) per 10% increase of the predicted FEV1 and 1.06 (1.02–1.10) per 4 units increase in total SGRQ score. The risk of rehospitalisation was also increased in subjects with anxiety (HR 1.76 (1.16–2.68)) and in subjects with low health status (total SGRQ score >60 units). When comparing the different subscales in the SGRQ, the closest relation between the risk of rehospitalisation was seen with the activity scale (HR 1.07 (1.03–1.11) per 4 unit increase). In patients with low health status, anxiety is an important risk factor for rehospitalisation. This may be important for patient treatment and warrants further studies.

Increased prevalence of sleep disturbances and daytime sleepiness in subjects with bronchial asthma: a population study of young adults in three European Countries.

The aim of this study was to investigate whether asthma is associated with decreased quality of sleep and increased daytime sleepiness. The study involved a random population of 2,202 subjects supplemented by 459 subjects with suspected asthma, aged 20-45 yrs. The subjects were from Reykjavik (Iceland), Uppsala and Göteborg (Sweden) and Antwerp (Belgium), and participated in the European Community Respiratory Health Survey. The investigation included a structured interview, methacholine challenge, skinprick tests and a questionnaire on sleep disturbances. Participants in Iceland and Sweden also estimated their sleep times and made peak expiratory flow (PEF) recordings during a period of 1 week. Asthma was defined as self-reported physician-diagnosed asthma with current asthma-related symptoms (n = 267). Difficulties inducing sleep (DIS) and early morning awakenings (EMA) were about twice as common, and daytime sleepiness 50% more common, in asthmatics compared with subjects without asthma. After adjusting for possible confounders, a positive association was found between asthma and: DIS (odds ratio (OR) = 1.8); EMA (OR = 2.0); daytime sleepiness (OR = 1.6); snoring (OR = 1.7); and self reported apnoeas (OR = 3.7). Allergic rhinitis, which was reported by 71% of subjects with asthma, was independently related to DIS (OR = 2.0) and daytime sleepiness (OR = 1.3). A significant correlation was found between the number of asthma-related symptoms and sleep disturbances (p < 0.001). Asthma is associated with decreased subjective quality of sleep and increased daytime sleepiness. Concurrent allergic rhinitis may be an important underlying cause of sleep impairment in asthmatic patients.

Obstructive Sleep Apnea and Cardiovascular Disease: A Perspective and Future Directions

Data from animal and human studies provide a biological plausibility to the notion that obstructive sleep apnea activates pathways that lead to insulin resistance, atherosclerosis and hypertension. Sleep apnea thus activates the same pathways as does obesity. That obstructive sleep apnea is a risk factor for cardiovascular disease is supported by epidemiological association studies. Longitudinal cohort studies also provide evidence that patients with untreated severe sleep apnea have an increased rate of cardiovascular events. But these studies, while highly suggestive, do not provide the evidence needed to convince the skeptic. This would only be obtained by randomized treatment trials with hard cardiovascular endpoints such as cardiac events and deaths. While such studies are in the planning stages, they will be challenging. There are issues about randomizing individuals with severe sleep apnea and excessive sleepiness into no therapy, since they are at known increased risk for car crashes. Thus, lack of therapy puts others on the road at risk as well as the subject with sleep apnea. There is, moreover, the concern that treating obstructive sleep apnea in very obese individuals will have little impact, since any effect of therapy for OSA will be overwhelmed by the effects of obesity itself. Data from randomized treatment trials for cardiovascular endpoints will likely not be available for many years. In the interim, physicians need to consider how to treat such patients. It is proposed that given that CPAP treatment for obstructive sleep apnea is highly effective and essentially totally safe, and that the evidence is suggestive that sleep apnea is a risk factor for cardiovascular disease, then we propose all patients with severe sleep apnea should be treated to reduce cardiovascular risk.

Increased mortality among sleepy snorers: a prospective population based study

BACKGROUND The long term health consequences of snoring and sleep apnoea syndrome are still uncertain. This study was conducted to assess the mortality risk associated with snoring and excessive daytime sleepiness (EDS), the two main symptoms of sleep apnoea syndrome, in men. METHODS In 1984 a sample of 3100 men aged 30–69 responded to a postal questionnaire including questions about snoring, EDS, and the prevalence of various diseases (response rate 77.1%). Mortality data for the period 1985–1995 were collected for the complete sample. RESULTS During the 10 year follow up period 213 men died, 88 of cardiovascular diseases. Compared with subjects with no snoring or EDS in 1984, men with isolated snoring or EDS displayed no significantly increased mortality. The combination of snoring and EDS was associated with a significant increase in mortality. However, the relative rates decreased with increasing age, and in men aged 60 and above no effect on mortality was found. Men below the age of 60 with both snoring and EDS had an age adjusted total death rate which was 2.7 times higher than men with no snoring or EDS (95% CI 1.6 to 4.5). The corresponding age adjusted hazard ratio for cardiovascular mortality was 2.9 (95% CI 1.3 to 6.7) for subjects with both snoring and EDS. Further adjustment for body mass index and reported hypertension, cardiac disease, and diabetes reduced the relative mortality risk associated with the combination of snoring and EDS to 2.2 (95% CI 1.3 to 3.8) and the relative risk of cardiovascular mortality to 2.0 (95% CI 0.8 to 4.7). CONCLUSION Snoring without EDS does not appear to carry an increased risk of mortality. The combination of snoring and EDS appears to be associated with an increased mortality rate, but the effects seems to be age dependent. The increased mortality is partly explained by an association between “snoring and EDS” and cardiovascular disease.

Smoking cessation, lung function, and weight gain : a follow-up study

BACKGROUND Only one population-based study in one country has reported effects of smoking cessation and weight change on lung function, and none has reported the net effect. We estimated the net benefit of smoking cessation, and the independent effects of smoking and weight change on change in ventilatory lung function in the international European Community Respiratory Health Survey. METHODS 6654 participants in 27 centres had lung function measured in 1991-93, when aged 20-44 years, and in 1998-2002. Smoking information was obtained from detailed questionnaires. Changes in lung function were analysed by change in smoking and weight, adjusted for age and height, in men and women separately and together with interaction terms. FINDINGS Compared with those who had never smoked, decline in FEV1 was lower in male sustained quitters (mean difference 5.4 mL per year, 95% CI 1.7 to 9.1) and those who quit between surveys (2.5 mL, -1.9 to 7.0), and greater in smokers (-4.8 mL, -7.9 to -1.6). In women, estimates were 1.3 mL per year (-1.5 to 4.1), 2.8 mL (-0.8 to 6.3) and -5.1 mL (-7.5 to -2.8), respectively. These sex differences were not significant. FEV1 changed by -11.5 mL (-13.3 to -9.6) per kg weight gained in men, and by -3.7 mL per kg (-5.0 to -2.5) in women, which diminished the benefit of quitting by 38% in men, and by 17% in women. INTERPRETATION Smoking cessation is beneficial for lung function, but maximum benefit needs control of weight gain, especially in men.

Risk factors for chronic obstructive pulmonary disease in a European cohort of young adults.

RATIONALE Few studies have investigated the factors associated with the early inception of chronic obstructive pulmonary disease (COPD). OBJECTIVES We investigated COPD risk factors in an international cohort of young adults using different spirometric definitions of the disease. METHODS We studied 4,636 subjects without asthma who had prebronchodilator FEV(1)/FVC measured in the European Community Respiratory Health Survey both in 1991 to 1993 (when they were 20-44 yr old) and in 1999 to 2002. COPD was defined according to the Global Initiative for Chronic Obstructive Lung Disease fixed cut-off criterion (FEV(1)/FVC < 0.70), and two criteria based on the Quanjer and LuftiBus reference equations (FEV(1)/FVC less than lower limit of normal). COPD determinants were studied using two-level Poisson regression models. MEASUREMENTS AND MAIN RESULTS COPD incidence ranged from 1.85 (lower limit of normal [Quanjer]) to 2.88 (Global Initiative for Chronic Obstructive Lung Disease) cases/1,000/yr. Although about half of the cases had smoked less than 20 pack-years, smoking was the main risk factor for COPD, and it accounted for 29 to 39% of the new cases during the follow-up. Airway hyperresponsiveness was the second strongest risk factor (15-17% of new cases). Other determinants were respiratory infections in childhood and a family history of asthma, whereas the role of sex, age, and of being underweight largely depended on the definition of COPD used. CONCLUSIONS COPD may start early in life. Smoking prevention should be given the highest priority to reduce COPD occurrence. Airway hyperresponsiveness, a family history of asthma, and respiratory infections in childhood are other important determinants of COPD. We suggest the need for a definition of COPD that is not exclusively based on spirometry.

Mortality in COPD patients discharged from hospital: the role of treatment and co-morbidity

BackgroundThe aim of this study was to analyse mortality and associated risk factors, with special emphasis on health status, medications and co-morbidity, in patients with chronic obstructive pulmonary disease (COPD) that had been hospitalized for acute exacerbation.MethodsThis prospective study included 416 patients from each of the five Nordic countries that were followed for 24 months. The St. Georges Respiratory Questionnaire (SGRQ) was administered. Information on treatment and co-morbidity was obtained.ResultsDuring the follow-up 122 (29.3%) of the 416 patients died. Patients with diabetes had an increased mortality rate [HR = 2.25 (1.28–3.95)]. Other risk factors were advanced age, low FEV1 and lower health status. Patients treated with inhaled corticosteroids and/or long-acting beta-2-agonists had a lower risk of death than patients using neither of these types of treatment.ConclusionMortality was high after COPD admission, with older age, decreased lung function, lower health status and diabetes the most important risk factors. Treatment with inhaled corticosteroids and long-acting bronchodilators may be associated with lower mortality in patients with COPD.

A sequence variant on 17q21 is associated with age at onset and severity of asthma

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0–5 years OR=1.51, P=6.89·10−9) and adolescence (age: 14–17 years OR=1.71, P=5.47·10−9). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.

Gender differences in prevalence, diagnosis and incidence of allergic and non-allergic asthma: a population-based cohort

Background Although women with severe non-allergic asthma may represent a substantial proportion of adults with asthma in clinical practice, gender differences in the incidence of allergic and non-allergic asthma have been little investigated in the general population. Methods Gender differences in asthma prevalence, reported diagnosis and incidence were investigated in 9091 men and women randomly selected from the general population and followed up after 8–10 years as part of the European Community Respiratory Health Survey. The protocol included assessment of bronchial responsiveness, IgE specific to four common allergens and skin tests to nine allergens. Results Asthma was 20% more frequent in women than in men over the age of 35 years. Possible under-diagnosis of asthma appeared to be particularly frequent among non-atopic individuals, but was as frequent in women as in men. The follow-up of subjects without asthma at baseline showed a higher incidence of asthma in women than in men (HR 1.94; 95% CI 1.40 to 2.68), which was not explained by differences in smoking, obesity or lung function. More than 60% of women and 30% of men with new-onset asthma were non-atopic. The incidence of non-allergic asthma was higher in women than in men throughout all the reproductive years (HR 3.51; 95% CI 2.21 to 5.58), whereas no gender difference was observed for the incidence of allergic asthma. Conclusions This study shows that female sex is an independent risk factor for non-allergic asthma, and stresses the need for more careful assessment of possible non-allergic asthma in clinical practice, in men and women.