Bruno H. Stricker

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10−6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

The Rotterdam Study: 2018 update on objectives, design and main results

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45xa0years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40xa0years and over. The findings of the Rotterdam Study have been presented in over 1500 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Prevalence of Pulmonary Hypertension in the General Population: The Rotterdam Study

Background Pulmonary hypertension is characterized by increased pulmonary artery pressure and carries an increased mortality. Population-based studies into pulmonary hypertension are scarce and little is known about its prevalence in the general population. We aimed to describe the distribution of echocardiographically-assessed pulmonary artery systolic pressure (ePASP) in the general population, to estimate the prevalence of pulmonary hypertension, and to identify associated factors. Methods Participants (n = 3381, mean age 76.4 years, 59% women) from the Rotterdam Study, a population-based cohort, underwent echocardiography. Echocardiographic pulmonary hypertension was defined as ePASP>40 mmHg. Results Mean ePASP was 26.3 mmHg (SD 7.0). Prevalence of echocardiographic pulmonary hypertension was 2.6% (95%CI: 2.0; 3.2). Prevalence was higher in older participants compared to younger ones (8.3% in those over 85 years versus 0.8% in those between 65 and 70), and in those with underlying disorders versus those without (5.9% in subjects with COPD versus 2.3%; 9.2% in those with left ventricular systolic dysfunction versus 2.3%; 23.1% in stages 3 or 4 left ventricular diastolic dysfunction versus 1.9% in normal or stage 1). Factors independently associated with higher ePASP were older age, higher BMI, left ventricular diastolic dysfunction, COPD and systemic hypertension. Conclusion In this large population-based study, we show that pulmonary hypertension as measured by echocardiography has a low prevalence in the overall general population in the Netherlands, but estimates may be higher in specific subgroups, especially in those with underlying diseases. Increased pulmonary arterial pressure is likely to gain importance in the near future due to population aging and the accompanying prevalences of underlying disorders.

Adherence to the 2015 Dutch dietary guidelines and risk of non-communicable diseases and mortality in the Rotterdam Study

We aimed to evaluate the criterion validity of the 2015 food-based Dutch dietary guidelines, which were formulated based on evidence on the relation between diet and major chronic diseases. We studied 9701 participants of the Rotterdam Study, a population-based prospective cohort in individuals aged 45xa0years and over [median 64.1xa0years (95%-range 49.0–82.8)]. Dietary intake was assessed at baseline with a food-frequency questionnaire. For all participants, we examined adherence (yes/no) to fourteen items of the guidelines: vegetables (≥200xa0g/day), fruit (≥200xa0g/day), whole-grains (≥90xa0g/day), legumes (≥135xa0g/week), nuts (≥15xa0g/day), dairy (≥350xa0g/day), fish (≥100xa0g/week), tea (≥450xa0mL/day), ratio whole-grains:total grains (≥50%), ratio unsaturated fats and oils:total fats (≥50%), red and processed meat (<300xa0g/week), sugar-containing beverages (≤150xa0mL/day), alcohol (≤10xa0g/day) and salt (≤6xa0g/day). Total adherence was calculated as sum-score of the adherence to the individual items (0–14). Information on disease incidence and all-cause mortality during a median follow-up period of 13.5xa0years (range 0–27.0) was obtained from data collected at our research center and from medical records. Using Cox proportional-hazards models adjusted for confounders, we observed every additional component adhered to was associated with a 3% lower mortality risk (HR 0.97, 95% CI 0.95; 0.98), lower risk of stroke (HR 0.95, 95% CI 0.92; 0.99), chronic obstructive pulmonary disease (HR 0.94, 95% CI 0.91; 0.98), colorectal cancer (HR 0.90, 95% CI 0.84; 0.96), and depression (HR 0.97, 95% CI 0.95; 0.999), but not with incidence of coronary heart disease, type 2 diabetes, heart failure, lung cancer, breast cancer, or dementia. These associations were not driven by any of the individual dietary components. To conclude, adherence to the Dutch dietary guidelines was associated with a lower mortality risk and a lower risk of developing some but not all of the chronic diseases on which the guidelines were based.

Normal spirometry values in healthy elderly: the Rotterdam Study

Although many different reference values for spirometry are available from various studies, the elderly are usually underrepresented. Therefore, our objective was to assess reference values in a sample of healthy participants from a prospective population-based cohort study, including a large proportion of elderly. We included spirometry measurements of healthy, never smokers, from the Rotterdam Study and excluded participants with respiratory symptoms or prescriptions for respiratory medication. Age- and height-specific curves for the 5th (lower limit of normal) and the 50th (median) percentile of Forced Expiratory Volume in 1xa0s (FEV1), Forced Vital Capacity (FVC), and the ratio (FEV1/FVC) were calculated by quantile regression models. The group of healthy elderly study subjects consisted of 1,125 individuals, with a mean age of 68xa0years, ranging from 47 to 96xa0years of age. Sex stratified equations for the median and the lower limit of normal were calculated adjusted for age and height. In this study, we report age- and height-dependent reference limits for FEV1, FVC, and FEV1/FVC in a large population, and prediction equations for the lower limit of normal and median values for a sample containing a large proportion of healthy elderly.

Design of a frailty index among community living middle-aged and older people: The Rotterdam study

OBJECTIVESnTo design a frailty index (FI) and evaluate three methods to handle missing data. Furthermore, we evaluated its construct (i.e., skewed distribution, correlation with age and sub-maximum score) and criterion validity (based on mortality risk).nnnSTUDY DESIGNnWe included 11,539 participants (45± years) from a population-based cohort in the Netherlands. Frailty was measured with a FI, which we constructed based on the accumulation of 45 health-related variables, related to mood, cognition, functional status, diseases and conditions, biomarkers, and nutritional status. A total FI-score was calculated by averaging the scores of the deficits, resulting in a score between 0 and 1, with higher scores indicating increasing frailty. Mean imputation, single- and multiple imputation were applied.nnnMAIN OUTCOME MEASUREnMortality data were obtained by notification from the municipal administration. Median follow-up time was 9.5 years, during which 3902 (34%) participants died.nnnRESULTSnThe median FI for the full population was 0.16 (IQR=0.11-0.23). The distribution of the FI was slightly right-skewed, the absolute maximum score was 0.78 and there was a strong correlation with age (Pearson correlation=0.52;95%CI=0.51-0.54). The adjusted HR per unit increase in FI-score on mortality was 1.05 (95%CI=1.05-1.06). Multiple imputation seemed to provide more robust results than mean imputation.nnnCONCLUSIONnBased on our results we advise to the use of at least 30 deficits from different health domains to construct a FI if data are not imputed. Future research should use the continuous nature of the FI to monitor trajectories in frailty and find preventive strategies.

Dietary mineral intake and lung cancer risk: the Rotterdam Study

ObjectiveLimited data are available on the role of mineral intake in the development of lung cancer (LC). We investigated whether dietary calcium, copper, iron, magnesium, selenium and zinc intake were associated with LC risk.MethodsWe analyzed data from 5435 participants of the Rotterdam Study, a prospective population-based cohort study among subjects aged 55xa0years and older. At baseline (1990–1993), diet was measured by a validated food frequency questionnaire. LC events were diagnosed on the basis of pathology data and medical records. Hazard ratios (HRs) on LC for energy-adjusted mineral intake were calculated using Cox regression models while adjusting for potential confounders.ResultsDuring a follow-up period of 22xa0years, we identified 211 incident cases of LC. A higher zinc intake was associated with 42xa0% reduction in risk of LC (top tertile vs. first tertile: HR 0.58, 95xa0% CI 0.35; 0.94, P-for trendxa0=xa00.039). Similarly, high intake of iron was associated with reduced risk of LC (top tertile vs. first tertile: HR 0.58, 95xa0% CI 0.37; 0.92, P-for trendxa0=xa00.021). There was no association between dietary intake of calcium, copper, magnesium and selenium and LC risk.ConclusionsOur results suggest that dietary zinc and iron intake are associated with reduced risk of LC. No evidence was found for an association between calcium, copper, magnesium and selenium intake and LC risk.

Development of a Healthy Aging Score in the Population-Based Rotterdam Study: Evaluating Age and Sex Differences

OBJECTIVESnTo develop a healthy aging score (HAS), to assess age and sexxa0differences in HAS, and to evaluate the association of the HAS with survival.nnnDESIGNnProspective population-based cohort.nnnSETTINGnInhabitants of Ommoord, Rotterdam, The Netherlands.nnnPARTICIPANTSnA total of 1405 men and 2122 women, mean (standard deviation) age 75.9 (6.4) years.nnnMAIN MEASURESnWe included 7 domains in the total score of HAS: chronic diseases, mental health, cognitive function, physical function, pain, social support, and quality of life; each scored 0, 1, or 2 in each domain. A total score (range 0-14) was constructed and was assessed continuously and in tertiles (13-14: healthy aging, 11-12: intermediate aging, 0-10: poor aging). Sex-specific change in the mean HAS was computed for the age categories of 65-69, 70-74, 75-79, 80-84, and ≥85xa0years. The association between HAS and mortality was assessed with Cox proportional hazards models.nnnRESULTSnMean follow-up was 8.6 (3.4) years. Men had poorer scores in the chronic disease domain than women. However, women had poorer mental health, worse physical function, more pain, and lower quality of life compared with men. The prevalence of healthy aging was higher in men (nxa0=xa0396, 28.2%), than in women (nxa0=xa0526, 24.8%). The mean (standard deviation) HAS was 11.1 (2.2) in men and 10.7 (2.3) in women. Mean HAS was higher in men than in women for all age categories. The β for change in mean HAS across the 5 increasing age categories wasxa0-0.55 (-0.65 toxa0-0.45) in men andxa0-0.65 (-0.73 toxa0-0.57) in women. The age-adjusted hazard ratio per unit increase in HAS with mortality was 0.86 (0.83-0.89) in men, and 0.89 (0.87-0.91) in women.nnnCONCLUSIONSnLevels of HAS were lower in women compared with men, in all age categories. The HAS declined with increasing age for both sexes, albeit slightly steeper in women. The HAS was strongly associated with mortality in both sexes. A better understanding of population healthy aging and sex differences in this regard could aid to implement strategies for sustainable healthcare in aging populations.

Epidemiology and impact of chronic bronchitis in chronic obstructive pulmonary disease

Research on the association between chronic bronchitis and chronic obstructive pulmonary disease (COPD) exacerbations has led to discordant results. Furthermore, the impact of chronic bronchitis on mortality in COPD subjects is unclear. Within the Rotterdam Study, a population-based cohort study of subjects aged ≥45u2005years, chronic bronchitis was defined as having a productive cough for ≥3u2005months per year for two consecutive years. Linear, logistic regression and Cox proportional hazard models were adjusted for age, sex and pack-years. Out of 972 included COPD subjects, 752 had no chronic phlegm production (CB−) and 220 had chronic phlegm production, of whom 172 met the definition of chronic bronchitis (CB+). CB+ subjects were older, more frequently current smokers and had more pack-years than CB− subjects. During a median 6.5u2005years of follow-up, CB+ subjects had greater decline in lung function (−38u2005mL·year−1, 95% CI −61.7–−14.6; p=0.024). CB+ subjects had an increased risk of frequent exacerbations (OR 4.0, 95% CI 2.7–5.9; p<0.001). In females, survival was significantly worse in CB+ subjects compared to CB− subjects. Regarding cause-specific mortality, CB+ subjects had an increased risk of respiratory mortality (hazard ratio 2.16, 95% CI 1.12–4.17; p=0.002). COPD subjects with chronic bronchitis have an increased risk of exacerbations and respiratory mortality compared to COPD subjects without chronic phlegm production. Chronic bronchitis increases the risk of exacerbations and mortality among patients with COPD http://ow.ly/o1fq30bFf9Q

Pulmonary artery to aorta ratio and risk of all-cause mortality in the general population: the Rotterdam Study

A pulmonary artery to aorta ratio (PA:A) >1 is a proxy of pulmonary hypertension. It is not known whether this measure carries prognostic information in the general population and in individuals with chronic obstructive pulmonary disease (COPD). Between 2003 and 2006, 2197 participants from the population-based Rotterdam Study (mean±sd age 69.7±6.7u2005years; 51.3% female), underwent cardiac computed tomography (CT) scanning with PA:A quantification, defined as the ratio between the diameters of the pulmonary artery and the aorta. COPD was diagnosed based on spirometry or clinical presentation and obstructive lung function measured by a treating physician. Cox regression was used to investigate the risk of mortality. We observed no association between 1-sd increase of PA:A and mortality in the general population. Larger PA:A was associated with an increased risk of mortality in individuals with COPD, particularly in moderate-to-severe COPD (hazard ratio 1.36, 95% CI 1.03–1.79). We demonstrated that the risk of mortality in COPD was driven by severe COPD, and that this risk increased with decreasing diffusing capacity. Larger PA:A is not associated with mortality in an older general population, but is an independent determinant of mortality in moderate-to-severe COPD. Measuring PA:A in CT scans obtained for other indications may yield important prognostic information in individuals with COPD. An increased pulmonary artery to aorta ratio is an independent determinant of mortality in moderate-to-severe COPD http://ow.ly/A12C30a0H9f