Claes Göran Östenson

Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE)

BACKGROUND Ambient air pollution is suspected to cause lung cancer. We aimed to assess the association between long-term exposure to ambient air pollution and lung cancer incidence in European populations. METHODS This prospective analysis of data obtained by the European Study of Cohorts for Air Pollution Effects used data from 17 cohort studies based in nine European countries. Baseline addresses were geocoded and we assessed air pollution by land-use regression models for particulate matter (PM) with diameter of less than 10 μm (PM10), less than 2·5 μm (PM2·5), and between 2·5 and 10 μm (PMcoarse), soot (PM2·5absorbance), nitrogen oxides, and two traffic indicators. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses. FINDINGS The 312 944 cohort members contributed 4 013 131 person-years at risk. During follow-up (mean 12·8 years), 2095 incident lung cancer cases were diagnosed. The meta-analyses showed a statistically significant association between risk for lung cancer and PM10 (hazard ratio [HR] 1·22 [95% CI 1·03-1·45] per 10 μg/m(3)). For PM2·5 the HR was 1·18 (0·96-1·46) per 5 μg/m(3). The same increments of PM10 and PM2·5 were associated with HRs for adenocarcinomas of the lung of 1·51 (1·10-2·08) and 1·55 (1·05-2·29), respectively. An increase in road traffic of 4000 vehicle-km per day within 100 m of the residence was associated with an HR for lung cancer of 1·09 (0·99-1·21). The results showed no association between lung cancer and nitrogen oxides concentration (HR 1·01 [0·95-1·07] per 20 μg/m(3)) or traffic intensity on the nearest street (HR 1·00 [0·97-1·04] per 5000 vehicles per day). INTERPRETATION Particulate matter air pollution contributes to lung cancer incidence in Europe. FUNDING European Communitys Seventh Framework Programme.

Effects of long-term exposure to air pollution on natural-cause mortality: an analysis of 22 European cohorts within the multicentre ESCAPE project

BACKGROUND Few studies on long-term exposure to air pollution and mortality have been reported from Europe. Within the multicentre European Study of Cohorts for Air Pollution Effects (ESCAPE), we aimed to investigate the association between natural-cause mortality and long-term exposure to several air pollutants. METHODS We used data from 22 European cohort studies, which created a total study population of 367,251 participants. All cohorts were general population samples, although some were restricted to one sex only. With a strictly standardised protocol, we assessed residential exposure to air pollutants as annual average concentrations of particulate matter (PM) with diameters of less than 2.5 μm (PM2.5), less than 10 μm (PM10), and between 10 μm and 2.5 μm (PMcoarse), PM2.5 absorbance, and annual average concentrations of nitrogen oxides (NO2 and NOx), with land use regression models. We also investigated two traffic intensity variables-traffic intensity on the nearest road (vehicles per day) and total traffic load on all major roads within a 100 m buffer. We did cohort-specific statistical analyses using confounder models with increasing adjustment for confounder variables, and Cox proportional hazards models with a common protocol. We obtained pooled effect estimates through a random-effects meta-analysis. FINDINGS The total study population consisted of 367,251 participants who contributed 5,118,039 person-years at risk (average follow-up 13.9 years), of whom 29,076 died from a natural cause during follow-up. A significantly increased hazard ratio (HR) for PM2.5 of 1.07 (95% CI 1.02-1.13) per 5 μg/m(3) was recorded. No heterogeneity was noted between individual cohort effect estimates (I(2) p value=0.95). HRs for PM2.5 remained significantly raised even when we included only participants exposed to pollutant concentrations lower than the European annual mean limit value of 25 μg/m(3) (HR 1.06, 95% CI 1.00-1.12) or below 20 μg/m(3) (1.07, 1.01-1.13). INTERPRETATION Long-term exposure to fine particulate air pollution was associated with natural-cause mortality, even within concentration ranges well below the present European annual mean limit value. FUNDING European Communitys Seventh Framework Program (FP7/2007-2011).

Human neuropeptide Y signal peptide gain-of-function polymorphism is associated with increased body mass index: Possible mode of function

Neuropeptide Y (NPY) has been implicated in the control of food intake and energy balance based on many observations in animals. We have studied single nucleotide polymorphisms (SNPs) within the regulatory and coding sequences of the human NPY gene. One variant (1128 T>C), which causes an amino acid change from leucine to proline at codon 7 in the signal peptide of NPY, was associated with increased body mass index (BMI) in two separate Swedish populations of normal and overweight individuals. In vitro transcription and translation studies indicated the unlikelihood that this signal peptide variation affects the site of cleavage and targeting or uptake of NPY into the endoplasmic reticulum (ER). However, the mutant, and to a lesser extent the wild-type, signal peptide by themselves markedly potentiated NPY-induced food intake, as well as hypothalamic NPY receptor signaling. Our findings in humans strongly indicate that the NPY signaling system is implicated in body weight regulation and suggest a new and unexpected functional role of a signal peptide.

Long-term exposure to elemental constituents of particulate matter and cardiovascular mortality in 19 European cohorts : Results from the ESCAPE and TRANSPHORM projects

BACKGROUND Associations between long-term exposure to ambient particulate matter (PM) and cardiovascular (CVD) mortality have been widely recognized. However, health effects of long-term exposure to constituents of PM on total CVD mortality have been explored in a single study only. AIMS The aim of this study was to examine the association of PM composition with cardiovascular mortality. METHODS We used data from 19 European ongoing cohorts within the framework of the ESCAPE (European Study of Cohorts for Air Pollution Effects) and TRANSPHORM (Transport related Air Pollution and Health impacts--Integrated Methodologies for Assessing Particulate Matter) projects. Residential annual average exposure to elemental constituents within particle matter smaller than 2.5 and 10 μm (PM2.5 and PM10) was estimated using Land Use Regression models. Eight elements representing major sources were selected a priori (copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc). Cohort-specific analyses were conducted using Cox proportional hazards models with a standardized protocol. Random-effects meta-analysis was used to calculate combined effect estimates. RESULTS The total population consisted of 322,291 participants, with 9545 CVD deaths. We found no statistically significant associations between any of the elemental constituents in PM2.5 or PM10 and CVD mortality in the pooled analysis. Most of the hazard ratios (HRs) were close to unity, e.g. for PM10 Fe the combined HR was 0.96 (0.84-1.09). Elevated combined HRs were found for PM2.5 Si (1.17, 95% CI: 0.93-1.47), and S in PM2.5 (1.08, 95% CI: 0.95-1.22) and PM10 (1.09, 95% CI: 0.90-1.32). CONCLUSION In a joint analysis of 19 European cohorts, we found no statistically significant association between long-term exposure to 8 elemental constituents of particles and total cardiovascular mortality.

Modifiable Socio-Behavioural Factors Associated with Overweight and Hypertension among Persons Aged 35 to 60 Years in Eastern Uganda

Background Few studies have examined the behavioural correlates of non-communicable, chronic disease risk in low-income countries. The objective of this study was to identify socio-behavioural characteristics associated with being overweight or being hypertensive in a low-income setting, so as to highlight possible interventions and target groups. Methods A population based survey was conducted in a Health and Demographic Surveillance Site (HDSS) in eastern Uganda. 1656 individuals aged 35 to 60 years had their Body Mass Index (BMI) and blood pressure (BP) assessed. Seven lifestyle factors were also assessed, using a validated questionnaire. Logistic regression was used to identify socio-behavioural factors associated with being overweight or being hypertensive. Results Prevalence of overweight was found to be 18% (25.2% of women; 9.7% of men; p<0.001) while prevalence of obesity was 5.3% (8.3% of women; 2.2% of men). The prevalence of hypertension was 20.5%. Factors associated with being overweight included being female (OR 3.7; 95% CI 2.69–5.08), peri-urban residence (OR 2.5; 95% CI 1.46–3.01), higher socio-economic status (OR 4.1; 95% CI 2.40–6.98), and increasing age (OR 1.8; 95% CI 1.12–2.79). Those who met the recommended minimum physical activity level, and those with moderate dietary diversity were less likely to be overweight (OR 0.5; 95% CI 0.35–0.65 and OR 0.7; 95% CI 0.49–3.01). Factors associated with being hypertensive included peri-urban residence (OR 2.4; 95%CI 1.60–3.66), increasing age (OR 4.5; 95% CI 2.94–6.96) and being over-weight (OR 2.8; 95% CI 1.98–3.98). Overweight persons in rural areas were significantly more likely to be hypertensive than those in peri-urban areas (p = 0.013). Conclusions Being overweight in low-income settings is associated with sex, physical activity and dietary diversity and being hypertensive is associated with being overweight; these factors are modifiable. There is need for context-specific health education addressing disparities in lifestyles at community levels in rural Africa.

Serum 25-Hydroxyvitamin D Concentration in Subclinical Carotid Atherosclerosis

Objective—Vitamin D deficiency has been implicated in cardiovascular disease and is associated with multiple cardiovascular risk factors. We investigated the serum 25-hydroxyvitamin D (25(OH)D) concentration in relation to latitude, baseline carotid intima-media thickness (IMT), and IMT progression, the carotid IMT measures being surrogate markers of subclinical atherosclerosis and cardiovascular disease risk. Approach and Results—Serum 25(OH)D concentration was related to high-resolution carotid IMT measures in 3430 middle-aged and elderly subjects with high cardiovascular risk but no prevalent disease, who were recruited at 7 centers in Finland, Sweden, The Netherlands, France, and Italy. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30 after entry into the study, whereas blood samples, clinical data, and information about lifestyle were collected at baseline. Serum 25(OH)D levels were positively associated with latitude (Jonckheere–Terpstra &khgr;=166.643; P<0.001) and, as previously reported, associated with a range of cardiovascular risk factors. There were no independent relationships between 25(OH)D and segment-specific or composite IMT measures in the entire cohort. In analyses stratified by sex, diabetes mellitus, and statin treatment, weak associations with some baseline and progression measures of carotid IMT were observed in males, diabetics, and nonstatin-treated individuals. Conclusions—Levels of 25(OH)D differed across Europe, were highest in the North, showed multiple associations with established and emerging cardiovascular risk factors but were not consistently, independently related to measures of carotid IMT. This argues against a protective role of vitamin D against subclinical atherosclerosis in high-risk individuals.

Functional and genetic analysis in type 2 diabetes of Liver X receptor alleles – a cohort study

BackgroundLiver X receptor alpha (LXRA) and beta (LXRB) regulate glucose and lipid homeostasis in model systems but their importance in human physiology is poorly understood. This project aimed to determine whether common genetic variations in LXRA and LXRB associate with type 2 diabetes (T2D) and quantitative measures of glucose homeostasis, and, if so, reveal the underlying mechanisms.MethodsEight common single nucleotide polymorphisms in LXRA and LXRB were analyzed for association with T2D in one French cohort (N = 988 cases and 941 controls), and for association with quantitative measures reflecting glucose homeostasis in two non-diabetic population-based samples comprising N = 697 and N = 1344 adults. Investigated quantitative phenotypes included fasting plasma glucose, serum insulin, and HOMAIR as measure of overall insulin resistance. An oral glucose tolerance test was performed in N = 1344 of adults. The two alleles of the proximal LXRB promoter, differing only at the SNP rs17373080, were cloned into reporter vectors and transiently transfected, whereupon allele-specific luciferase activity was measured. rs17373080 overlapped, according to in silico analysis, with a binding site for Nuclear factor 1 (NF1). Promoter alleles were tested for interaction with NF1 using direct DNA binding and transactivation assays.ResultsGenotypes at two LXRB promoter SNPs, rs35463555 and rs17373080, associated nominally with T2D (P values 0.047 and 0.026). No LXRA or LXRB SNP associated with quantitative measures reflecting glucose homeostasis. The rs17373080 C allele displayed higher basal transcription activity (P value < 0.05). The DNA-mobility shift assay indicated that oligonucleotides corresponding to either rs17373080 allele bound NF1 transcription factors in whole cell extracts to the same extent. Different NF1 family members showed different capacity to transactivate the LXRB gene promoter, but there was no difference between promoter alleles in NF1 induced transactivation activity.ConclusionVariations in the LXRB gene promoter may be part of the aetiology of T2D. However, the association between LXRB rs35463555 and rs17373080, and T2D are preliminary and needs to be investigated in additional larger cohorts. Common genetic variation in LXRA is unlikely to affect the risk of developing T2D or quantitative phenotypes related to glucose homeostasis.

Estrogen receptor alpha gene variants associate with type 2 diabetes and fasting plasma glucose

Objective Estrogen receptor 1 (ESR1) mediates effects of estrogens on glucose homeostasis. Polymorphisms in intron 1, 2, and 4 of the ESR1 gene have been found to be associated with type 2 diabetes (T2D) in Hungarian, Chinese, and African–American and European–American cohorts. The aim of this study was to investigate the association between ESR1 polymorphisms and T2D as well as quantitative phenotypes related to glucose homeostasis in French and Swedish Caucasians. Methods The French cohort included 941 normoglycemic controls and 988 T2D patients. The Swedish cohort consisted of 1045 controls with normal glucose tolerance, 324 participants with impaired glucose tolerance, and 276 T2D patients. A total of 20 single nucleotide polymorphisms (SNPs) distributed across the ESR1 gene were genotyped. Results SNPs in introns 3 and 4 of the ESR1 gene associated significantly with T2D in the French cohort (rs3020314, rs985694, P=0.0009–0.001) and with fasting plasma glucose in Swedish men (rs9397456, rs3020314 rs3020317, P=0.0002–0.0022) after Bonferroni correction for the analysis of 20 SNPs. In addition, nominal association of ESR1 rs1884051 (P=0.011) with T2D in the French cohort replicates a previously observed association in Finns (empirical P=0.024) (http://www.broad.mit.edu/diabetes/). Conclusion This study provides further evidence that ESR1 genetic polymorphisms are associated with T2D and with fasting plasma glucose. No current evidence that the investigated SNPs are functional is present, thus, we suggest that the association between T2D and ESR1 variants may be because of other unidentified ESR1 polymorphisms that regulate glucose homeostasis.

Decreased cortical bone thickness in spontaneously non-insulin-dependent diabetic GK rats

We studied the occurrence of osteopenia, as reflected by decreased cortical bone thickness, in a nonobese animal model of hereditary non-insulin-dependent diabetes with long duration, i.e., 8-month-old Goto-Kakizaki (GK) rats. In addition, motor nerve-conduction velocity was measured in the GK rats. Age- and weight-matched Wistar rats served as controls. The GK rats displayed marked glucose intolerance, as compared to control rats, in an intraperitoneal glucose tolerance test. Decreased cortical bone thickness by approximately 15%, was evident in X-ray analysis of metatarsal bones (p < 0.001) and humerus (p < 0.05) of the GK rats. Motor nerve-conduction velocity, measured in the sciatic nerve, was also decreased (by 10%) in the GK as compared with the age-matched control rats (p < 0.05). In conclusion, reduction of cortical bone thickness is present in 8-month-old GK rats, which simultaneously demonstrate signs of peripheral neuropathy. Thus, the GK rat appears to be a model of NIDDM suitable for studies of diabetic bone disease in the absence of obesity.

New concepts in the pathogenesis of NIDDM

Two dozen papers present theories on the molecular and genetic mechanisms responsible for the development of glucose intolerance in non-insulin-dependent diabetes mellitus. They cover the regulation of insulin secretion; insulin, insulin receptors, and glucose transporters; insulin action; gluconeog