Do high participation rates improve effects of population-based general health checks?

The aim is to investigate if the effect of a health check differs between areas with different participation rates. The Inter99 population-based randomized lifestyle intervention study covered 73 areas within the suburbs of Copenhagen, Denmark. Adults aged 30-60years were randomly drawn from a population and were randomized to intervention group (n=11,483) or control group (n=47,122). Participation rates in the health check varied considerably between areas (mean 52%; range 35-85%). In separate survival analyses, area participation rate was included both as a continuous exposure variable and as a categorical variable (tertiles; low: 35-49%, meddle: 50-54%, high: 55-84%). All persons in the intervention and control group were followed in registers for 10-year total mortality and combined events (ischemic heart disease, stroke, or both). In adjusted models (including sociodemographic variables, ethnicity, number of children and comorbidity), among men, there was no difference in risk of death between areas with varying participation rates. Surprisingly, among women living in high-participation areas a significantly higher risk of all-cause mortality (HR: 1.32 [1.03-1.69]) was found in the intervention group (ref=controls). For both men and women, in no areas there was any difference between intervention and control group in incident IHD/stroke. Higher participation rates in population based health checks is probably unlikely to improve the effects of these, and may in worst case be harmful in subgroups of the population. Further well-designed studies within non-participation research should have high priority and are required to establish link between health checks and risk of death in subgroups of the population.

Filaggrin loss-of-function mutations and incident cancer: a population-based study.

BACKGROUND: Loss-of-function mutations in the filaggrin gene (FLG) could have opposing effects on cancer risk, as mutations are associated with both 10% higher serum vitamin D levels, which may protect against cancer, and with impaired skin barrier function, which may lead to higher cancer susceptibility. OBJECTIVES: To investigate the association of the FLG genotype and cancer types in four population-based cohorts. METHODS: A total of 13,376 individuals were genotyped for FLG mutations. Information on cancer was obtained from the Danish Cancer Registry. Persons with a history of cancer at baseline were excluded from prospective analyses. RESULTS: There were 1339 incident cancers (median follow-up 11·4 years). The hazard ratios (HRs) and 95% confidence intervals (CIs) for FLG mutation carriers vs. wild types were: for any cancer (HR 0·95, 95% CI 0·78-1·16), any cancer excluding nonmelanoma skin cancer (NMSC) (HR 1·05, 95% CI 0·84-1·31), head and neck cancer (HR 1·72, 95% CI 0·71-4·15), colorectal cancer (HR 0·82, 95% CI 0·44-1·52), bronchus and lung cancer (HR 1·34, 95% CI 0·77-2·33), breast cancer (HR 0·58, 95% CI 0·30-1·14), uterine cancer (HR 0·42, 95% CI 0·06-3·10), prostate cancer (HR 1·09, 95% CI 0·61-1·94), urinary cancer (HR 1·30, 95% CI 0·51-3·29), malignant melanoma (HR 1·03, 95% CI 0·41-2·58) and NMSC (HR 0·70, 95% CI 0·47-1·05). Among participants aged over 60 years at baseline, we found statistically significant lower risks of all cancers and NMSC among FLG mutation carriers. CONCLUSIONS: The only significant associations between FLG loss-of-function mutations and cancer were in subgroup analyses.

Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose-stimulated insulin release.

AIMS/HYPOTHESIS: By combining multiple genome-wide association (GWA) studies and comprehensive replication efforts, 12 novel type 2 diabetes associated loci have recently been discovered. Here we evaluate the effect of lead variants of these loci on estimates of insulin release and insulin resistance derived from an oral glucose tolerance test. METHODS: We examined 12 lead variants in or near HMGA2, CENTD2 (also known as ARAP1), KLF14, PRC1, TP53INP1, ZBED3, ZFAND6, CHCHD9, DUSP9, KCNQ1, BCL11A and HNF1A in 5,722 middle-aged people from the population-based Inter99 sample. RESULTS: Carriers of the major diabetogenic allele of rs1552224 in CENTD2 had increased 30-min plasma glucose values (2.0%, p = 2 × 10(-5)) as well as 4.2% reduced insulin release 30 min after an oral glucose load (p = 0.001). Risk allele carriers also had decreased BIGTT-acute insulin release (AIR), which is a surrogate measure of insulin release where sex, BMI, plasma glucose and serum insulin are integrated (5.3%, p = 8 × 10(-7)). In addition, a decreased corrected insulin response (CIR; 9.9%, p = 3 × 10(-8)) was observed. For rs5945326 near DUSP9 on the X-chromosome we stratified according to sex. Male carriers of the risk allele showed nominally decreased BIGTT-AIR (2.6%, p = 0.01). No associations with intermediate metabolic traits were found in women. For the remaining ten lead variants no consistent associations were demonstrated. CONCLUSIONS/INTERPRETATION: Of the lead variants from 12 novel type 2 diabetes associated loci, CENTD2 significantly associated with increased plasma glucose values and decreased glucose-stimulated insulin release, suggesting that the diabetogenic effect of this locus is mediated through an impaired pancreatic beta cell function.

The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals.

AIMS/HYPOTHESIS: A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/C2CD4A/C2CD4B locus was replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant and diabetes-related intermediary traits. METHODS: We genotyped the rs7172432 variant in the population-based Inter99 cohort (n = 6,784) and analysed quantitative diabetes-related traits in 5,722 non-diabetic participants who all were examined by an OGTT. RESULTS: The diabetes-associated A allele was associated with 0.60 cm higher waist circumference (p = 0.004), 0.037 mmol/l higher fasting plasma glucose (p = 4 × 10(-5)) and 0.11 mmol/l higher plasma glucose at 30 min during an OGTT (p = 4 × 10(-4)). In analyses adjusted for concomitant insulin sensitivity levels the diabetogenic allele was associated with a lower acute glucose-stimulated insulin response (GSIR) as estimated by 30 min serum insulin (ß = -0.039, p = 2 × 10(-7)), insulinogenic index (ß = -0.057, p = 1 × 10(-8)) and BIGTT-acute insulin release (ß = -0.041, p = 9 × 10(-9)). As rs7172432 is situated in a region previously associated with glycaemic traits, we tested linkage disequilibrium (LD) with the reported regional lead single-nucleotide polymorphisms for fasting (rs11071657) and 2 h plasma glucose (rs17271305), and performed conditional analyses of rs7172432. Rs7172432 showed moderate LD with rs11071657 and rs17271305 (R (2) < 0.34) and we found strong association by almost unchanged effect sizes of rs7172432 with plasma glucose and estimates of GSIR in analyses conditional on rs11071657 and rs17271305. CONCLUSIONS/INTERPRETATION: The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 A allele associates with GSIR in non-diabetic individuals from the general population, suggesting an impaired beta cell function as an intermediary diabetes-related trait.

Does a population-based multifactorial lifestyle intervention increase social inequality in physical activity? The Inter99 study.

AIM: To examine the effect of a multifactorial lifestyle intervention on 5-year change in physical activity (PA) and to explore whether length of education had an impact on the effect of the intervention. METHODS: Two random samples (high intervention group A, n=11 708; low intervention group B, n=1308) were invited for a health examination, assessment of absolute risk of ischemic heart disease and individual lifestyle counselling. The participation rate was 52.5%. High-risk individuals in group A were also offered group-based counselling on diet and PA and/or smoking cessation. High-risk individuals in group B were referred to usual care. All high-risk individuals were reinvited for examination and counselling after 1 and 3 years, and all participants were reexamined after 5 years. The control group (group C, n=5264, response rate 61.1%) answered a mailed questionnaire. Change in self-reported PA from baseline to 5-year follow-up was the main outcome. Level of education was classified as no vocational training, ≤4 years and >4 years. Data were analysed using longitudinal linear regression models with random intercepts. RESULTS: In men, the high-intensity intervention had a beneficial effect on PA level after 5 years. The age- or time-related decrease in PA was approximately 30 min/week less compared to men in the control group (p<0.0001). Level of education had no significant impact on the effect of the intervention neither in men (p=0.39) nor in women (p=0.32). CONCLUSION: A population-based multifactorial lifestyle intervention did not influence social inequality in PA.

Low birthweight and premature birth are both associated with type 2 diabetes in a random sample of middle-aged Danes.

AIMS/HYPOTHESIS: We studied the associations of size at birth and prematurity with type 2 diabetes, insulin sensitivity and beta cell function in the Danish population-based Inter99 study (ClinicalTrials.gov NCT00289237). METHODS: Information about size at birth and prematurity was identified from original midwife records in 4,744 middle-aged Danes. Type 2 diabetes status, insulin sensitivity (Matsuda index) and beta cell function (disposition index) were assessed using a 75 g oral glucose tolerance test. Participants born prematurely were compared with a group of at-term participants born small for gestational age. RESULTS: An increase in birthweight of 1 kg was associated with a 51% (OR 0.49, 95% CI 0.35-0.69) reduced risk of type 2 diabetes. Ponderal index, reflecting thinness at birth, was associated with type 2 diabetes to the same extent as birthweight. The prevalence of type 2 diabetes was increased to a similar degree in participants born prematurely and participants born small for gestational age, although the former had a higher ponderal index at birth. In addition, birthweight z-scores, reflecting fetal growth rate, were unrelated to the risk of type 2 diabetes and to other measures of glucose regulation in participants born prematurely. While low birthweight was inversely associated with insulin sensitivity and beta cell function, prematurity was associated solely with decreased insulin sensitivity. CONCLUSIONS/INTERPRETATION: While the association between birthweight and risk of type 2 diabetes is mediated via combined effects on beta cell function and insulin sensitivity, prematurity seems to influence risk of type 2 diabetes via attenuated insulin sensitivity only and independently of fetal growth rates.

Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight.

AIMS/HYPOTHESIS: The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. METHODS: Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. RESULTS: Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (beta = -33 g [95% CI -55, -10], p = 0.004) and CDKAL1 rs7756992 (beta = -22 g [95% CI -43, -1], p = 0.04). The association for the latter locus was confirmed in a meta-analysis (n = 24,885) (beta = -20 g [95% CI -29, -11], p = 5 x 10(-6)). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p = 0.09); however, in a meta-analysis (n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight (beta = -16 g [95% CI -24, -8], p = 8 x 10(-5)). On average, individuals with high genetic risk (>or=25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (beta = -35 g [95% CI -69, -2], p = 0.037). CONCLUSIONS/INTERPRETATION: We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.

Insulin resistance as a predictor of incident asthma-like symptoms in adults.

BACKGROUND: There is accumulating evidence that obesity is associated with an increased risk of asthma. It has been hypothesized that insulin resistance may be involved in obesity-induced asthma, but till date there is no prospective data on this issue. OBJECTIVE: To investigate the association of obesity and insulin resistance with the incidence of asthma-like symptoms in adults. METHODS: Out of a random sample of 12 934 persons from a general population, 6784 (52.5%) were included and participated in a health examination in 1999-2001. After 5 years they were re-invited and 4516 (66.6%) participated at follow-up. At baseline three obesity measures were considered: body mass index, waist circumference, and waist-to-hip ratio. In addition, fasting glucose and insulin were measured for determination of insulin resistance. Information on asthma-like symptoms at baseline and follow-up were obtained by questionnaires. A total of 3441 participants defined as non-asthmatic at baseline and with complete information on all the considered variables were included in the analyses. Data were controlled for confounding by sex, age, social status, and smoking. RESULTS: All obesity measures were associated with incident wheezing and asthma-like symptoms. In addition, insulin resistance was associated with incident wheezing [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38-2.54] and asthma-like symptoms (OR 1.61, 95% CI 1.23-2.10). The effect of insulin resistance was stronger than that of obesity and was independent of sex. CONCLUSION: We found that insulin resistance was associated with an increased risk of developing asthma-like symptoms. This finding supports the hypothesis that obesity and asthma may be linked through inflammatory pathways also involved in insulin resistance.

Five-year change in physical activity is associated with changes in cardiovascular disease risk factors: the Inter99 study.

OBJECTIVE: To evaluate whether five-year changes in self-reported physical activity level were associated with changes in waist circumference, weight, serum lipids and blood pressure. METHODS: In the Inter99 study (1999-2006) in Copenhagen, Denmark, 4039 men and women (30-60 years) answered questions on lifestyle and provided blood samples and anthropometric measures at baseline and after five years. Multiple regression analyses were performed with five-year value of each cardiovascular biomarker as outcome and change in physical activity level as explanatory variable. RESULTS: Approximately 50% of the study population were men (n=2023). Change in physical activity level was inversely associated with change in weight (p<0.0001), waist (p<0.0001), diastolic blood pressure (p=0.04), total cholesterol (p=0.006), LDL (p=0.007), triglycerides (p=0.02) and with a composite risk score "the Copenhagen risk score" (p<0.0001), and positively associated with HDL in men (p=0.01). CONCLUSION: Five-year changes in physical activity level were significantly associated with relevant changes in weight, waist circumference, diastolic BP and serum lipids in a population-based cohort of adult men and women. Change in physical activity level induced a significant change in HDL concentration in men only. Women's use of hormone replacement therapy may partly explain this gender difference.

Can lifestyle factors explain why body mass index and waist-to-hip ratio increase with increasing tobacco consumption? The Inter99 study.

BACKGROUND: The relationship between smoking, lifestyle, and weight, body mass index (BMI) and waist-to-hip ratio (WH ratio) is complex, and not fully understood. METHODS: In total, 6784 subjects (2408 daily smokers) were included in a population-based study (the Inter99 study) in Denmark. Weight, height, and waist and hip circumference were measured. Self-reported tobacco consumption and lifestyle variables (dietary quality, energy intake, physical activity in leisure time and alcohol consumption) were registered. RESULTS: Daily smokers had a significantly lower BMI and significantly higher WH ratio than never smokers (P<0.001). Unhealthy lifestyle increased with increasing tobacco consumption (P<0.001 for all variables). Both BMI and WH ratio increased with increasing tobacco consumption. The association between increasing WH ratio and increasing tobacco consumption was largely explained by sociodemographic factors, rather than lifestyle factors. However, neither sociodemographic nor lifestyle factors could fully explain the increased BMI associated with heavier smoking. CONCLUSIONS: Sociodemographic and lifestyle factors could not fully explain why BMI increased with increasing daily tobacco consumption, but these factors did largely explain the increasing WH ratio. The relationship between BMI and tobacco consumption is complex, and the public needs to be informed that smoking is not a 'diet'.

Association of obesity and insulin resistance with asthma and aeroallergen sensitization.

BACKGROUND: It has been hypothesized that obesity and insulin resistance may play a role in the development of asthma and allergy. The aim of the study was to examine the association of obesity and insulin resistance with asthma and aeroallergen sensitization. METHODS: Cross-sectional population-based study of 3609 Danish men and women aged 30-60 years. Aeroallergen sensitization was defined as positive levels of specific IgE against a panel of inhalant allergens. Asthma was defined as self-reported physician diagnosed asthma. Allergic asthma was defined as the presence of both asthma and aeroallergen sensitization. The homeostasis model assessment of insulin resistance was used to estimate the degree of insulin resistance. Body mass index, waist-to-hip ratio, and waist circumference were used as measures of obesity. Data were analyzed by multiple logistic regression analyses. RESULTS: Obesity was associated with increased risk of aeroallergen sensitization as well as allergic and nonallergic asthma. Insulin resistance was asssociated with aeroallergen sensitization and allergic asthma, but not nonallergic asthma. The associations of obesity with aeroallegen sensitization and allergic asthma became nonsignificant after adjustment for insulin resistance, whereas the association of obesity with nonallergic asthma was unaffected. No sex-differences were observed. CONCLUSION: Obesity may be related to an increased risk of aeroallergen sensitization and allergic asthma through mechanisms also involved in the development of insulin resistance.

The ban on smokeless tobacco products is systematically violated in Chennai, India.

BACKGROUND: India is the world's third largest consumer of tobacco. There are twice as many users of smokeless tobacco products (STPs) as cigarette smokers. The Government of Tamil Nadu has banned the sale of gutkha and pan masala in 2013. Our aim was to identify the varieties of illegal STP available in Chennai, India. METHODS: In systematically chosen zones and regions of Chennai city, we randomly identified three kinds of kiosks (n = 18) and asked for "gutkha" and "pan masala," one of each product available. Details of each product were reviewed based on the information printed on the sachets. RESULTS: Totally 65 STPs were collected; 26 distinct products and 23 brands. All products were claimed to be "tobacco" by the shop keepers. Sixty-five percent of the products informed to contain tobacco and 15.4% to contain pan masala. Five sachets did not inform about the content; 30.8% did not have a pictorial warning; a text warning was printed on 80.8%, but only two products had the messages in Tamil; 70% had promotional messages printed, and 57% had their registration numbers printed. CONCLUSION: The ban on STP is being systematically violated in Chennai. STP are cheap and easily available and due to promotional laudatory messages and lacking information about the content and warning of health damage, the consumers are left with the perception that they buy more or less harmless product. The Indian Government must introduce policies to control production, import, and sale of illicit STP but we also call for a coordinated international solution.

Adequacy of oxygenation in a group of Danish patients with COPD on long-term oxygen therapy.

The aim of this study was to assess the adequacy of oxygenation in patients with chronic obstructive pulmonary disease (COPD) on long-term oxygen therapy (LTOT) in Copenhagen county. Twenty-six patients were enrolled and assessed prospectively by 24-h pulse oximetry. Patients comprised seven males and 19 females with a mean age of 69 +/- 5 yrs, arterial oxygen tension of 6.5 +/- 0.6 kPa, forced vital capacity of 1.47 L, forced expiratory volume in one second of 0.5 +/- 0.2 L (22 +/- 9% of predicted) and St. George's Respiratory Questionnaire total score of 61 +/- 14. The mean 24-h arterial oxygen saturation measured by pulse oximetry (Sp,O2) was within normal limits (94 +/- 1%), but mild hypoxaemia with a mean Sp,O2 of 89 +/- 4% and a total of 12 +/- 15 desaturation episodes per patient were observed, mostly during daily activities. Multiple regression analysis revealed no significant predictors for patient oxygenation. In summary, 24-h pulse oximetry showed adequate oxygenation in this group of COPD patients on LTOT, though mild hypoxaemia was present during some daily activities.

[Compliance of patients with chronic obstructive lung disease receiving oxygen therapy at home]. / Behandlingskomplians hos patienter med kronisk obstruktiv lungesygdom i behandling med ilt i hjemmet.

Twenty-nine patients with severe chronic obstructive pulmonary disease (COPD) on long-term oxygen therapy (LTOT) were prospectively studied for compliance with therapy. Seven patients (24%) used oxygen < 16 hours/day and their mean 24-hour pulse oximetry showed mild hypoxaemia. In addition, we found that eight patients (28%) were smokers. We suggest that the follow-up of these patients should focus on the daily duration of the use of oxygen and cessation of smoking to optimise the effect of this therapy.

Impact of size at birth and prematurity on adult anthropometry in 4744 middle-aged Danes - The Inter99 study.

Low birth weight is related to increased risk of developing cardiovascular disease and type 2 diabetes in adult life. Since obesity is closely associated with type 2 diabetes and cardiovascular disease, the relationship between size at birth and adult anthropometry is of interest as a mediator of the relationship between birth weight and metabolic diseases. The aim of this study was, therefore, to examine the effect of size at birth and prematurity on measures of adult anthropometry taking adult socio-economic status and lifestyle variables into account. Midwife records with information on mother's age and parity as well as weight, length and maturity at birth were traced in 4744 Danes born between 1939 and 1970. Measures of adult anthropometry (weight, height, body mass index (BMI), waist circumference, hip circumference and waist/hip ratio) had previously been recorded together with information on socio-economic factors, lifestyle and parental diabetes status. Mother's age, parity and diabetes status were associated with offspring birth weight. Size at birth was positively associated with adult height and weight, but only weakly associated with BMI and not associated with waist/hip ratio when adjusted for socio-economic and lifestyle factors. Infants born preterm were less growth restricted at birth and grew to be taller and heavier compared with term infants born small for gestational age. Altogether, this study does not find evidence that obesity or a central fat distribution is mediating the relationship between low birth weight and risk of cardiovascular disease or type 2 diabetes in later life.

Depression and chronic obstructive pulmonary disease (COPD). Impact on survival.

OBJECTIVE: To determine if the presence of depression in patients suffering from chronic obstructive pulmonary disease (COPD) would have an independent impact on mortality. METHOD: Prospective evaluation of the impact of depression according to the ICD-10 criteria for depression. Cox proportional hazards regression was used to evaluate the independent impact of depression after controlling for significant univariate clinical predictors in the data set. Consenting out-patients (n = 49) who meet the criteria for COPD between September 1997 and September 1998. There were no age limits (range: 53-90 years). The sample was 67% female. Survival status at follow-up after a mean of 803 days was measured. RESULTS: At follow-up, 16 patients had died. Depression significantly reduced the mortality risk at follow-up (hazard ratio, 0.30; 95% confidence interval, 0.10-0.93; P = 0.037). The impact of depression remained after control for forced expiratory volume during the first second (FEV1), the only multivariate significant predictor of mortality in the data set (hazard ratio, 0.27; 95% confidence interval, 0.09-0.84; P = 0.024). CONCLUSION: Depression in out-patients suffering from COPD appears to be an independent protector for mortality. Additional studies in larger samples are needed to replicate this finding and to determine possible underlying pathogenetic mechanisms.