Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Abstract: BACKGROUND: Current evidence concerning sedentary behaviour and mortality risk has used single time point assessments of sitting. Little is known about how changes in sitting levels over time affect subsequent mortality risk. AIM: To examine the associations between patterns of sitting time assessed at two time points 11 years apart and risk of all-cause and cardio-metabolic disease mortality. METHODS: Participants were 25,651 adults aged > =20 years old from the Nord-Trondelag Health Study with self-reported total sitting time in 1995-1997 (HUNT2) and 2006-2008 (HUNT3). Four categories characterised patterns of sitting: (1) low at HUNT2/ low at HUNT3, 'consistently low sitting'; (2) low at HUNT2/high at HUNT3, 'increased sitting'; (3) high at HUNT2/low at HUNT3, 'reduced sitting'; and (4) high at HUNT2 /high at HUNT3, 'consistently high sitting'. Associations of sitting pattern with all-cause and cardio-metabolic disease mortality were analysed using Cox regression adjusted for confounders. RESULTS: Mean follow-up was 6.2 years (158880 person-years); 1212 participants died. Compared to 'consistently low sitting', adjusted hazard ratios for all-cause mortality were 1.51 (95% CI: 1.28-2.78), 1.03 (95% CI: 0.88-1.20), and 1.26 (95% CI: 1.06-1.51) for 'increased sitting', 'reduced sitting' and 'consistently high sitting' respectively. CONCLUSIONS: Examining patterns of sitting over time augments single time-point analyses of risk exposures associated with high sitting time. Whilst sitting habits can be stable over a long period, life events (e.g., changing jobs, retiring or illness) may influence sitting trajectories and therefore sitting-attributable risk. Reducing sitting may yield mortality risks comparable to a stable low-sitting pattern.

Abstract: AIMS: We aimed to evaluate bleeding risk in clinical practice in patients with atrial fibrillation (AF) being prescribed dabigatran, rivaroxaban, or apixaban compared with warfarin. METHODS: Using nationwide registries (Norwegian Patient Registry and Norwegian Prescription Database), we identified AF patients with a first prescription of oral anticoagulants between January 2013 and June 2015. Patients were followed until discontinuation or switching of oral anticoagulants, death, or end of follow-up. The primary endpoint was major or clinically relevant non-major (CRNM) bleeding. RESULTS: In total 32 675 AF patients were identified (58% men, median age 74 years): 11 427 patients used warfarin, 7925 dabigatran, 6817 rivaroxaban, and 6506 apixaban. After a median follow-up of 173 days (25th, 75th percentile 84, 340), 2081 (6.37%) patients experienced a first major or CRNM bleeding. Using a Cox proportional hazard model adjusting for baseline characteristics, use of apixaban [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.61-0.80, P < 0.001] and dabigatran (HR 0.74, 95% CI 0.66-0.84, P < 0.001) were associated with a lower risk of major or CRNM bleeding compared with warfarin whereas use of rivaroxaban was not (HR: 1.05, 95% CI 0.94-1.17, P = 0.400). Use of dabigatran and rivaroxaban were associated with higher risk of gastrointestinal bleeding, whereas use of apixaban and dabigatran were associated with lower risk of intracranial bleeding, compared with warfarin. CONCLUSION: In this nationwide cohort study in AF patients, apixaban and dabigatran were associated with a lower risk of major or CRNM bleeding compared with warfarin. The risk of gastrointestinal bleeding was higher with rivaroxaban and dabigatran compared with warfarin.

Abstract: OBJECTIVE: To investigate whether parity, age at menarche, menopausal status, age at menopause, use of oral contraceptives (OC) or use of hormone replacement therapy (HRT) were associated with total knee replacement (TKR) or total hip replacement (THR) due to primary osteoarthritis. METHOD: In a prospective cohort study of 30,289 women from the second and third surveys of the Nord-Trondelag Health Study, data were linked to the Norwegian Arthroplasty Register (NAR) in order to identify TKR or THR due to primary osteoarthritis. Cox proportional hazards models were used to estimate the hazard ratios (HRs). RESULTS: We observed 430 TKRs and 675 THRs during a mean follow-up time of 8.3 years. Increasing age at menarche was inversely associated with the risk of TKR (P-trend < 0.001). Past users and users of systemic HRT were at higher risk of TKR compared to never users (HR 1.42 (95% confidence interval (CI) 1.06-1.90) and HR 1.40 (95% CI 1.03-1.90), respectively). No association was found between parity, age at menarche, menopausal status, age at menopause, oral contraceptive use or HRT use and THR. CONCLUSION: We found that increasing age at menarche reduced the risk of TKR. Past users and users of systemic HRT were at higher risk of TKR compared to never users. Parity did not increase the risk of THR or TKR.

Abstract: The concept of asthma and COPD as separate conditions has been questioned, and the term asthma-COPD overlap syndrome has been introduced. We assessed the prevalence, symptoms, and lifestyle factors of asthma-COPD overlap (ACO) in a large Norwegian population-based study. From 2006 to 2008, a total of 50,777 residents of Nord-Trondelag participated in the Nord-Trondelag Health Study, Norway. They completed questionnaires regarding respiratory symptoms, disease status, and medication use. We estimated the prevalence and 95% confidence intervals of ACO. Additionally, spirometry was used to estimate the prevalence of ACO in a subgroup. The prevalence of self-reported ACO was 1.9%, and in age groups <40, 40-60 and >/=60 years it was 0.7%, 1.4%, and 3.2%, respectively. Among those reporting COPD, the proportion of ACO was 0.56. In the spirometry subgroup when ACO was defined as doctor diagnosed asthma ever and FEV1/FVC < 0.70, the prevalence of ACO was 2.0%. All respiratory symptoms, separately or in combination, as well as medication use were reported most frequently in those with ACO compared to the other groups. Strikingly, we observed a two-fold higher proportion of allergic rhinitis in ACO compared to COPD only. In this Norwegian population, the prevalence of self-reported ACO was 1.9%, and the corresponding proportion of ACO among those with COPD was 0.56. Participants with ACO generally had the highest proportions of respiratory symptoms compared to asthma or COPD.

Abstract: BACKGROUND: Physical activity may counteract the adverse effects of adiposity on cardiovascular mortality; however, the evidence of a similar effect on diabetes is sparse. This study examines whether physical activity may compensate for the adverse effect of adiposity on diabetes risk. METHODS: The study population consisted of 38 231 individuals aged 20 years or more who participated in two consecutive waves of the prospective longitudinal Nord-Trondelag Health Study in Norway: in 1984-1986 and in 1995-1997. A Poisson regression model with SEs derived from robust variance was used to estimate adjusted risk ratios of diabetes between categories of body mass index and physical activity. RESULTS: Risk of diabetes increased both with increasing body mass (Ptrend <0.001) and with decreasing physical activity level (Ptrend <0.001 in men and 0.01 in women). Combined analyses showed that men who were both obese and had low activity levels had a risk ratio of 17 (95% CI 9.52 to 30) compared to men who were normal weight and highly active, whereas obese men who reported high activity had a risk ratio of 13 (95% CI 6.92 to 26). Corresponding analysis in obese women produced risk ratios of 15 (95% CI 9.18 to 25) and 13 (95% CI 7.42 to 21) among women reporting low and high activity levels, respectively. CONCLUSIONS: This study shows that overweight and obesity are associated with a substantially increased risk of diabetes, particularly among those who also reported being physically inactive. High levels of physical activity were associated with a lower risk of diabetes within all categories of body mass index, but there was no clear evidence that being physically active could entirely compensate for the adverse effect of adiposity on diabetes risk.

Abstract: Using a rich Norwegian longitudinal data set, this study explores the effects of different social capital variables on the probability of cigarette smoking. There are four social capital variables available in two waves of our data set. Our results based on probit (and OLS) analyses (with municipality fixed-effects) show that the likelihood of smoking participation is negatively and significantly associated with social capital attributes, namely, community trust (-0.017), participation in organizational activities (-0.032), and cohabitation (-0.045). Significant negative associations were also observed in panel data, pooled OLS, and random effects models for community trust (-0.024; -0.010) and cohabitation (-0.040; -0.032). Fixed-effects models also showed significant negative effects for cohabitation (-0.018). Estimates of alternative instrumental variables (IV) based on recursive bivariate probit and IV-GMM models also confirmed negative and significant effects for three of its characteristics: cohabitation (-0.030; -0.046), community trust (-0.065; -0.075), and participation in organizational activities (-0.035; -0.046). The limitations of our conclusions are discussed, and the significance of our study for the field of social capital and health is described, along with suggested avenues for future research.

Abstract: To investigate the total effect of smoking on total hip or knee replacement (THR/TKR) due to primary osteoarthritis (OA) and to quantify the indirect effect of smoking through body mass index (BMI). Participants from the Nord-Trondelag Health Study (the HUNT Study) were linked to the Norwegian Arthroplasty Register to detect the first THR or TKR due to primary OA. A mediation analysis was used to decompose the total effect of smoking into a direct and indirect effect. BMI was considered a mediator in the analysis. All effects were estimated as hazard ratios (HRs) with 95% confidence intervals (CIs). The indirect effect of smoking mediated through BMI was expressed as a percentage (proportion*100). In total 55 188 participants were followed up during 17.2 years (median). We identified 1322 THRs and 754 TKRs. For men, the total effect of current vs. never smoking revealed a decreased risk of THR (HR 0.59, 95% CI 0.46-0.76) and TKR (HR 0.47, 95% CI 0.32-0.66). For women, current smoking increased the risk of THR (HR 1.34, 95% CI 1.11-1.60). For men, 6% and 7% of the risk reduction for THR and TKR, respectively, was mediated by BMI. We found a negative association between smoking and THR or TKR for men. On the contrary, smoking was associated with increased risk of THR for women. Most of the effect of smoking on joint replacement risk remained unexplained by BMI.

Abstract: BACKGROUND: Suggested strategies in reducing the impact of non-communicable diseases (NCD) are early diagnosing and screening. We have limited proof of benefit of population screening for NCD. Increased mortality in persons with diagnosed NCD has been shown for decades. However, mortality in undetected NCD has barely been studied. This paper explores whether all-cause mortality differed between persons with diagnosed hypothyroidism, type 2 diabetes (T2DM), and hypertension, compared with persons with undetected-, and with persons without the corresponding disease. METHODS: A prospective cohort study of the general population in Nord-Trondelag, Norway. Persons >/=20 years at baseline 1995-97 were followed until death or June 15, 2016. Cox proportional hazards models were used to compute age and multiple adjusted hazard ratios (HR) with 95% confidence intervals (CI) for the association between disease status and all-cause mortality. The number of participants in the hypothyroidism study was 31,960, in the T2DM study 37,957, and in the hypertension study 63,371. RESULTS: Mortality was increased in persons with diagnosed type 2 diabetes and hypertension, compared to persons without corresponding disease; HR 1.69 (95% CI 1.55-1.84) and HR 1.23 (95% CI 1.09-1.39), respectively. Among persons with undetected T2DM, the HR was 1.21 (95% CI 1.08-1.37), whilst among undetected hypothyroidism and hypertension, mortality was not increased compared with persons without the diseases. Further, the association with mortality was stronger in persons with long duration of T2DM (HR 1.96 (95% CI 1.57-2.44)) and hypertension (HR 1.32 (95% CI 1.17-1.49)), compared with persons with short duration (HR 1.29 (1.09-1.53) and HR 1.16 (1.03-1-30) respectively). CONCLUSIONS: Mortality was increased in persons with diagnosed T2DM and hypertension, and in undetected T2DM, compared with persons without the diseases. The strength of the association with mortality in undetected T2DM was however lower compared with persons with diagnosed T2DM, and mortality was not increased in persons with undetected hypothyroidism and hypertension, compared with persons without the diseases. Thus, future research needs to test more thoroughly if early diagnosing of these diseases, such as general population screening, is beneficial for health.

Abstract: Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

Abstract: OBJECTIVE: Tobacco smoking is a risk factor for gastroesophageal reflux, but whether other tobacco products increase the risk is unclear. The aim of this study was to investigate if snus increases the risk of gastroesophageal reflux symptoms (GERS). MATERIAL AND METHODS: The study was based on the third Nord-Trondelag health study (HUNT3), a population-based study of all adult residents in Nord-Trondelag County, Norway, performed in 2006-2009. The association between self-reported severe heartburn/regurgitation and snus use was assessed by logistic regression. RESULTS: Compared to never snus users, daily snus users had a reduced risk of GERS (OR 0.77, 95% confidence interval [CI] 0.64-0.93), while previous snus users and those using <2 boxes of snus/month had an increased risk (OR 1.20, 95% CI 1.00-1.46 and OR 1.41, 95% CI 1.02-1.96, respectively). There was no association between age when starting using snus and GERS. Snus users who started using snus to quit or cut down on cigarette smoking, who started using both snus and cigarettes or cigarettes alone had an increased risk of GERS. Snus users <30 years of age had an increased risk of GERS (OR 1.49, 95% CI 1.02-2.16), while those aged between 50-60 and 60-70 years had a reduced risk (OR 0.67, 95% CI 0.49-0.93 and OR 0.51, 95% CI 0.28-0.94, respectively). CONCLUSIONS: Daily snus users had a reduced risk of GERS. However, previous snus users and subgroups of snus users had an increased risk of GERS indicating reverse causality, such that snus use could increase the risk of GERS.

Abstract: BACKGROUND: Lifestyle risk behaviours are responsible for a large proportion of disease burden and premature mortality worldwide. Risk behaviours tend to cluster in populations. We developed a new lifestyle risk index by including emerging risk factors (sleep, sitting time, and social participation) and examine unique risk combinations and their associations with all-cause and cardio-metabolic mortality. METHODS: Data are from a large population-based cohort study in a Norway, the Nord-Trondelag Health Study (HUNT), with an average follow-up time of 14.1 years. Baseline data from 1995-97 were linked to the Norwegian Causes of Death Registry. The analytic sample comprised 36 911 adults aged 20-69 years. Cox regression models were first fitted for seven risk factors (poor diet, excessive alcohol consumption, current smoking, physical inactivity, excessive sitting, too much/too little sleep, and poor social participation) separately and then adjusted for socio-demographic covariates. Based on these results, a lifestyle risk index was developed. Finally, we explored common combinations of the risk factors in relation to all-cause and cardio-metabolic mortality outcomes. RESULTS: All single risk factors, except for diet, were significantly associated with both mortality outcomes, and were therefore selected to form a lifestyle risk index. Risk of mortality increased as the index score increased. The hazard ratio for all-cause mortality increased from 1.37 (1.15-1.62) to 6.15 (3.56-10.63) as the number of index risk factors increased from one to six respectively. Among the most common risk factor combinations the association with mortality was particularly strong when smoking and/or social participation were included. CONCLUSIONS: This study adds to previous research on multiple risk behaviours by incorporating emerging risk factors. Findings regarding social participation and prolonged sitting suggest new components of healthy lifestyles and potential new directions for population health interventions.