Insomnia symptoms and risk for atrial fibrillation - The HUNT study.

Studies on the effect of insomnia on atrial fibrillation risk in the general population are limited, therefore we investigated the association between insomnia and the risk of atrial fibrillation in a large-scale population-based study with valid atrial fibrillation measure. A total of 33,983 participants (55% women) reported their insomnia symptoms in the third wave of the HUNT study (between 2006 and 2008) in Norway, and they were followed for their first atrial fibrillation diagnosis until 2020 using hospital registers. Atrial fibrillation diagnoses were validated by physicians based on medical records and electrocardiograms. Insomnia symptoms were assessed by four questions, and analysed both individually and as cumulative symptoms. Cox regression, adjusted for age, sex, social and marital status, working in shiftwork, alcohol consumption, smoking, physical activity, body mass index, systolic blood pressure, and symptoms of anxiety and depression, was conducted. Overall, 1592 atrial fibrillation cases were identified during the follow-up and 31.6% of individuals reported at least one insomnia symptom. In our analysis, we did not detect meaningful associations between insomnia symptoms and the risk of atrial fibrillation. In conclusion, in this population there was no evidence for an association between insomnia symptoms and the risk of subsequent atrial fibrillation.

Preconception diet in adolescence and its association with hypertensive disorders of pregnancy and preterm birth. Results from the HUNT study.

Our aim was to estimate associations of adolescent dietary patterns and meal habits with hypertensive disorders of pregnancy (HDP) and preterm birth. We used data from a prospective cohort study (Norwegian Young-HUNT1) where dietary information was collected during adolescence and pregnancy outcomes were obtained through record linkage to the Norwegian national birth registry. The outcomes were HDP, hypertension, pre-eclampsia/eclampsia, and preterm birth in the first pregnancy and in any pregnancy. Diet was self-reported from validated questionnaires, and exposures were dietary indexes (healthy; unhealthy; fruit and vegetable; fibre index) and meal habits. Recruitment took place in schools. Eligible participants were females aged 13-19 years at the time of dietary assessment with a subsequent singleton pregnancy (n 3622). Women who reported a higher fibre intake in adolescence had a lower risk of pre-eclampsia in the first pregnancy (Relative Risk: 0·84; 95 % CI 0·7, 1·0), although this was weaker in sensitivity analyses. Regular meal habits in mid-adolescence (aged 13-15 years), particularly breakfast and lunch, were weakly associated with a lower risk of hypertension in pregnancy. Our results are the first to indicate an association between aspects of diet and dietary behaviour in mid-adolescence and subsequent HDP. More evidence is needed from larger studies to replicate the results and from alternative study designs to disentangle causality.

The causal role of C-reactive protein and interleukin-6 on anxiety and depression symptoms and life satisfaction: Mendelian randomisation analyses in the HUNT study.

BACKGROUND: Serum levels of C-reactive protein (CRP) and interleukin-6 (IL-6) have been associated with anxiety and depression in cross-sectional and Mendelian randomisation studies, but results regarding the effect size and direction have been mixed. A recent Mendelian Randomisation (MR) study suggested that CRP may decrease and IL-6 may increase anxiety and depression symptoms. METHODS: Among 68 769 participants of the population-based Trøndelag Health Study (HUNT), we performed cross-sectional observational and one-sample MR analyses of serum CRP and two-sample MR analysis of serum IL-6. The main outcomes were symptoms of anxiety and depression assessed using the Hospital Anxiety and Depression Scale (HADS) and life satisfaction assessed using a seven-level ordinal questionnaire where higher scores indicate lower life satisfaction. RESULTS: In cross-sectional observational analyses, a doubling in serum CRP level was associated with 0.27% (95% CI -0.20 to 0.75) difference in HADS depression score (HADS-D), -0.77% (95% CI -1.24 to -0.29) difference in HADS anxiety score (HADS-A) and -0.10% (95% CI -0.41 to 0.21) difference in life satisfaction score. In one-sample MR analyses, a doubling in serum CRP was associated with 2.43% (95% CI -0.11 to 5.03) higher HADS-D, 1.94% (95% CI -0.58 to 4.52) higher HADS-A, and 2.00% (95% CI 0.45 to 3.59) higher life satisfaction score. For IL-6, causal point estimates were in the opposite direction, but imprecise and far from conventional criteria for statistical significance. CONCLUSIONS: Our results do not support a major causal role of serum CRP on anxiety and depression symptoms and life satisfaction, but provides weak evidence that serum CRP may modestly increase anxiety and depression symptoms and reduce life satisfaction. Our findings do not support the recent suggestion that serum CRP may lower anxiety and depression symptoms.

Body mass index and incidence of lung cancer in the HUNT study: using observational and Mendelian randomization approaches.

BACKGROUND: Traditional observational studies have shown an inverse association between body mass index (BMI) and lung cancer risk. Mendelian randomization (MR) analysis using genetic variants as instruments for BMI may clarify the nature of the association. AIMS: We studied the causal association between BMI and lung cancer incidence using observational and MR approaches. METHODS: We followed up 62,453 cancer-free Norwegian adults from 1995-97 (HUNT2) until 2017. BMI at baseline in HUNT2 was classified as < 25.0, 25.0-29.9 and ≥ 30.0 kg/m2. BMI change over ten years between HUNT1 (1984-86) and HUNT2 was calculated and classified into quartiles. Seventy-five genetic variants were included as instruments for BMI (among which 14 also associated with smoking behavior). Incident lung cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Multivariable MR was used to examine the effect of BMI after genetically controlling for smoking. RESULTS: During a median follow-up of 21.1 years, 1009 participants developed lung cancer including 327 with lung adenocarcinoma. The HRs and 95% CIs for incidence of adenocarcinoma were 0.73 (0.58-0.92) for BMI 25.0-29.9 kg/m2 and 0.53 (0.37-0.76) for BMI ≥ 30 kg/m2 compared with BMI < 25.0 kg/m2 in HUNT2 (P for trend < 0.001). However, there was little evidence of a dose-response relationship between the BMI change from HUNT1 to HUNT2 in quartiles and the incidence of adenocarcinoma (P for trend = 0.08). Furthermore, multivariable MR approach suggested a positive association between genetically determined 1 kg/m2 increase in BMI and the incidence of adenocarcinoma (HR 1.25, 95% CI 1.02-1.53). No associations were found with other lung cancer histologic types. CONCLUSIONS: Our study suggests that the inverse association between baseline BMI and lung adenocarcinoma in observational analysis may not be causal. More MR studies are needed to confirm our finding of a positive association between BMI and lung adenocarcinoma.

Physical activity, sugar-sweetened beverages, whole grain bread and insomnia among adolescents and psychological distress in adulthood: prospective data from the population-based HUNT study.

BACKGROUND: In this study, we examined the relationship between low levels of physical activity, high consumption of sugar-sweetened beverages and low consumption of whole grain bread and experiencing insomnia in adolescence and psychological distress in young adults. METHODS: This prospective study was based on information retrieved from the Trøndelag Health Study (HUNT) in Norway and included adolescents (age 13-19) participating in Young-HUNT3 (2006-2008) and in HUNT4 (2017-2019) 11 years later (age 23-31). The study sample consisted of 2,230 participants (1,287 females and 943 males). The exposure variables collected in adolescence included self-reported physical activity, consumption of sugar-sweetened beverages and whole grain bread and insomnia, and psychological distress in young adulthood was used as an outcome variable. The relationship between lifestyle behaviours in adolescence and psychological distress in young adulthood was examined using multivariable logistic regression, adjusted for gender, age and psychological distress in adolescence and educational level in young adulthood. RESULTS: An increased odds of psychological distress was shown among young adults who reported low levels of physical activity (OR: 1.44, 95 % CI: 1.10-2.89), high consumption of sugar-sweetened beverages (OR: 1.49, 95 % CI: 1.12-1.98), low consumption of whole grain bread (OR: 1.35, 95 % CI: 1.04-1.77) and insomnia (OR: 1.69, 95 % CI: 1.23-2.33) in adolescence. In terms of absolute differences, unhealthy lifestyle behaviours increased the risk of psychological distress in young adulthood between 3.18 (95 % CI: 0.29-6.07) (low whole grain bread consumption) and 6.01 (95 % CI: 1.95-10.07) (insomnia) percentage points. CONCLUSIONS: Low levels of physical activity, high consumption of sugar-sweetened beverages and low consumption of whole grain bread and insomnia during adolescence were associated with psychological distress in young adulthood.

Genetic polymorphisms associated with sleep-related phenotypes; relationships with individual nocturnal symptoms of insomnia in the HUNT study.

BACKGROUND: In recent years, several GWAS (genome wide association studies) of sleep-related traits have identified a number of SNPs (single nucleotides polymorphism) but their relationships with symptoms of insomnia are not known. The aim of this study was to investigate whether SNPs, previously reported in association with sleep-related phenotypes, are associated with individual symptoms of insomnia. METHODS: We selected participants from the HUNT study (Norway) who reported at least one symptom of insomnia consisting of sleep onset, maintenance or early morning awakening difficulties, (cases, N = 2563) compared to participants who presented no symptoms at all (controls, N = 3665). Cases were further divided in seven subgroups according to different combinations of these three symptoms. We used multinomial logistic regressions to test the association among different patterns of symptoms and 59 SNPs identified in past GWAS studies. RESULTS: Although 16 SNPS were significantly associated (p < 0.05) with at least one symptom subgroup, none of the investigated SNPs remained significant after correction for multiple testing using the false discovery rate (FDR) method. CONCLUSIONS: SNPs associated with sleep-related traits do not replicate on any pattern of insomnia symptoms after multiple tests correction. However, correction in this case may be overly conservative.

Female sex hormones and risk of incident abdominal aortic aneurysm in Norwegian women in the HUNT study.

OBJECTIVE: The delayed development of abdominal aortic aneurysm (AAA) in women compared with men might be secondary to a protective effect from endogenous estrogens. The role of postmenopausal hormone therapy remains unclear. The aim of the present study was to evaluate the effect of female sex hormones compared with other risk factors associated with AAA through a long-term study of a large female cohort. METHODS: The present prospective cohort study included 20,024 postmenopausal women from the Norwegian Nord-Trøndelag Health Study. A total of 201 cases of AAA were identified during a median follow-up period of 18 years (295,554 person-years; 1995-2014). The data were recorded from questionnaires, physical measurements, medical records, blood sample test results, and the Norwegian Cause of Death Registry. The effect of risk factors was evaluated in a multiple Cox regression analysis. Multiple imputation was performed for missing data (n = 50 data sets). The serum estradiol concentrations in women with and without incidental AAAs were compared. The median interval from blood sample collection to the AAA diagnosis was 7 years. RESULTS: Current smokers had >10-fold increased risk of incident AAA during the follow-up period (hazard ratio [HR], 10.9; 95% confidence interval [CI], 7.4-16.1). Positive associations were found for hypertension (HR, 2.0; 95% CI, 1.4-3.0) and coronary heart disease (HR, 2.2; 95% CI, 1.6-3.2). The HR associated with the current use of postmenopausal hormone therapy was 0.58 (95% CI, 0.6-1.5). No substantial difference in estradiol concentrations was found between women with and without AAA (P = .075). CONCLUSIONS: The effect of female sex hormones on the risk of incident AAAs in women, as evaluated by the serum concentrations of estradiol and the use of postmenopausal hormone therapy, is clinically less important than the strong associations found with smoking, hypertension, and coronary heart disease.

Powerful extreme phenotype sampling designs and score tests for genetic association studies.

We consider cross-sectional genetic association studies (common and rare variants) where non-genetic information is available or feasible to obtain for N individuals, but where it is infeasible to genotype all N individuals. We consider continuously measurable Gaussian traits (phenotypes). Genotyping n < N extreme phenotype individuals can yield better power to detect phenotype-genotype associations, as compared to randomly selecting n individuals. We define a person as having an extreme phenotype if the observed phenotype is above a specified threshold or below a specified threshold. We consider a model where these thresholds can be tailored to each individual. The classical extreme sampling design is to set equal thresholds for all individuals. We introduce a design (z-extreme sampling) where personalized thresholds are defined based on the residuals of a regression model including only non-genetic (fully available) information. We derive score tests for the situation where only n extremes are analyzed (complete case analysis) and for the situation where the non-genetic information on N - n non-extremes is included in the analysis (all case analysis). For the classical design, all case analysis is generally more powerful than complete case analysis. For the z-extreme sample, we show that all case and complete case tests are equally powerful. Simulations and data analysis also show that z-extreme sampling is at least as powerful as the classical extreme sampling design and the classical design is shown to be at times less powerful than random sampling. The method of dichotomizing extreme phenotypes is also discussed.

Heart rate and suicide: findings from two cohorts of 533 000 Taiwanese and 75 000 Norwegian adults.

OBJECTIVE: To investigate the association of resting heart rate with suicide in two large cohorts. METHOD: The MJ cohort (Taiwan) included 532 932 adults from a health check-up programme (1994-2008). The HUNT cohort (Norway) included 74 977 adults in the Nord-Trøndelag County study (1984-1986), followed up to 2004. In both cohorts heart rate was measured at baseline, and suicide was ascertained through linkage to cause-of-death registers. Risk of suicide was estimated using Cox proportional hazards models. RESULTS: There were 569 and 188 suicides (average follow-up period of 8.1 and 16.9 years) in the MJ and HUNT cohorts respectively. Sex- and age-adjusted hazard ratio for every 10 beat increase in heart rate per minute was 1.08 (95% Confidence Interval 1.00-1.16) and 1.24 (1.12-1.38) in the MJ and HUNT cohorts, respectively. In the MJ cohort this association was confined to individuals with a history of heart diseases vs. those without such a history (P for interaction = 0.008). In the HUNT cohort the association did not differ by history of heart diseases and was robust to adjustment for health-related life style, medication use, and symptoms of anxiety and depression. CONCLUSION: Elevated resting heart rate may be a marker of increased suicide risk.

Exploring lifestyle and risk in preventing type 2 diabetes-a nested qualitative study of older participants in a lifestyle intervention program (VEND-RISK).

BACKGROUND: Lifestyle intervention may reduce the development of type 2 diabetes among high-risk individuals. The aim of this study was to explore how older adults perceived their own lifestyle and being at increased risk for type 2 diabetes while they participated in a lifestyle intervention programme. METHODS: A nested qualitative study was performed with 26 participants (mean age 68 years) in the VEND-RISK Study. Participants had previously participated in the HUNT3 Study and the HUNT DE-PLAN Study, where their risk for developing type 2 diabetes (FIND-RISC ≥ 15) had been identified. The data were analysed using systematic text condensation. RESULTS: Two main themes were identified. The first theme was having resources available for an active lifestyle, which included having a family and being part of a social network, having a positive attitude toward life, and maintaining established habits from childhood to the present. The second theme was being at increased risk for type 2 diabetes, which included varied reactions to the information on increased risk, how lifestyle intervention raised awareness about risk behaviour, and health-related worries and ambitions as type 2 diabetes prevention. CONCLUSIONS: Assessing a participant's resources could improve the outcomes of lifestyle intervention programmes. Both family history and risk perception could be used in preventive strategies to enhance changes in lifestyle. TRIAL REGISTRATION: The VEND-RISK Study was registered in ClinicalTrials.gov on April 26, 2010, with the registration number NCT01135901 .

Iodine status and determinants in adults in Norway - results from a population-based health examination survey (The HUNT Study).

Background: In Norway, there is a lack of knowledge about the iodine status in the general and older adult population, and there is no established national monitoring programme for iodine. Several studies have indicated that iodine deficiency is prevalent in subgroups of the population. Salt iodisation is currently being considered as a measure to increase the population iodine status. In this cross-sectional study, the aim was to evaluate iodine status and determinants in the adult and older adult population in Mid-Norway, before salt iodisation is likely to be initiated. Methods: The study sample was a subsample of participants in the fourth wave of the population-based Trøndelag Health Study (HUNT4, 2017-2019) with available spot-urine samples. This subsample included participants with 25-64 years (n = 500) and 70-79 years (n = 250). The urine samples were analysed for iodine and creatinine. Information on the habitual intake of milk/yoghurt, fish, supplement use, use of thyroid medication and relevant background factors was collected through a general questionnaire. Multivariable quantile regression was used to model differences in the median urinary iodine concentration (UIC) by determinants. Estimates were weighted to match the age and sex distribution of the Norwegian population aged 25-79 years in 2019. Results: Median UIC was 97 µg/L (95% confidence interval [CI]: 92, 103) indicating borderline iodine deficiency at a group level. The median UIC increased with age, and iodine status was insufficient in participants below age 55 years (median 92 µg/L [95% CI: 85, 99]). Important determinants of UIC were habitual milk/yoghurt intake, daily supplement use and current use of thyroid medication, but not intake of lean or fatty fish. Risk of mild-to-moderate iodine deficiency was seen in those with a low intake of milk/yoghurt, no supplement use and who did not use thyroid medication. No group was identified as being at risk of iodine excess. Conclusion: Iodine status was adequate in older adults but mildly deficient in adults under 55 years. Milk intake, supplement use and use of thyroid medication are important determinants of iodine intake in Norway.

Profiling of serum metabolome of breast cancer: multi-cancer features discriminate between healthy women and patients with breast cancer.

Introduction: The progression of solid cancers is manifested at the systemic level as molecular changes in the metabolome of body fluids, an emerging source of cancer biomarkers. Methods: We analyzed quantitatively the serum metabolite profile using high-resolution mass spectrometry. Metabolic profiles were compared between breast cancer patients (n=112) and two groups of healthy women (from Poland and Norway; n=95 and n=112, respectively) with similar age distributions. Results: Despite differences between both cohorts of controls, a set of 43 metabolites and lipids uniformly discriminated against breast cancer patients and healthy women. Moreover, smaller groups of female patients with other types of solid cancers (colorectal, head and neck, and lung cancers) were analyzed, which revealed a set of 42 metabolites and lipids that uniformly differentiated all three cancer types from both cohorts of healthy women. A common part of both sets, which could be called a multi-cancer signature, contained 23 compounds, which included reduced levels of a few amino acids (alanine, aspartate, glutamine, histidine, phenylalanine, and leucine/isoleucine), lysophosphatidylcholines (exemplified by LPC(18:0)), and diglycerides. Interestingly, a reduced concentration of the most abundant cholesteryl ester (CE(18:2)) typical for other cancers was the least significant in the serum of breast cancer patients. Components present in a multi-cancer signature enabled the establishment of a well-performing breast cancer classifier, which predicted cancer with a very high precision in independent groups of women (AUC>0.95). Discussion: In conclusion, metabolites critical for discriminating breast cancer patients from controls included components of hypothetical multi-cancer signature, which indicated wider potential applicability of a general serum metabolome cancer biomarker.

Serum vitamin D, blood pressure and hypertension risk in the HUNT study using observational and Mendelian randomization approaches.

Limited studies have triangulated the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and systolic blood pressure (SBP), diastolic blood pressure (DBP) or hypertension risk utilizing both observational and Mendelian randomization (MR) approaches. We employed data from the Norwegian Trøndelag Health Study (HUNT) to conduct cross-sectional (n = 5854) and prospective (n = 3592) analyses, as well as one-sample MR (n = 86,324). We also used largest publicly available data for two-sample MR. Our cross-sectional analyses showed a 25 nmol/L increase in 25(OH)D was associated with a 1.73 mmHg decrease in SBP (95% CI - 2.46 to - 1.01), a 0.91 mmHg decrease in DBP (95% CI - 1.35 to - 0.47) and 19% lower prevalence of hypertension (OR 0.81, 95% CI 0.74 to 0.90) after adjusting for important confounders. However, these associations disappeared in prospective analyses. One-sample and two-sample MR results further suggested no causal relationship between serum vitamin D levels and blood pressure or hypertension risk in the general population.

Cardiovascular disease risk factors and infertility: multivariable analyses and one-sample Mendelian randomization analyses in the Trøndelag Health Study.

STUDY QUESTION: Are cardiovascular disease (CVD) risk factors causally associated with higher risk of infertility among women and men? SUMMARY ANSWER: We found evidence to support a causal relationship between smoking initiation and history of infertility in women. WHAT IS KNOWN ALREADY: Several CVD risk factors are associated with history of infertility. Previous studies using Mendelian randomization (MR) further support a causal relationship between BMI and infertility in women. STUDY DESIGN SIZE DURATION: We used data from the Trøndelag Health Study (HUNT) in Norway, a prospective population-based cohort study, including 26 811 women and 15 598 men participating in three survey collections in 1995-1997 (HUNT2), 2006-2008 (HUNT3), and 2017-2019 (HUNT4). PARTICIPANTS/MATERIALS SETTING METHODS: Our outcome was women's self-reported history of infertility, defined as ever having tried to conceive for 12 months or more or having used ART. We assigned the history of infertility reported by women to their male partners; therefore, the measure of infertility was on the couple level. We used both conventional multivariable analyses and one-sample MR analyses to evaluate the association between female and male CVD risk factors (including BMI, blood pressure, lipid profile measurements, and smoking behaviours) and history of infertility in women and men, separately. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 4702 women (18%) and 2508 men (16%) were classified with a history of infertility. We found a higher risk of infertility among female smokers compared to non-smokers in both multivariable and MR analyses (odds ratio (OR) in multivariable analysis, 1.20; 95% CI, 1.12-1.28; OR in MR analysis, 1.13; CI, 1.02-1.26), and potentially for higher BMI (OR in multivariable analysis, 1.13; CI, 1.09-1.18; OR in MR analysis, 1.11, CI, 0.92-1.34). In multivariable analysis in women, we also found evidence of associations between triglyceride levels, high-density lipoprotein cholesterol, lifetime smoking index, and smoking intensity with higher risk of infertility. However, these results were not consistent in MR analyses. We found no robust or consistent associations between male CVD risk factors and infertility. LIMITATIONS REASONS FOR CAUTION: Our main limitation was that the CVD risk factors measured might not adequately capture the relevant time periods for when couples were trying to conceive. Additionally, we did not have information on causes of infertility in either women or men. WIDER IMPLICATIONS OF THE FINDINGS: Women with infertility could have a worse CVD risk factor profile and thus public health interventions aimed at reducing the impact of some CVD risk factors, such as smoking and BMI, could reduce the burden of infertility. However, additional MR studies of the relationship between CVD risk factors and infertility with a larger sample size would be of value. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreements no. 947684). This research was also supported by the Research Council of Norway through its Centres of Excellence funding scheme (project no. 262700) and partly funded by the Research Council of Norway, project: Women's fertility-an essential component of health and well-being (project no. 320656). D.A.L. and A.F. work in a unit that is supported by the University of Bristol and the UK Medical Research Council (MC_UU_00011/6). D.A.L.'s contribution to the article is supported by the European Research Council (101021566), the British Heart Foundation (CH/F/20/90003 and AA/18/7/34219). S.B.'s contribution to the article is supported by the Wellcome Trust (225790/Z/22/Z). B.M.B. is funded by The Liaison Committee for education, research and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The genotyping in HUNT was financed by the National Institute of Health (NIH); University of Michigan; The Research Council of Norway; The Liaison Committee for education, research and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. None of the funding organizations influenced the study design, reporting, or interpretation of results. The views expressed in the present article are those of the authors and not necessarily any acknowledged funding organization. D.A.L. reports grants from Medtronic Ltd and Roche Diagnostics outside the submitted work. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Risk of cardiovascular disease in women and men with subfertility: the Trøndelag Health Study.

OBJECTIVE: To investigate the association between subfertility and risk of cardiovascular disease (CVD) outcomes. DESIGN: Prospective study. SETTING: Population-based cohort. PATIENT(S): We studied 31,629 women and 17,630 men participating in the Trøndelag Health Study. INTERVENTION(S): Self-reported subfertility. As men were not directly asked about fertility, male partners of female participants were identified through linkage to the Medical Birth Registry of Norway and assigned the fertility information obtained from their partners. MAIN OUTCOME MEASURE(S): The primary outcomes were stroke and coronary heart disease in women and men with and without a history of subfertility. The secondary outcomes were myocardial infarction and angina (subgroups of coronary heart disease) and any CVD (stroke or coronary heart disease). Information on CVD was available by linkage to hospital records. We used Cox proportional hazards models adjusted for age at participation in the Trøndelag Health Study (linear + squared), birth year, smoking history, cohabitation, and education. Cardiometabolic factors were assessed in separate models. RESULT(S): A total of 17% of women and 15% of men reported subfertility. In women, subfertility was modestly associated with an increased risk of stroke (age-adjusted hazard ratio [aaHR], 1.19; 95% confidence interval [CI], 1.02-1.39; adjusted hazard ratio [aHR]; 1.18; 95% CI, 1.01-1.37) and coronary heart disease (aaHR, 1.19; 95% CI, 1.06-1.33; aHR, 1.16; 95% CI, 1.03-1.30) compared with fertile women. In men, we observed a weak positive association for stroke (aaHR, 1.11; 95% CI, 0.91-1.34; aHR, 1.10; 95% CI, 0.91-1.33) and a weak inverse association for coronary heart disease (aaHR, 0.92; 95% CI, 0.81-1.05; aHR, 0.93; 95% CI, 0.81-1.06). CONCLUSION(S): We observed modestly increased risks of CVD outcomes in women and some weak associations in men, although with no strong statistical evidence on sex differences. We acknowledge that we were only able to include men linked to pregnancies ending at 12 completed gestational weeks or later, potentially resulting in selection bias and misclassification of history of subfertility in analyses of male partners. Despite the large sample size, our results indicate the need for larger studies to obtain precise results in both sexes and determine whether there are true sex differences.

Subtypes of insomnia and the risk of chronic spinal pain: the HUNT study.

OBJECTIVE: To examine the association between subtypes of insomnia and the risk of chronic spinal pain. METHODS: The study comprised 16,401 participants without chronic spinal pain at baseline who were followed for ∼11 years. People were categorized into 'no insomnia symptoms', 'subthreshold insomnia', and 'insomnia'. Insomnia was defined according to the diagnostic classification system requiring both daytime and nighttime symptoms, and further categorized into subtypes based on nighttime symptoms (ie, sleep onset latency [SOL-insomnia], wake after sleep onset [WASO-insomnia], early morning awakening [EMA-insomnia], or combinations of these). Subthreshold insomnia comprised those with only daytime impairment or one or more nighttime symptoms. Chronic spinal pain was defined as pain in either 'neck', 'low back', or 'upper back', or a combination of these. RESULTS: In multivariable regression analysis using people without insomnia as reference, people with subthreshold insomnia or insomnia had relative risks (RRs) of chronic spinal pain of 1.29 (95% confidence interval [CI] 1.21-1.38) and 1.50 (95% CI 1.34-1.68), respectively. The RRs for people with one nighttime symptom were 1.30 (95% CI 0.83-2.05) for WASO-insomnia, 1.32 (95% CI 1.06-1.65) for EMA-insomnia, and 1.70 (95% CI 1.32-2.18) for SOL-insomnia, respectively. Combinations of nighttime insomnia symptoms gave RRs from 1.45 (95% CI 1.08-1.94) for WASO + EMA-insomnia to 1.72 (95% CI 1.36-2.19) for all nighttime symptoms (SOL + WASO + EMA-insomnia). CONCLUSIONS: These findings suggest that the risk of chronic spinal pain is highest among persons with insomnia subtypes characterized by sleep onset latency or among those having insomnia symptoms in all parts of the sleep period.

Are Faecal Microbiota Analyses on Species-Level Suitable Clinical Biomarkers? A Pilot Study in Subjects with Morbid Obesity.

BACKGROUND: An abnormal faecal microbiota could be a causal factor for disease. This study evaluated a new method for faecal microbiota analysis in subjects with obesity and irritable bowel syndrome. METHODS: The study had a matched case-control design. Forty-six subjects with morbid obesity (defined as BMI > 40 or >35 kg/m2 with obesity-related complications) of whom 23 had irritable bowel syndrome (IBS), were compared with 46 healthy volunteers. The faecal microbiota was analysed with Precision Microbiome Profiling (PMP™) which quantified 104 bacteria species. The primary aim was comparisons between the cases and controls. RESULTS: Two men and 44 women with a mean age of 43.6 years were included in each of the groups; BMI in the groups was (mean and SD) 41.9 (3.5) and 22.5 (1.5) kg/m2, respectively. Seventeen bacterial species showed statistically significant differences between the groups after adjusting for multiple testing. In a post hoc analysis, the sensitivity and specificity were 78%. Alpha diversity was lower in the group with obesity. In subjects with morbid obesity, no clinically significant differences were seen between subjects with and without IBS or from before to six months after bariatric surgery. CONCLUSIONS: The results encourage further evaluation of the new microbiome profiling tool.

Underestimation of Overweight and Health Beneficial Outcomes in Two Adolescent Cohorts in Norway - The HUNT Study.

PURPOSE: Underestimating overweight may prevent efforts toward reducing weight, but simultaneously benefit mental health and well-being. The magnitude of underestimation of overweight and obesity in adolescents is largely unknown, and so is to what extent this underestimation is associated with dieting behaviors, mental distress, and life satisfaction. As overweight has become more common during the past decades, associations between body size underestimation and mental health may have changed. METHODS: Overweight (iso-body mass index, iso-BMI ≥25) adolescents (aged 13-19 years) who participated in The Young-HUNT1 (1995-97, n = 1,338) or The Young-HUNT3 (2006-08, n = 1,833) surveys were included. Being overweight, but perceiving oneself as average-weighted or underweighted was defined as underestimation. Results were based on clinical examinations and self-report questionnaires. Multivariable logistic regression models were used to examine associations between body size underestimation, dieting behaviors, and symptoms of anxiety, depression, and life satisfaction. RESULTS: Among adolescents with overweight and obesity (iso-BMI ≥25), the prevalence of obesity (iso-BMI ≥30), body size underestimation, and having symptoms of anxiety and depression had increased from the first survey to the next. At both time points, body size underestimation was more common among boys than girls. In 2006-08, body size underestimation was negatively associated with symptoms of anxiety and depression in both sexes, and overall associated with higher life satisfaction equally over time. Dieting behavior was negatively associated with underestimation of body size. CONCLUSIONS: Body size underestimation in adolescents with overweight/obesity has become more prevalent and a phenomenon associated with less dieting, better life satisfaction and mental health in both boys and girls.

Socioeconomic Position, Multimorbidity and Mortality in a Population Cohort: The HUNT Study.

Multimorbidity and socioeconomic position are independently associated with mortality. We investigated the association of occupational position and several multimorbidity measures with all-cause mortality. A cohort of people aged 35 to 75 years who participated in the Trøndelag Health Study in 2006-2008 and had occupational data was linked to the Norwegian National Population Registry for all-cause mortality from study entry until 1 February 2019. Logistic regression models for each occupational group were used to analyze associations between the number of conditions and 10-year risk of death. Cox regression models were used to examine associations between combinations of multimorbidity, occupational position, and mortality. Analyses were conducted for men and women. Included were 31,132 adults (16,950 women (54.4%)); occupational groups: high, 7501 (24.1%); low, 15,261 (49.0%)). Increased mortality was associated with lower occupational group, more chronic conditions, and all multimorbidity measures. The joint impact of occupational group and multimorbidity on mortality was greater in men than women. All multimorbidity measures are strongly associated with mortality, with varying occupational gradients. Social differences in multimorbidity are a public health challenge and necessitate consideration in health care. Men in lower occupational groups seem to be a particularly vulnerable group.

ADAMTS13 gene variants and function in women with preeclampsia: a population- based nested case- control study from the HUNT Study.

INTRODUCTION: Known genetic variants with reference to preeclampsia only explain a proportion of the heritable contribution to the development of this condition. The association between preeclampsia and the risk of cardiovascular disease later in life has encouraged the study of genetic variants important in thrombosis and vascular inflammation also in relation to preeclampsia. The von Willebrand factor-cleaving protease, ADAMTS13, plays an important role in micro vascular thrombosis, and partial deficiencies of this enzyme have been observed in association with cardiovascular disease and preeclampsia. However, it remains unknown whether decreased ADAMTS13 levels represent a cause or an effect of the event in placental and cardiovascular disease. METHODS: We studied the distribution of three functional genetic variants of ADAMTS13, c.1852C>G (rs28647808), c.4143_4144dupA (rs387906343), and c.3178C>T (rs142572218) in women with preeclampsia and their controls in a nested case-control study from the second Nord-Trøndelag Health Study (HUNT2). We also studied the association between ADAMTS13 activity and preeclampsia, in serum samples procured unrelated in time of the preeclamptic pregnancy. RESULTS: No differences were observed in genotype, allele or haplotype frequencies of the different ADAMTS13 variants when comparing cases and controls, and no association to preeclampsia was found with lower levels of ADAMTS13 activity. CONCLUSION: Our findings indicate that ADAMTS13 variants and ADAMTS13 activity do not contribute to an increased risk of preeclampsia in the general population.