HUNT for better public health.

AIMS: The Trøndelag Health Study (HUNT) has collected population data through comprehensive decennial surveys over the last four decades and has so far collected data from 240,000 participants. The participants are identified with the unique Norwegian birth number, which enables them to be followed throughout different life stages, from survey to survey, and to endpoint measures in Norwegian national health registers without attrition bias. METHODS: The study design of HUNT offers several advantages: it provides an overview of the public health development in the population over decades, the data can be used in health services research, clinical epidemiology, studies of causation, trajectories, and consequences of diseases, and to study gene × environment interactions. RESULTS: HUNT data have shown major shifts in public health trends, such as decreasing mean blood pressure and resting heart rate among adults, increasing prevalence of obesity, geographical and socioeconomic inequalities in health, increasing mental health distress among adolescents and young adults with an opposite development among the elderly. Data from HUNT have been used in several major international research projects, where data harmonization with several other population cohorts internationally has been done. HUNT has placed great emphasis on safeguarding research ethics, privacy, and data security. The Norwegian authorities established national regulations for the surveys from the time General Data Protection Regulation was introduced in 2018. CONCLUSIONS: Researchers can apply for HUNT data access from HUNT Research Centre provided they have obtained project approval from the Regional Committee for Medical and Health Research Ethics. Researchers not affiliated to a Norwegian research institution must collaborate with and apply through a Norwegian principal investigator. Information on the application and conditions for data access is available at www.ntnu.edu/hunt/data.

The HUNT study: A population-based cohort for genetic research.

The Trøndelag Health Study (HUNT) is a population-based cohort of ∼229,000 individuals recruited in four waves beginning in 1984 in Trøndelag County, Norway. Approximately 88,000 of these individuals have available genetic data from array genotyping. HUNT participants were recruited during four community-based recruitment waves and provided information on health-related behaviors, self-reported diagnoses, family history of disease, and underwent physical examinations. Linkage via the Norwegian personal identification number integrates digitized health care information from doctor visits and national health registries including death, cancer and prescription registries. Genome-wide association studies of HUNT participants have provided insights into the mechanism of cardiovascular, metabolic, osteoporotic, and liver-related diseases, among others. Unique features of this cohort that facilitate research include nearly 40 years of longitudinal follow-up in a motivated and well-educated population, family data, comprehensive phenotyping, and broad availability of DNA, RNA, urine, fecal, plasma, and serum samples.

Intergenerational polygenic obesity risk throughout adolescence in a cross-sectional study design: The HUNT study, Norway.

OBJECTIVE: This study examined the relationship between parental obesity polygenic risk and children's BMI throughout adolescence. Additionally, from a smaller subsample, the objective was to assess whether parental polygenic risk score (PRS) may act as a proxy for offspring PRS in studies lacking offspring genetic data. METHODS: A total of 8,561 parent-offspring (age 13-19 years) trios from the Trøndelag Health Study (the HUNT Study) were included, of which, 1,286 adolescents had available genetic data. Weighted parental PRSs from 900 single-nucleotide polymorphisms robustly associated with adult BMI were constructed and applied in linear mixed-effects models. RESULTS: A positive association between parental PRS and offspring sex- and age-adjusted BMI (iso-BMI) throughout adolescence was identified. The estimated marginal effects per standard deviation increase in parental PRS were 0.26 (95% CI: 0.18-0.33), 0.36 (95% CI: 0.29-0.43), and 0.62 kg/m2 (95% CI: 0.51-0.72) for maternal, paternal, and combined parental PRS, respectively. In subsample analyses, the magnitude of association of the parental PRS versus offspring PRS with iso-BMI in adolescents was similar. CONCLUSIONS: Parental PRS was consistently associated with offspring iso-BMI throughout adolescence. Results from subsample analyses support the use of parental PRS of obesity as a proxy for adolescent PRS in the absence of offspring genetic data.

Implications of parental lifestyle changes and education level on adolescent offspring weight: a population based cohort study - The HUNT Study, Norway.

OBJECTIVE: Obesity tends to cluster in families reflecting both common genetics and shared lifestyle patterns within the family environment. The aim of this study was to examine whether parental lifestyle changes over time, exemplified by changes in weight and physical activity, could affect offspring weight in adolescents and if parental education level influenced the relationship. DESIGN, SETTING AND PARTICIPANTS: The population-based cohort study included 4424 parent-offspring participants from the Nord-Trøndelag Health Study, Norway. Exposition was parental change in weight and physical activity over 11 years, and outcome was offspring weight measured in z-scores of body mass index (BMI) in mixed linear models. RESULTS: Maternal weight reduction by 2-6 kg was significantly associated with lower offspring BMI z-scores: -0.132 (95% CI -0.259 to -0.004) in the model adjusted for education. Parental weight change displayed similar effect patterns on offspring weight regardless of parents' education level. Further, BMI was consistently lower in families of high education compared with low education in the fully adjusted models. In mothers, reduced physical activity level over time was associated with higher BMI z-scores in offspring: 0.159 (95% CI 0.030 to 0.288). Associations between physical activity change and adolescent BMI was not moderated by parental education levels. CONCLUSION: Lifestyle changes in mothers were associated with offspring BMI; reduced weight with lower-and reduced physical activity with higher BMI. Father's lifestyle changes, however, did not significantly affect adolescent offspring's weight. Overall, patterns of association between parental changes and offspring's BMI were independent of parental education levels, though adolescents with parents with high education had lower weight in general.

Circulating Folate, Vitamin B6, and Methionine in Relation to Lung Cancer Risk in the Lung Cancer Cohort Consortium (LC3).

Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown. Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models. Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups. Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.

Impaired functional vitamin B6 status is associated with increased risk of lung cancer.

Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4thvs.1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.

Influence of Storage and Inter- and Intra-Assay Variability on the Measurement of Inflammatory Biomarkers in Population-Based Biobanking.

BACKGROUND: In the present study, we examined the effect of sample storage on the reproducibility of several inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP), high-sensitivity interleukin-6 (hsIL6), and high-sensitivity tumor necrosis factor alpha (hsTNFα). In addition, we assessed inter- and intra-assay variability between collaborating biobanks. METHODS: In total, 240 fasting plasma samples were obtained from the LifeLines biobank. Samples had been stored for less than 2 or more than 4 years at -80°C. Measurements were performed at three different laboratories. hsCRP was measured by immunonephelometry and ELISA, hsIL6, and hsTNFα samples were measured with ELISAs from two different manufacturers. For confirmation, similar analyses were performed on samples obtained from a subpopulation of 80 obese individuals. Passing-Bablok regression analysis and Bland-Altman plots were used to compare the results. RESULTS: We observed good stability of samples stored at -80°C. hsCRP measured on the day of blood draw was similar to levels measured after more than 4 years of storage. There were small interlaboratory differences with the R&D ELISAs for hsIL6 and hsTNFα. We found a linear correlation between the Bender Medsystems ELISA and the R&D ELISA for hsIL6, with significantly higher levels measured with the R&D ELISA. Over 90% of hsTNFα samples measured with the IBL ELISA were below the detection limit of 0.13 ng/L, rendering this assay unsuitable for large-scale analysis. Similar results were found in the confirmation study. CONCLUSION: In summary, plasma hsCRP showed good stability in samples stored for either less than 2 years or more than 4 years at -80°C. Both the R&D and Bender Medsystems for hsIL6 measurement yielded similar results. The IBL hsTNFα assay is not suited for use in biobanking samples. Assays for the measurement of inflammatory biomarker assays should be rigorously tested before large sample sets are measured.

Circulating concentrations of biomarkers and metabolites related to vitamin status, one-carbon and the kynurenine pathways in US, Nordic, Asian, and Australian populations.

Background: Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies.Objective: We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions.Design: The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory.Results: Circulating concentrations of riboflavin, pyridoxal 5'-phosphate, folate, vitamin B-12, all-trans retinol, 25-hydroxyvitamin D, and α-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users.Conclusions: The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents.

Intergenerational Transmission of Overweight and Obesity from Parents to Their Adolescent Offspring - The HUNT Study.

PURPOSE: The main aim of this study was to examine weight associations between parents and offspring at two time points: 1995-97 and 2006-08, taking into account body mass index (BMI) and waist circumference. METHODS: The study included 8425 parent-offspring trios who participated in the population based Health Study of Nord Trøndelag (the HUNT Study), Norway, at either the HUNT2 (1995-97) or the HUNT3 (2006-08) survey. We used linear mixed effects models with siblings clustered within mothers to analyze the associations between 1) parental grouped BMI and offspring BMI z-scores and 2) parental grouped waist circumference and offspring waist circumference z-scores. RESULTS: Adolescent and adult overweight and obesity were higher in 2006-08 than in 1995-97, with the greatest increase observed in waist circumference. Both mother's and father's BMI and waist circumference were strongly associated with corresponding measures in offspring. Compared with both parents being normal weight (BMI <25 kg/m2), having two overweight or obese parents (BMI ≥25 kg/m2) was associated with a higher offspring BMI z-score of 0.76 (95% CI; 0.65, 0.87) and 0.64 (95% CI; 0.48, 0.80) in daughters, and 0.76 (95% CI; 0.65, 0.87) and 0.69 (95% CI; 0.53, 0.80) in sons, in 1995-97 and 2006-08 respectively. Offspring with one parent being overweight/obese had BMI z-scores of approximately half of offspring with two parents categorized as overweight/obese. The results of the waist circumference based analyses did not differ substantially from the BMI based analyses. CONCLUSIONS: Parental overweight was strongly positively associated with offspring weight both in 1995-97 and 2006-08 where both parents being overweight/obese gave the largest effect. This seemingly stable association, strongly address the importance of public health initiatives towards preventing obesity in parents of both sexes to decrease further obesity expansion in offspring.

Ovulation Prevalence in Women with Spontaneous Normal-Length Menstrual Cycles - A Population-Based Cohort from HUNT3, Norway.

BACKGROUND: Ovulatory menstrual cycles are essential for women's fertility and needed to prevent bone loss. There is a medical/cultural expectation that clinically normal menstrual cycles are inevitably ovulatory. Currently within the general population it is unknown the proportion of regular, normal-length menstrual cycles that are ovulatory. Thus, the objective of this study was to determine the population point prevalence of ovulation in premenopausal, normally menstruating women. The null hypothesis was that such cycles are ovulatory. METHODS: This is a single-cycle, cross-sectional, population-based study-a sub-study of the HUNT3 health study in the semi-rural county (Nord Trøndelag) in mid-Norway. Participants included >3,700 spontaneously (no hormonal contraception) menstruating women, primarily Caucasian, ages 20-49.9 from that county. Participation rate was 51.9%. All reported the date previous flow started. A single, random serum progesterone level was considered ovulatory if ≥9.54 nmol/L on cycle days 14 to -3 days before usual cycle length (CL). RESULTS: Ovulation was assessed in 3,168 women mean age 41.7 (interquartile range, [IQR] 36.8 to 45.5), cycle length 28 days (d) (IQR 28 to 28) and body mass index (BMI) 26.3 kg/m2 (95% CI 26.1 to 26.4). Parity was 95.6%, 30% smoked, 61.3% exercised regularly and 18% were obese. 1,545 women with a serum progesterone level on cycle days 14 to -3 were presumed to be in the luteal phase. Of these, 63.3% of women had an ovulatory cycle (n = 978) and 37% (n = 567) were anovulatory. Women with/ without ovulation did not differ in age, BMI, cycle day, menarche age, cigarette use, physical activity, % obesity or self-reported health. There were minimal differences in parity (96.7% vs. 94.5%, P = 0.04) and major differences in progesterone level (24.5 vs. 3.8 nmol/L, P = 0.001). CONCLUSION: Anovulation in a random population occurs in over a third of clinically normal menstrual cycles.