Body mass index and all-cause mortality in HUNT and UK biobank studies: revised non-linear Mendelian randomisation analyses.

OBJECTIVES: To estimate the shape of the causal relationship between body mass index (BMI) and mortality risk in a Mendelian randomisation framework. DESIGN: Mendelian randomisation analyses of two prospective population-based cohorts. SETTING: Individuals of European ancestries living in Norway or the UK. PARTICIPANTS: 56 150 participants from the Trøndelag Health Study (HUNT) in Norway and 366 385 participants from UK Biobank recruited by postal invitation. OUTCOMES: All-cause mortality and cause-specific mortality (cardiovascular, cancer, non-cardiovascular non-cancer). RESULTS: A previously published non-linear Mendelian randomisation analysis of these data using the residual stratification method suggested a J-shaped association between genetically predicted BMI and mortality outcomes with the lowest mortality risk at a BMI of around 25 kg/m2. However, the 'constant genetic effect' assumption required by this method is violated. The reanalysis of these data using the more reliable doubly-ranked stratification method provided some indication of a J-shaped relationship, but with much less certainty as there was less precision in estimates at the lower end of the BMI distribution. Evidence for a harmful effect of reducing BMI at low BMI levels was only present in some analyses, and where present, only below 20 kg/m2. A harmful effect of increasing BMI for all-cause mortality was evident above 25 kg/m2, for cardiovascular mortality above 24 kg/m2, for cancer mortality above 30 kg/m2 and for non-cardiovascular non-cancer mortality above 26 kg/m2. In UK Biobank, the association between genetically predicted BMI and mortality at high BMI levels was stronger in women than in men. CONCLUSION: This research challenges findings from previous conventional observational epidemiology and Mendelian randomisation investigations that the lowest level of mortality risk is at a BMI level of around 25 kg/m2. Our results provide some evidence that reductions in BMI will increase mortality risk for a small proportion of the population, and clear evidence that increases in BMI will increase mortality risk for those with BMI above 25 kg/m2.

Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.

The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies (GWASs) on sex hormones and from the Trøndelag Health (HUNT) Study and large consortia on cancers. There was suggestive evidence of genetically predicted 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio (HR) 0.60, 95% CI 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.

Increased expression of individual genes in whole blood is associated with late-stage lung cancer at and close to diagnosis.

Lung cancer (LC) mortality rates are still increasing globally. As survival is linked to stage, there is a need to identify markers for earlier LC diagnosis and individualized treatment. The whole blood transcriptome of LC patients represents a source of potential LC biomarkers. We compared expression of > 60,000 genes in whole blood specimens taken from LC cases at diagnosis (n = 128) and controls (n = 62) using genome-wide RNA sequencing, and identified 14 candidate genes associated with LC. High expression of ANXA3, ARG1 and HP was strongly associated with lower survival in late-stage LC cases (hazard ratios (HRs) = 2.81, 2.16 and 2.54, respectively). We validated these markers in two independent population-based studies with pre-diagnostic whole blood specimens taken up to eight years prior to LC diagnosis (n = 163 cases, 184 matched controls). ANXA3 and ARG1 expression was strongly associated with LC in these specimens, especially with late-stage LC within two years of diagnosis (odds ratios (ORs) = 3.47 and 5.00, respectively). Additionally, blood CD4 T cells, NK cells and neutrophils were associated with LC at diagnosis and improved LC discriminative ability beyond candidate genes. Our results indicate that in whole blood, increased expression levels of ANXA3, ARG1 and HP are diagnostic and prognostic markers of late-stage LC.

Age at Menarche, age at Natural Menopause, and Risk of Lung and Colorectal Cancers: A Mendelian Randomization Study.

Background: The roles of age at menarche and age at menopause in the etiology of lung and colorectal cancers are unclear. Objective: We aimed to investigate potential causal associations between age at menarche, age at natural menopause, and risk of lung and colorectal cancers using a Mendelian randomization (MR) approach. Methods: From the Trøndelag Health Study in Norway, we defined two cohorts of 35 477 and 17 118 women to study the effects of age at menarche and age at natural menopause, respectively. We ran univariable MR to evaluate the potential causal associations. We performed multivariable MR adjusting for genetic variants of adult body mass index (BMI) to estimate the direct effect of age at menarche. Results: Genetically predicted 1-year increase in age at menarche was associated with a lower risk of lung cancer overall (hazard ratio [HR, 0.64; 95% CI, 0.48-0.86), lung adenocarcinoma (HR, 0.61; 95% CI, 0.38-0.99), and lung non-adenocarcinoma (HR, 0.66; 95% CI, 0.45-0.95). After adjusting for adult BMI using a multivariable MR model, the direct effect estimates reduced to HR 0.72 (95% CI, 0.54-0.95) for lung cancer overall, HR 0.67 (95% CI, 0.43-1.03) for lung adenocarcinoma, and HR 0.77 (95% CI, 0.54-1.09) for lung non-adenocarcinoma. Age at menarche was not associated with colorectal cancer. Moreover, genetically predicted age at natural menopause was not associated with lung and colorectal cancers. Conclusion: Our MR study suggested that later age at menarche was causally associated with a decreased risk of lung cancer overall and its subtypes, and adult BMI might be a mediator.

Estimated cardiorespiratory fitness in relation to overall, breast and prostate cancer incidence: the Norwegian HUNT study.

PURPOSE: To investigate the relationships between the estimated cardiorespiratory fitness (eCRF) and the incidence of overall, breast, and prostate cancer in a large prospective cohort study. METHODS: We included 46,968 cancer-free adults who participated in the second survey of the Trøndelag Health Study in Norway. Sex-specific non-exercise algorithms were used to estimate CRF. eCRF was classified into sex and age-specific tertiles, that is, into low, medium and high levels. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a median of 22.1 years' follow-up, there were 7752 overall, 858 breast and 1376 prostate cancer cases. Medium and high levels of eCRF were associated with a reduced incidence of overall cancer in a dose-response manner in all participants (HR 0.96; 95% CI, 0.90-1.01 and HR 0.85; 95% CI, 0.79-0.91, respectively, and P-value for trend <.001). No association was observed between eCRF and breast cancer incidence in women. Only the high level of eCRF seemed to be associated with a reduced incidence of prostate cancer in men (HR 0.85; 95% CI, 0.72-1.02). CONCLUSIONS: eCRF may be a practical and cost-effective means of investigating the association between the CRF and cancer incidence.

Reproductive Factors in Relation to Incidence of Lung and Colorectal Cancers in a Cohort of Norwegian Women: The HUNT Study.

Context: The roles of reproductive factors in the etiology of lung and colorectal cancers, among the most common cancers in women, are unclear. Objective: We aimed to explore whether female reproductive factors were associated with the incidence of lung and colorectal cancers. Methods: We followed up 33 314 cancer-free women who participated in the HUNT Study in Norway from 1995-1997 to 2018. A large panel of reproductive factors were self-reported at baseline. Incident lung and colorectal cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% CIs after adjustment for important confounders. Results: During a median follow-up interval of 22.2 years, 467 women developed lung cancer (including 169 lung adenocarcinoma), 660 developed colon cancer, and 211 had rectal cancer. Early menarche (≤12 years) was associated with an increased incidence of lung adenocarcinoma (HR 1.43; 95% CI, 1.02-2.03). Women with one or no child had an increased colon cancer incidence (HR 1.26; 95% CI, 1.03-1.54). Hormone therapy appeared to be associated with a decreased incidence of rectal cancer (HR 0.68; 95% CI, 0.44-1.04). Results in the subgroup of postmenopausal women were similar or strengthened. Other reproductive factors were not related to the risk of lung, colon, and rectal cancers. Conclusion: Certain reproductive factors might play a role in the etiology of lung and colorectal cancers. Further investigations are warranted to study if they are causal associations.

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.

Assessing the role of genome-wide DNA methylation between smoking and risk of lung cancer using repeated measurements: the HUNT study.

BACKGROUND: It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development. METHODS: We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009-13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995-97) and HUNT3 (2006-08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer. RESULTS: The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P < 5 × 10-8), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer. CONCLUSIONS: DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk.

Asthma and asthma symptom control in relation to incidence of lung cancer in the HUNT study.

Large prospective studies on asthma, especially asthma symptom control, as a potential risk factor for lung cancer are limited. We followed up 62,791 cancer-free Norwegian adults from 1995-1997 to 2017. Self-reported doctor-diagnosed asthma was categorized into active and non-active asthma. Levels of asthma symptom control were classified into controlled and partially controlled (including partly controlled and uncontrolled) according to the Global Initiative for Asthma guidelines. 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) for possible associations. Totally, 984 participants developed lung cancer during a median follow-up of 21.1 years. After adjustment for smoking and other potential confounders, an increased incidence of lung cancer was found for adults with partially controlled asthma (HR 1.39, 95% CI 1.00-1.92) compared with those without asthma at baseline. Adults with active asthma had a tendency of increased lung cancer incidence (HR 1.29, 95% CI 0.95-1.75). Sensitivity analyses indicated that the observed associations were less likely resulted from reverse causation or residual confounding by smoking. Our findings suggested that proper control of asthma symptoms might contribute to a reduced incidence of lung cancer.

Hours lying down per day, as a proxy for sedentary behaviour and risk of diabetes in young and middle-aged adults in Norway: an 11-year follow-up of the HUNT study.

OBJECTIVE: We aimed to examine relationship between hours lying down per day, as a proxy for sedentary behaviour and risk of diabetes in young and middle-aged adults, and to assess if leisure-time physical activity and body mass index (BMI) modified this relationship. DESIGN: A population-based prospective cohort study. SETTING: Nord-Trøndelag, Norway. PARTICIPANTS: The cohort included 17 058 diabetes-free adults, at an age of 20-55 years in 1995-1997, who were followed-up to 2006-2008. PRIMARY OUTCOME MEASURES: Incident diabetes was defined by self-report of diabetes or non-fasting glucose levels greater than 11 mmol/L at the follow-up. METHODS: Multivariable logistic regression models were used to obtain OR with 95% CI for risk of diabetes by the categories of hours lying down (≤7, 8 and ≥9 hours/day). RESULTS: 362 individuals (2.1%) developed diabetes during an average of 11-year follow-up. Individuals who reported lying down ≥9 hours/day had an adjusted OR of 1.35 (95% CI 1.01 to 1.80) for incident diabetes compared with those lying down 8 hours/day. Lying down ≤7 hours/day was not associated with the risk of diabetes. In analysis stratified by physical activity, the ORs associated with lying down ≥9 hours/day were 1.41 (95% CI 1.05 to 1.90) and 0.90 (95% CI 0.23 to 3.55), respectively, among the less active and highly active individuals (pinteraction=0.048). There was little evidence that the association differed by BMI status (pinteraction=0.62). CONCLUSIONS: Prolonged hours lying down per day was associated with an increased risk of diabetes in young and middle-aged adults. The positive association appeared to be modified by physical activity but not by BMI.

Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses.

OBJECTIVE: To investigate the shape of the causal relation between body mass index (BMI) and mortality. DESIGN: Linear and non-linear mendelian randomisation analyses. SETTING: Nord-Trøndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom). PARTICIPANTS: Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank. MAIN OUTCOME MEASURES: All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality. RESULTS: 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0-29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI <18.5) and a 14% (-1% to 27%) lower risk in low normal weight participants (BMI 18.5-19.9). Non-linear mendelian randomisation indicated a J shaped relation between genetically predicted BMI and the risk of all cause mortality, with the lowest risk at a BMI of around 22-25 for the overall sample. Subgroup analyses by smoking status, however, suggested an always-increasing relation of BMI with mortality in never smokers and a J shaped relation in ever smokers. CONCLUSIONS: The previously observed J shaped relation between BMI and risk of all cause mortality appears to have a causal basis, but subgroup analyses by smoking status revealed that the BMI-mortality relation is likely comprised of at least two distinct curves, rather than one J shaped relation. An increased risk of mortality for being underweight was only evident in ever smokers.

Prolonged Sitting, Its Combination With Physical Inactivity and Incidence of Lung Cancer: Prospective Data From the HUNT Study.

Background: Prolonged sitting as a major sedentary behavior potentially contributes to illness, but its relation with lung cancer risk is unclear. Prolonged sitting can be presented in physically active or inactive individuals. Those who are extendedly seated and also physically inactive may represent the most sedentary people. We therefore aimed to prospectively examine if total sitting time daily itself or in combination with physical activity is associated with lung cancer incidence overall and histologic types. Methods: We included 45,810 cancer-free adults who participated in the second survey of HUNT Study in Norway (1995-97), with a median follow-up of 18.3 years. Total sitting time daily and physical activity were self-reported at baseline. Lung cancer cases were ascertained from the Cancer Registry of Norway. Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results: In total, 549 participants developed lung cancer during the follow-up. Total sitting time daily was not associated with the incidence of lung cancer overall and histologic subtypes. Compared with participants sitting < 8 h daily and being physically active, those sitting ≥8 h daily (prolonged sitting) and being physically inactive had an increased incidence of lung cancer (overall: adjusted HR = 1.44, 95% CI: 1.07-1.94; small cell lung cancer: adjusted HR = 2.58, 95% CI: 1.23-5.41). Prolonged sitting only or physical inactivity only was not associated with the incidence of lung cancer. Conclusions: Our study suggested that prolonged sitting was not independently associated with lung cancer incidence. The combination of prolonged sitting and physical inactivity might increase the risk of lung cancer. However, residual confounding by smoking cannot be excluded completely even though smoking was adjusted for with detailed information.

Serum 25-hydroxyvitamin D levels and risk of lung cancer and histologic types: a Mendelian randomisation analysis of the HUNT study.

We aimed to investigate potential causal associations between serum 25-hydroxyvitamin D (25(OH)D) levels and incidence of lung cancer overall and histologic types.We performed a Mendelian randomisation analysis using a prospective cohort study in Norway, including 54 580 individuals and 676 incident lung cancer cases. A 25(OH)D allele score was generated based on the vitamin D-increasing alleles rs2282679, rs12785878 and rs10741657. Hazard ratios with 95% confidence intervals for incidence of lung cancer and histologic types were estimated in relation to the allele score. The inverse-variance weighted method using summarised data of individual single nucleotide polymorphisms was applied to calculate the Mendelian randomisation estimates.The allele score accounted for 3.4% of the variation in serum 25(OH)D levels. There was no association between the allele score and lung cancer incidence overall, with HR 0.99 (95% CI 0.93-1.06) per allele score. A 25 nmol·L-1 increase in genetically determined 25(OH)D level was not associated with the incidence of lung cancer overall (Mendelian randomisation estimate HR 0.96, 95% CI 0.54-1.69) or any histologic type.Mendelian randomisation analysis did not suggest a causal association between 25(OH)D levels and risk of lung cancer overall or histologic types in this population-based cohort study.

Associations of serum 25-hydroxyvitamin D level with incidence of lung cancer and histologic types in Norwegian adults: a case-cohort analysis of the HUNT study.

Previous prospective studies have shown inconsistent associations between serum 25-hydroxyvitamin D [25(OH)D] level and lung cancer incidence. The aim of the present study was to explore the associations of serum 25(OH)D levels with incidence of lung cancer overall and different histologic types. We performed a population-based prospective case-cohort study including 696 incident lung cancer cases and 5804 individuals in a subcohort who participated in the second survey of the Nord-Trøndelag Health Study in Norway. Cox proportional hazards regression models counting for the case-cohort design were used to estimate hazard ratios (HRs) with 95% confidence interval (CIs) for lung cancer overall or histologic types in relation to serum 25(OH)D levels. Compared with the fourth season-specific quartile of 25(OH)D (median 68.0 nmol/L), lower 25(OH)D levels were not associated with the incidence of overall, small or squamous cell lung cancer. However, the risk of adenocarcinoma was lower in the second and third quartiles (median 39.9 and 51.5 nmol/L) compared with the fourth quartile, with HRs of 0.63 (95% CI 0.41-0.98) and 0.58 (0.38-0.88), respectively. The associations of lower levels of 25(OH)D with a reduced risk of adenocarcinoma were only observed in the overweight/obese subjects [HRs for second and third quartiles: 0.40 (0.22-0.72) and 0.50 (0.27-0.92)] but not in the normal weight subjects [HRs: 0.95 (0.52-1.75) and 0.60 (0.32-1.10)]. Serum 25(OH)D levels were not associated with the risk of lung cancer in general. The observation that lower 25(OH)D levels were associated with a lower risk of adenocarcinoma should be interpreted with caution.

Is there an association between vitamin D status and risk of chronic low back pain? A nested case-control analysis in the Nord-Trøndelag Health Study.

OBJECTIVES: To explore potential associations between vitamin D status and risk of chronic low back pain (LBP) in a Norwegian cohort, and to investigate whether relationships depend on the season of blood sample collection. DESIGN: A nested case-control study in a prospective data set. SETTING: The Norwegian community-based Nord-Trøndelag Health Study (HUNT). Data were collected in the HUNT2 (1995-1997) and HUNT3 (2006-2008) surveys. MAIN OUTCOME MEASURE: Chronic LBP, defined as LBP persisting at least 3 months continuously during the past year. PARTICIPANTS: Among individuals aged 19-55 years without LBP in HUNT2, a data set was generated including 1685 cases with LBP in HUNT3 and 3137 controls without LBP. METHODS: Blood samples from the participants collected in HUNT2 were analysed for serum 25-hydroxyvitamin D (25(OH)D) level. Associations with LBP in HUNT3 were evaluated by unconditional logistic regression analysis with adjustment for age, sex, work status, physical activity at work and in leisure time, education, smoking, and body mass index. RESULTS: No association between vitamin D status and risk of chronic LBP was found in the total data set (OR per 10 nmol/L 25(OH)D=1.01, 95% CI 0.97 to 1.06) or in individuals with blood samples collected in summer/autumn (OR per 10 nmol/L 25(OH)D=0.99, 95% CI 0.93 to 1.06). For blood samples drawn in winter/spring, associations differed significantly between women and men (p=0.004). Among women a positive association was seen (OR per 10 nmol/L 25(OH)D=1.11, 95% CI 1.02 to 1.20), but among men no significant association was observed (OR per 10 nmol/L 25(OH)D=0.90, 95% CI 0.81 to 1.01). CONCLUSIONS: Overall, no association between vitamin D status and risk of LBP was demonstrated. The association suggested in women for the winter/spring season cannot be regarded as established.

Vitamin D and Lung Function Decline in Adults With Asthma: The HUNT Study.

We investigated whether low 25-hydroxyvitamin D (25(OH)D) levels were associated with more lung function decline in adults with asthma and whether this association was modified by smoking status or inhaled corticosteroid (ICS) use. We analyzed data on 395 adults with asthma from the Nord-Trøndelag Health Study (1995-2008), Norway. Plasma 25(OH)D and lung function were measured at baseline, and lung function measurements were repeated at follow-up, approximately 11 years later. Linear regression was used to estimate lung function decline. Participants with low 25(OH)D (<50 nmol/L) had more decline in lung function measurements for forced expiratory volume in 1 second (FEV1) (388 mL), forced vital capacity (298 mL), and the FEV1/forced vital capacity ratio (3.7%) over the follow-up, compared with those with high 25(OH)D (≥50 nmol/L) who declined 314 mL, 246 mL, and 3.0%, respectively (P = 0.08, 0.30, and 0.23, respectively). The associations were stronger in never smokers and non-ICS users. In never smokers, low 25(OH)D levels were associated with more decline in FEV1 (445 vs. 222 mL) (P = 0.01). In non-ICS users, low 25(OH)D levels were associated with more decline in FEV1 (467 vs. 320 mL) (P = 0.02). Low serum 25(OH)D levels were weakly associated with more lung function decline in adults with asthma, and stronger associations were observed in never smokers and non-ICS users.

Serum 25-hydroxyvitamin D level, smoking and lung function in adults: the HUNT Study.

The association between serum 25-hydroxyvitamin D (25(OH)D) level and lung function changes in the general population remains unclear.We conducted cross-sectional (n=1220) and follow-up (n=869) studies to investigate the interrelationship of serum 25(OH)D, smoking and lung function changes in a random sample of adults from the Nord-Trøndelag Health (HUNT) Study, Norway.Lung function was measured using spirometry and included forced expiratory volume in 1 s (FEV1) % predicted, forced vital capacity (FVC) % pred and FEV1/FVC ratio. Multiple linear and logistic regression models estimated the adjusted difference in lung function measures or lung function decline, adjusted odds ratios for impaired lung function or development of impaired lung function and 95% confidence intervals.40% of adults had serum 25(OH)D levels <50 nmol·L(-1). Overall, those with a serum 25(OH)D level <50 nmol·L(-1) showed worse lung function and increased odds of impaired lung function compared to the ≥50 nmol·L(-1) group. These associations tended to be stronger among ever-smokers, including greater decline in FEV1/FVC ratio and greater odds of the development of impaired lung function (FEV1/FVC <70% OR 2.4, 95% CI 1.2-4.9). Associations among never-smokers were null. Results from cross-sectional and follow-up studies were consistent. There were no associations between serum 25(OH)D levels and lung function or lung function changes in never-smokers, whereas significant associations were observed in ever-smokers.

Factors associated with vitamin D deficiency in a Norwegian population: the HUNT Study.

Vitamin D deficiency occurs worldwide. Winter season and high Body Mass Index (BMI) are associated with low levels of serum 25-hydroxyvitamin D (25(OH)D). We estimated the prevalence of vitamin D deficiency in a Norwegian adult population and examined factors associated with vitamin D deficiency. A cohort of 25, 616 adults (19-55 years) who participated in both the second and third Nord-Trøndelag Health Study (HUNT 2 (1995-1997) and HUNT 3 (2006-2008)) was established in a previous study. A 10% random sample of the cohort population was recruited for serum 25(OH)D measurements (n=2584), which was used for the current cross-sectional study. Vitamin D deficiency was defined as serum 25(OH)D level <50 nmol/L. The overall prevalence of vitamin D deficiency was 40%, but varied by season (winter: 64%; summer: 20%). Winter season (adjusted prevalence ratio (PR): 3.16, 95% CI 2.42 to 4.12) and obesity (BMI ≥30.0 kg/m2) (PR: 1.74, 95% CI 1.45 to 2.10) were strongly associated with prevalent vitamin D deficiency. Current smoking also demonstrated an increased PR (1.41, 95% CI 1.21 to 1.65). Daily intake of cod liver oil (PR: 0.60, 95% CI 0.41 to 0.77), increased physical activity (PR: 0.80, 95% CI 0.68 to 0.95) and more frequent alcohol consumption (PR: 0.76, 95% CI 0.60 to 0.95) were associated with a reduced PR. The prevalence of vitamin D deficiency was high in Norwegian adults. Winter season, high BMI and current smoking were positively associated, and intake of cod liver oil, increased physical activity and more frequent alcohol consumption were inversely associated with vitamin D deficiency.

Lung function and respiratory symptoms in association with mortality: The HUNT Study.

Whether respiratory symptoms are associated with mortality independent of lung function is unclear. The authors explored the association of the exposures i) lung function, ii) respiratory symptoms, and iii) lung function and respiratory symptoms combined, with the outcomes all-cause and cardiovascular mortality. The study included 10,491 adults who participated in the Nord-Trøndelag Health Study (HUNT) Lung Study in 1995-1997 and were followed through 2009. Cox regression was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals for all-cause and cardiovascular mortality associated with pre-bronchodilator% predicted forced expiratory volume in 1 second (ppFEV1), chronic obstructive pulmonary disease (COPD) grades, and respiratory symptoms (chronic bronchitis, wheeze, and levels of dyspnoea). Lung function was inversely associated with all-cause mortality. Compared to ppFEV1 ≥100, ppFEV1 <50 increased the HR to 6.85 (4.46-10.52) in women and 3.88 (2.60-5.79) in men. Correspondingly, compared to normal airflow, COPD grade 3 or 4 increased the HR to 6.50 (4.33-9.75) in women and 3.57 (2.60-4.91) in men. Of the respiratory symptoms, only dyspnoea when walking remained associated with all-cause mortality after controlling for lung function (HR 1.73 [1.04-2.89] in women and 1.57 [1.04-2.36] in men). Analyses of lung function and dyspnoea when walking as a combined exposure further supported this finding. Overall, associations between lung function and cardiovascular mortality were weaker, and respiratory symptoms were not associated with cardiovascular mortality. In conclusion, lung function was inversely associated with all-cause and cardiovascular mortality, and dyspnoea when walking was associated with all-cause mortality independent of lung function.