Abstract: ATTENTION: This publication contains an error. In table 2 and table 3 the column labels for genders have been replaced; instead of Women / Men there should be Men /Women
BACKGROUND: Population based studies are important for prevalence, incidence and association studies, but their external validity might be threatened by decreasing participation rates. The 50 807 participants in the third survey of the HUNT Study (HUNT3, 2006-08), represented 54% of the invited, necessitating a nonparticipation study. METHODS: Questionnaire data from HUNT3 were compared with data collected from several sources: a short questionnaire to nonparticipants, anonymous data on specific diagnoses and prescribed medication extracted from randomly selected general practices, registry data from Statistics Norway on socioeconomic factors and mortality, and from the Norwegian Prescription Database on drug consumption. RESULTS: Participation rates for HUNT3 depended on age, sex and type of symptoms and diseases, but only small changes were found in the overall prevalence estimates when including data from 6922 nonparticipants. Among nonparticipants, the prevalences of cardiovascular diseases, diabetes mellitus and psychiatric disorders were higher both in nonparticipant data and data extracted from general practice, compared to that reported by participants, whilst the opposite pattern was found, at least among persons younger than 80 years, for urine incontinence, musculoskeletal pain and headache. Registry data showed that the nonparticipants had lower socioeconomic status and a higher mortality than participants. CONCLUSION: Nonparticipants had lower socioeconomic status, higher mortality and showed higher prevalences of several chronic diseases, whilst opposite patterns were found for common problems like musculoskeletal pain, urine incontinence and headache. The impact on associations should be analyzed for each diagnosis, and data making such analyses possible are provided in the present paper.

Abstract: BACKGROUND:
How different Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifications of chronic obstructive pulmonary disease (COPD) predict mortality is unclear.
OBJECTIVE:
To examine the association of spirometric GOLD grades and the new ABCD groups with mortality, and to compare their informativeness in relation to mortality.
METHODS:
We studied 1540 people with post-bronchodilator COPD who participated in the Norwegian Nord-Trøndelag Health Study 1995-1997 and were followed up on all-cause mortality until May 2012. The associations of spirometric GOLD grades and ABCD groups with mortality were estimated by sex specific adjusted HRs from Cox regression and standardised mortality ratios. To assess the informativeness of spirometric GOLD grades and ABCD groups at predicting mortality we used the difference in twice the log-likelihood of a Cox regression model with and without each COPD classification.
RESULTS:
The distribution of participants was 28% in GOLD 1, 57% in GOLD 2, 13% in GOLD 3 and 2% in GOLD 4, in contrast to 61% in group A, 18% in group B, 12% in group C and 10% in group D. During a median of 14.6 years of follow-up, 837 people (54%) died. Mortality increased gradually from GOLD 1 to 4, while it was generally similar in groups A and B, and in groups C and D. Spirometric GOLD grades were substantially more informative than ABCD groups at predicting mortality.
CONCLUSIONS:
Spirometric GOLD grades predicted mortality better than the new ABCD groups among people with COPD from a Norwegian general population.

Abstract: We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

Abstract: Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

Abstract: BACKGROUND/AIMS: Some previous studies have reported that hysterectomy predicts increased prevalence of cardiovascular diseases, but the findings are disputed. We aimed to examine associations between hysterectomy and cardiovascular disease in a Norwegian cross-sectional health study. METHODS: The data were obtained from the population-based cross-sectional Nord-Trondelag Health Study (The HUNT-2 Study). Of 46,709 invited females, 35,280 (76%) participated; 939 (3%) reported hysterectomy without oophorectomy (exposed women). Each exposed woman was age-matched with four randomly chosen women (n = 3,756) without hysterectomy or oophorectomy. Oophorectomy and hysterectomy status was self-reported by the women. Hazard ratio for cardiovascular diseases was calculated by Cox regression analyses with hysterectomy as a time-dependent covariate. RESULTS: Median time since hysterectomy was 14 years (range 0-56 years). We calculated a significantly larger cumulative probability of cardiovascular diseases after hysterectomy with a hazard ratio of 1.92, 95% CI (1.51-2.38) after adjustments for cardiovascular risk factors (diabetes, age, use of hormonal replacement therapy and positive family history of myocardial infarction). CONCLUSION: Women had a significantly increased risk of cardiovascular diseases after hysterectomy compared to age-matched controls. Studies with longitudinal design and confirmed medical outcome data are needed.

Abstract: OBJECTIVE: To examine if leisure-time physical activity could cancel out the adverse effect of diabetes on cardiovascular mortality. RESEARCH DESIGN AND METHODS: This study prospectively examined the combined effect of clinical diabetes and reported leisure-time physical activity on cardiovascular mortality. Data on 53,587 Norwegian men and women participating in the population-based Nord-Trondelag Health (HUNT) Study (1995-1997) were linked with the Cause of Death Registry at Statistics Norway. RESULTS: Overall, 1,716 people died of cardiovascular disease during follow-up through 2008. Compared with the reference group of 3,077 physically inactive people without diabetes, 121 inactive people with diabetes had an adjusted hazard ratio (HR) of 2.81 (95% CI 1.93-4.07). The HR (95% CI) among people who reported >/=3 h of light activity per week was 0.89 (0.48-1.63) if they had diabetes (n = 403) and 0.78 (0.63-0.96) if they did not (n = 17,714). Analyses stratified by total activity level showed a gradually weaker association of diabetes with mortality with increasing activity level (P(interaction) = 0.003). CONCLUSIONS: The data suggest that even modest physical activity may cancel out the adverse impact of diabetes on cardiovascular mortality.

Abstract: Low birth weight is associated with increased risk of cardiovascular disease and type 2 diabetes in later life. The fetal insulin hypothesis suggests that shared genetic factors partly explain this association. If fetal genes predispose to both low birth weight and cardiovascular disease in adulthood, fathers of offspring with low birth weight should display an unfavorable profile of cardiovascular risk factors. To study this, the authors linked data on more than 14,000 parents, collected from the second Health Study of Nord Trondelag County, Norway (HUNT 2, 1995-1997), to offspring data from the Norwegian Medical Birth Registry (1967-2005). Linear regression was used to study associations of offspring birth weight for gestational age with the parents' body mass index, waist circumference, blood pressure, glucose, and serum lipids. All analyses were adjusted for shared environment by means of the socioeconomic measures, lifestyle, and cardiovascular risk factors of the partner. The authors found that low offspring birth weight for gestational age was associated with increased paternal blood pressure, body mass index, waist circumference, and unfavorable levels of glucose and lipids. For mothers, associations similar to those for fathers were found for blood pressure, whereas associations in the opposite direction were found for glucose, lipids, and body mass index. The paternal findings strengthen the genetic hypothesis.

Abstract: OBJECTIVE: To assess the predictive value of estimated cardiorespiratory fitness (eCRF) and evaluate the additional contribution of traditional risk factors in cardiovascular disease (CVD) mortality prediction. PARTICIPANTS AND METHODS: The study included healthy men (n=18,721) and women (n=19,759) aged 30 to 74 years. A nonexercise algorithm estimated cardiorespiratory fitness. Cox proportional hazards models evaluated the primary (CVD mortality) and secondary (all-cause, ischemic heart disease, and stroke mortality) end points. The added predictive value of traditional CVD risk factors was evaluated using the Harrell C statistic and net reclassification improvement. RESULTS: After a median follow-up of 16.3 years (range, 0.04-17.4 years), there were 3863 deaths, including 1133 deaths from CVD (734 men and 399 women). Low eCRF was a strong predictor of CVD and all-cause mortality after adjusting for established risk factors. The C statistics for eCRF and CVD mortality were 0.848 (95% CI, 0.836-0.861) and 0.878 (95% CI, 0.862-0.894) for men and women, respectively, increasing to 0.851 (95% CI, 0.839-0.863) and 0.881 (95% CI, 0.865-0.897), respectively, when adding clinical variables. By adding clinical variables to eCRF, the net reclassification improvement of CVD mortality was 0.014 (95% CI, -0.023 to 0.051) and 0.052 (95% CI, -0.023 to 0.127) in men and women, respectively. CONCLUSION: Low eCRF is independently associated with CVD and all-cause mortality. The inclusion of traditional clinical CVD risk factors added little to risk discrimination and did not improve the classification of risk beyond this simple eCRF measurement, which may be proposed as a practical and cost-effective first-line approach in primary prevention settings.

Abstract: Gastro-oesophageal reflux disease (GORD) develops when reflux of gastric content causes troublesome symptoms or complications. The main symptoms are heartburn and acid regurgitation and complications include oesophagitis, strictures, Barrett's oesophagus and oesophageal adenocarcinoma. In addition to hereditary influence, GORD is associated with lifestyle factors, mainly obesity. Tobacco smoking is regarded as an aetiological factor of GORD, while alcohol consumption is considered a triggering factor of reflux episodes and not a causal factor. Yet, both tobacco smoking and alcohol consumption can reduce the lower oesophageal sphincter pressure, facilitating reflux. In addition, tobacco smoking reduces the production of saliva rich in bicarbonate, which is important for buffering and clearance of acid in the oesophagus. Alcohol also has a direct noxious effect on the oesophageal mucosa, which predisposes to acidic injury. Tobacco smoking cessation reduces the risk of GORD symptoms and avoidance of alcohol is encouraged in individuals where alcohol consumption triggers reflux.

Abstract: OBJECTIVE: Gastro-oesophageal reflux is a public health concern which could have associated oesophageal complications, including adenocarcinoma, and possibly also head-and-neck and lung cancers. The aim of this study was to test the hypothesis that reflux increases all-cause and cancer-specific mortalities in an unselected cohort. DESIGN: The Nord-Trondelag health study (HUNT), a Norwegian population-based cohort study, was used to identify individuals with and without reflux in 1995-1997 and 2006-2008, with follow-up until 2014. All-cause mortality and cancer-specific mortality were assessed from the Norwegian Cause of Death Registry and Cancer Registry. Multivariable Cox regression was used to calculate HRs with 95% CIs for mortality with adjustments for potential confounders. RESULTS: We included 4758 participants with severe reflux symptoms and 51 381 participants without reflux symptoms, contributing 60 323 and 747 239 person-years at risk, respectively. Severe reflux was not associated with all-cause mortality, overall cancer-specific mortality or mortality in cancer of the head-and-neck or lung. However, for men with severe reflux a sixfold increase in oesophageal adenocarcinoma-specific mortality was found (HR 6.09, 95% CI 2.33 to 15.93) and the mortality rate was 0.27 per 1000 person-years. For women, the corresponding mortality was not significantly increased (HR 3.68, 95% CI 0.88 to 15.27) and the mortality rate was 0.05 per 1000 person-years. CONCLUSIONS: Individuals with severe reflux symptoms do not seem to have increased all-cause mortality or overall cancer-specific mortality. Although the absolute risk is small, individuals with severe reflux symptoms have a clearly increased oesophageal adenocarcinoma-specific mortality.

Abstract: BACKGROUND: A new, high-sensitivity assay for cardiac troponin I (hs-cTnI)11 permits evaluation of the prognostic value of cardiac troponins within the reference interval. Men have higher hs-cTnI concentrations than women, but the underlying pathophysiological mechanisms and prognostic implications are unclear. The aim of this study was to assess the potential impact of sex on the association between hs-cTnI and cardiovascular death. METHODS: By use of the Architect STAT High-Sensitive Troponin assay, we measured hs-cTnI in 4431 men and 5281 women aged >/=20 years participating in the prospective observational Nord-Trondelag Health Study (HUNT). RESULTS: hs-cTnI was detectable in 98.5% of men and 94.7% of women. During a mean follow-up period of 13.9 years, 708 cardiovascular deaths were registered. hs-cTnI was associated with the incidence of cardiovascular death [adjusted hazard ratio (HR) per 1 SD in log hs-cTnI 1.23 (95% CI 1.15-1.31)], with higher relative risk in women than men [HR 1.44 (1.31-1.58) vs 1.10 (1.00-1.20); Pinteraction

Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5x10(-8)). SNP rs7560163 (P = 7.0x10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5x10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

Abstract: RATIONALE, AIMS AND OBJECTIVES: Many clinical guidelines for cardiovascular disease (CVD) prevention contain risk estimation charts/calculators. These have shown a tendency to overestimate risk, which indicates that there might be theoretical flaws in the algorithms. Total cholesterol is a frequently used variable in the risk estimates. Some studies indicate that the predictive properties of cholesterol might not be as straightforward as widely assumed. Our aim was to document the strength and validity of total cholesterol as a risk factor for mortality in a well-defined, general Norwegian population without known CVD at baseline. METHODS: We assessed the association of total serum cholesterol with total mortality, as well as mortality from CVD and ischaemic heart disease (IHD), using Cox proportional hazard models. The study population comprises 52 087 Norwegians, aged 20-74, who participated in the Nord-Trondelag Health Study (HUNT 2, 1995-1997) and were followed-up on cause-specific mortality for 10 years (510 297 person-years in total). RESULTS: Among women, cholesterol had an inverse association with all-cause mortality [hazard ratio (HR): 0.94; 95% confidence interval (CI): 0.89-0.99 per 1.0 mmol L(-1) increase] as well as CVD mortality (HR: 0.97; 95% CI: 0.88-1.07). The association with IHD mortality (HR: 1.07; 95% CI: 0.92-1.24) was not linear but seemed to follow a 'U-shaped' curve, with the highest mortality <5.0 and >/=7.0 mmol L(-1) . Among men, the association of cholesterol with mortality from CVD (HR: 1.06; 95% CI: 0.98-1.15) and in total (HR: 0.98; 95% CI: 0.93-1.03) followed a 'U-shaped' pattern. CONCLUSION: Our study provides an updated epidemiological indication of possible errors in the CVD risk algorithms of many clinical guidelines. If our findings are generalizable, clinical and public health recommendations regarding the 'dangers' of cholesterol should be revised. This is especially true for women, for whom moderately elevated cholesterol (by current standards) may prove to be not only harmless but even beneficial.