A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma.

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.

Associations of age with serum insulin, proinsulin and the proinsulin-to-insulin ratio: a cross-sectional study.

BACKGROUND: Insulin responses and insulin levels seem to decline with age. However, the question of beta cell impairment attributable to ageing has been sparsely addressed in population-based studies. Non-fasting insulin levels are determined by the ambient degree of insulin resistance together with the capacity of beta cells to compensate by insulin secretion to prevent hyperglycaemia. A raised proinsulin-to-insulin ratio (proinsulin/insulin) due to impaired processing of proinsulin is an early marker of beta cell dysfunction. We hypothesised that in a general population, signs of beta cell failure with advancing age manifest not only by decreases in random insulin, but also with a corresponding increase in its precursor proinsulin. METHODS: In the Tromsø Study 1994-95 we measured insulin and proinsulin concentrations in random blood samples from 6212 persons without self-reported diabetes mellitus and plotted the levels as percentiles according to age. In regression analyses we assessed the relationships between age and insulin, proinsulin, and proinsulin/insulin, while adjusting for the concomitant measurements of glucose and other metabolic variables, and the time since the last meal. RESULTS: Median insulin concentrations declined significantly with advancing age group in men, but not in women. Proinsulin levels and proinsulin/insulin increased across age groups in both genders. After adjustment, greater age was associated with lower log10(insulin) and higher log10(proinsulin) and log10(proinsulin/insulin) (p = 0.0001 for all). CONCLUSIONS: Negative associations of age with random insulin levels, together with positive associations of age with proinsulin and proinsulin/insulin, point towards a loss of beta cell function inherent in the ageing process.

Homocysteine lowering and cardiovascular events after acute myocardial infarction.

BACKGROUND: Homocysteine is a risk factor for cardiovascular disease. We evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infarction. METHODS: The trial included 3749 men and women who had had an acute myocardial infarction within seven days before randomization. Patients were randomly assigned, in a two-by-two factorial design, to receive one of the following four daily treatments: 0.8 mg of folic acid, 0.4 mg of vitamin B12, and 40 mg of vitamin B6; 0.8 mg of folic acid and 0.4 mg of vitamin B12; 40 mg of vitamin B6; or placebo. The primary end point during a median follow-up of 40 months was a composite of recurrent myocardial infarction, stroke, and sudden death attributed to coronary artery disease. RESULTS: The mean total homocysteine level was lowered by 27 percent among patients given folic acid plus vitamin B12, but such treatment had no significant effect on the primary end point (risk ratio, 1.08; 95 percent confidence interval, 0.93 to 1.25; P=0.31). Also, treatment with vitamin B6 was not associated with any significant benefit with regard to the primary end point (relative risk of the primary end point, 1.14; 95 percent confidence interval, 0.98 to 1.32; P=0.09). In the group given folic acid, vitamin B12, and vitamin B6, there was a trend toward an increased risk (relative risk, 1.22; 95 percent confidence interval, 1.00 to 1.50; P=0.05). CONCLUSIONS: Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction. A harmful effect from combined B vitamin treatment was suggested. Such treatment should therefore not be recommended. (ClinicalTrials.gov number, NCT00266487.).

Cancer incidence and mortality after treatment with folic acid and vitamin B12.

CONTEXT: Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk. OBJECTIVE: To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials. DESIGN, SETTING, AND PARTICIPANTS: Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. INTERVENTIONS: Oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) alone (40 mg/d) (n = 1705); or placebo (n = 1721). MAIN OUTCOME MEASURES: Cancer incidence, cancer mortality, and all-cause mortality. RESULTS: During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B(12) vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B(12) vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B(12) vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12). Vitamin B(6) treatment was not associated with any significant effects. CONCLUSION: Treatment with folic acid plus vitamin B(12) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00671346.

Carotid atherosclerosis is a stronger predictor of myocardial infarction in women than in men: a 6-year follow-up study of 6226 persons: the Tromsø Study.

BACKGROUND AND PURPOSE: Ultrasound of carotid arteries provides measures of intima media thickness (IMT) and plaque, both widely used as surrogate measures of cardiovascular disease. Although IMT and plaques are highly intercorrelated, the relationship between carotid plaque and IMT and cardiovascular disease has been conflicting. In this prospective, population-based study, we measured carotid IMT, total plaque area, and plaque echogenicity as predictors for first-ever myocardial infarction (MI). METHODS: IMT, total plaque area, and plaque echogenicity were measured in 6226 men and women aged 25 to 84 years with no previous MI. The subjects were followed for 6 years and incident MI was registered. RESULTS: During follow-up, MI occurred in 6.6% of men and 3.0% of women. The adjusted relative risk (RR; 95% CI) between the highest plaque area tertile versus no plaque was 1.56 (1.04 to 2.36) in men and 3.95 (2.16 to 7.19) in women. In women, there was a significant trend toward a higher MI risk with more echolucent plaque. The adjusted RR (95% CI) in the highest versus lowest IMT quartile was 1.73 (0.98 to 3.06) in men and 2.86 (1.07 to 7.65) in women. When we excluded bulb IMT from analyses, IMT did not predict MI in either sex. CONCLUSIONS: In a general population, carotid plaque area was a stronger predictor of first-ever MI than was IMT. Carotid atherosclerosis was a stronger risk factor for MI in women than in men. In women, the risk of MI increased with plaque echolucency.

Body mass index and coronary heart disease risk score: the Tromsø study, 1979 to 2001.

PURPOSE: The purpose of the study is to examine the association between longitudinal change in body mass index (BMI) and change in coronary heart disease (CHD) risk score by using the Framingham risk score equation. METHODS: A general adult population in the municipality of Tromsø, Norway, was invited to four consecutive examinations in 1979 to 1980, 1986 to 1987, 1994 to 1995, and 2001. A total of 10,214 men and women aged 20 to 61 years at baseline attended at least three times. Associations were examined by using fixed-effects regression methods for longitudinal data. RESULTS: We observed a significant association between BMI change and risk score change in all baseline age groups. The association was significantly strengthened by age in women, but not men. A BMI increase of 3 kg/m(2) in subjects aged 40 to 49 years was associated with risk score increases of 0.45 points (95% confidence interval [CI], 0.29-0.62) in men and 0.66 points (95% CI, 0.52-0.80) in women. CONCLUSIONS: The well-known increase in body weight is associated with adverse CHD risk in both men and women.

Elevated high-density lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis the Tromsø study.

BACKGROUND: There is an inverse relationship between HDL cholesterol and coronary heart disease. Experimental studies have indicated that HDL cholesterol may exert an antiatherogenic effect by inducing regression of atherosclerotic plaques and by turning lipid-rich plaques into more fibrotic lesions. In this prospective, population-based ultrasound study, we investigated how HDL cholesterol relates to carotid plaque progression. METHODS AND RESULTS: The study included 1952 men and women aged 25 to 82 years who had at least 1 plaque present in the right carotid artery at baseline examination (1994). All plaque images were computer processed to yield a measure of plaque area in square millimeters and echogenicity, expressed as the gray-scale median. After 7 years of follow-up, a new ultrasound screening was performed, and the changes in plaque area and echogenicity were assessed. In a multivariable adjusted model, HDL cholesterol, age, systolic blood pressure, and current smoking were independent predictors of plaque growth. For a 1-SD (0.41 mmol/L) lower HDL cholesterol level, mean (SE) plaque area increased by 0.93 mm2 (0.44 mm2; P=0.03). When users of lipid-lowering drugs were excluded from analysis, the HDL estimate was strengthened (beta=1.46 mm2, P=0.002). Although plaque area increased in 70% of cases, and most plaques became more echogenic over the follow-up interval, the plaques that became more echolucent grew more in size than those that became more echogenic (P=0.002). CONCLUSIONS: This study shows that a high level of HDL cholesterol reduces plaque growth in subjects with preexisting carotid atherosclerosis. Transformation of the plaque mass into higher echogenicity is associated with reduced growth. Our findings may indicate that HDL cholesterol stabilizes plaques and counteracts their growth by reducing their lipid content and inflammation.

Repeated visual and computer-assisted carotid plaque characterization in a longitudinal population-based ultrasound study: the Tromsø study.

In a longitudinal population-based ultrasound survey, we evaluated the reproducibility of carotid plaque detection, off-line vs. online visual classification of plaque echogenicity and computer-assisted plaque echogenicity (grey-scale median, GSM) classification and plaque area measurements. The number of paired observations in the reproducibility analyses was 107 in the baseline study and 83 in the follow-up study. In addition, 198 and 222 images were selected from the baseline and the follow-up study for GSM- and plaque-area analyses. The total number of plaque images (11,160) was used to obtain comparative reference values. Despite good agreement in the reproducibility study (kappa values ranging from 0.52 to 0.57), there was a substantial drift in online visual classification of plaque echogenicity during the survey period. Inter- and intraobserver agreement on computer-assisted GSM classification was substantial, with kappa values (95% CI) of 0.77 (0.73 to 0.80) and 0.79 (0.75 to 0.84), respectively. A systematic bias in plaque area measurements was observed. Visual online classification may introduce systematic measurement errors that are not intercepted in a reproducibility study of restricted duration. Computer-assisted off-line classification had better reproducibility. However, the method is influenced by measurement errors, both in the outlining of the plaque and in the standardization procedure.

Monocyte count is a predictor of novel plaque formation: a 7-year follow-up study of 2610 persons without carotid plaque at baseline the Tromsø Study.

BACKGROUND AND PURPOSE: Activation of monocytes and differentiation into lipid-laden macrophages are fundamental events in generation of atherosclerotic lesions. There exist few data on monocyte activity and the risk for atherosclerosis. In this prospective population-based study, we examined whether monocyte count in blood is a predictor of future plaque formation in persons without pre-existing carotid atherosclerosis. METHODS: At baseline, we measured monocyte count, white cell count (WCC), fibrinogen, intima-media thickness (IMT), and traditional cardiovascular risk factors in 2610 men and women aged 25 to 82 years who on ultrasound had no plaque in their right carotid artery. After 7 years of follow-up, a new ultrasound screening was performed and the number of novel plaques was grouped as none, 1 plaque, and 2 or more plaques. RESULTS: In multivariate analysis, monocyte count, age, sex, total cholesterol, current smoking, systolic blood pressure, and IMT were independent predictors of novel plaque formation. No significant association was found between plaque formation and either WCC or fibrinogen. For 1 standard deviation (0.17x10(9)) increase in monocyte count, the risk of being in a higher plaque category increased by 18% (OR, 1.18; 95% CI, 1.08 to 1.29). In the highest monocyte quartile, the risk for having plaque compared with the lowest quartile was 1.85 (OR) (95% confidence interval, 1.41 to 2.43). Repeating the analysis without IMT did not change the monocyte estimate. Excluding subjects with cardiovascular disease and diabetes mellitus from analysis neither changed the monocyte estimate. CONCLUSIONS: Monocyte count is an independent predictor of future plaque formation in subjects without pre-existing carotid atherosclerosis.

[A programme for boosting medical research in North Norway, 1992-2001]. / Programmet Medisinsk forskning i Nord-Norge 1992-2001.

BACKGROUND: Goals for the programme were recruitment of specialists and lowering turnover among them, generating new knowledge, quality assurance and professional development. Close to NOK 25 million were spent on this research programme in regional non-university hospitals over the 1992-2001 period. MATERIAL AND METHODS: 78 projects were funded, 77 responded to our questionnaire. RESULTS: 36 (47%) of respondents claim to have completed their projects, 5 (7%) have not, whereas 36 (47%) have ongoing projects. 70% of the projects have led to publications, 39% as part of doctoral theses, 61% have been done locally and 43 % also had other funding. In relation to the aims of the programme, those responding were very positive and 75 out of 77 suggested that a low-threshold, supportive programme of this type should be continued. INTERPRETATION: We conclude that the programme has had positive effects beyond the generation of new knowledge.

Predictors of death among long-term stroke survivors.

BACKGROUND AND PURPOSE: We evaluated the risk factors for death among long-term stroke survivors compared with stroke-free subjects. METHODS: In 1997 we investigated 221 stroke survivors (mean, 9.4 years after index stroke) and 243 stroke-free subjects; both groups were recruited from a population-based health study. During the subsequent 5 years, all deaths (51 and 21 in the stroke and stroke-free groups, respectively) were registered. RESULTS: The age- and sex-adjusted total mortality rate for the 5-year follow-up was 21.0% in the stroke group and 7.9% in the stroke-free group (P<0.0001), depending on different rates of cardiovascular deaths (P<0.0001). Better physical and social functioning (P<0.0001) and moderate use of alcohol (P

Change in serum lipids and body mass index by age, sex, and smoking status: the Tromsø study 1986-1995.

PURPOSE: The steady increase in body weight is becoming a major health problem in western societies. How body weight increase influences established disease risk factors is the focus of our study. METHODS: We assessed the association between 8-year change in body weight and serum lipids in a population-based study comprising 15,624 men and women aged 20 to 61 years at baseline in 1986. Comparisons between different strata of age, sex, initial weight, and categories of smoking status change were also addressed. RESULTS: Significant associations between body mass index (BMI) change and change in high density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides were observed in all 10-year age groups both in men and women. The weakest associations were observed in persons older than 50 years of age and the associations were also weaker in women than in men. In quartile groups of baseline BMI, a significant linear trend was observed for HDL cholesterol in men and for total cholesterol in both men and women. The associations were less adverse for persons in a higher quartile group of baseline BMI. The association between BMI change and serum lipid change was strongest for persons who were consistent smokers or non-smokers at each survey. CONCLUSIONS: We conclude that an increase in BMI has been shown to be associated with adverse changes in serum lipids. The associations were weaker in women than in men.

Determining lifestyle correlates of body mass index using multilevel analyses: the Tromsø Study, 1979-2001.

Increases in overweight and obesity have been observed globally in both developed and developing countries. The authors assessed the relation between lifestyle factors and body mass index (BMI) (weight (kg)/height (m)2) in a population-based longitudinal study, using BMI and its subsequent change as responses in a multilevel model. The authors included 11,115 men and women aged 20-61 years at baseline who were living in the municipality of Tromsø, Norway, and who participated in three or four consecutive health surveys between 1979-1980 and 2001. Baseline age, physical activity at work, coffee consumption, and desired BMI (i.e., the BMI that the subjects reported they would like to have) were positively associated with baseline BMI, whereas height, alcohol consumption, leisure-time physical activity, and level of education were inversely associated. Most relations were found to be stronger in women than in men. Clinically relevant effect sizes were observed for most of the significant associations, especially in women. For instance, on an ordinal scale, a one-category increase in educational level would decrease the mean baseline BMI among women by 0.30 kg/m2. Significant associations between several lifestyle factors and subsequent BMI change revealed that observed baseline associations were strengthened over time, especially in women.

Sex differences in plaque morphology may explain the higher male prevalence of myocardial infarction compared to angina pectoris. The Tromsø Study.

OBJECTIVES: To study whether the degree of carotid atherosclerosis and the male predominance of echolucent plaques could explain the sex difference in myocardial infarction (MI) compared to angina pectoris (AP). DESIGN: Ultrasound examination of the carotid artery was performed in 6727 persons. The presence of plaque, plaque thickness and number of segments with plaque were recorded. Plaque morphology in terms of echogenicity was scored as echolucent (soft plaque) or echogenic (hard plaque). A questionnaire was used to obtain information about coronary heart disease. RESULTS: In men with the most advanced atherosclerosis, the risk (OR, 95% CI) of having MI compared to those with no carotid atherosclerosis was less than half as the corresponding risk in women (2.2, 1.4-3.3 vs 5.3, 2.6-10.6). For MI, the male-to-female ratio was highest in the group with no carotid plaque and declined by increasing burden of atherosclerosis. For AP, the sex ratio was independent of the degree of atherosclerosis. CONCLUSIONS: The findings support the hypothesis that the sex difference in MI compared to AP is due to the higher male prevalence of echolucent plaque.

Impaired motor speed, visuospatial episodic memory and verbal fluency characterize cognition in long-term stroke survivors: the Tromsø Study.

The cognitive function after stroke is examined in acute and subacute phase, but poorly characterized in long-term stroke survivors. This paper discusses cognitive function among long-term stroke survivors, with matched stroke-free subjects, based on a population survey. General cognition, verbal, executive and visuospatial function, memory, attention, and motor speed were tested as well as motor function in upper extremities. Stroke survivors and controls were most effectively discriminated by means of motor speed, followed by visuospatial episodic memory and verbal fluency. This pattern of cognitive disturbances may be a consequence of cerebral lesions in frontal subcortical areas, and is different from Alzheimer's disease.

T cell autoimmunity to histones and nucleosomes is a latent property of the normal immune system.

OBJECTIVE: Investigators in this study undertook to determine whether in vitro antigen-responsive immune (polyomavirus T antigen [T-ag]- specific) and autoimmune (histone-specific) T cells from normal individuals share structural and genetic characteristics with those from patients with systemic lupus erythematosus (SLE). METHODS: Histone-specific T cells were generated by stimulation of peripheral blood mononuclear cells (PBMCs) with nucleosome-T-ag complexes and were subsequently maintained by pure histones. T-ag-specific T cell clones were initiated and maintained by T-ag. The frequencies of circulating histone- and T-ag-specific T cells were determined in healthy individuals and in SLE patients by limiting dilution of PBMCs. T cell receptor (TCR) gene usage and variable-region structures were determined by complementary DNA sequencing. These sequences were compared between T-ag- and histone-specific T cells and between normal individuals and SLE patients for each specificity. RESULTS: Individual in vitro-expanded histone- and T-ag-specific T cells from normal individuals displayed identical TCR V(alpha) and/or V(beta) chain third complementarity-determining region (CDR3) sequences, indicating that they were clonally expanded in vivo. The frequencies of in vitro antigen-responsive T-ag- or histone-specific T cells from normal individuals were similar to those from SLE patients. Although heterogeneous for variable-region structure and gene usage, histone-specific T cells from healthy individuals and SLE patients selected aspartic and/or glutamic acids at positions 99 and/or 100 of the V(beta) CDR3 sequence. CONCLUSION: Autoimmune T cells from healthy individuals can be activated by nucleosome- T-ag complexes and maintained by histones in vitro. Such T cells possessed TCR structures similar to those from SLE patients, demonstrating that T cell autoimmunity to nucleosomes may be a latent property of the normal immune system.