Serum calcium and the calcium-sensing receptor polymorphism rs17251221 in relation to coronary heart disease, type 2 diabetes, cancer and mortality: the Tromsø Study.

Serum calcium measured in 27,158 subjects in 1994 and the calcium-sensing receptor polymorphism rs17251221 genotyped in 9,404 subjects were related to cardiovascular risk factors, incident myocardial infarction (MI), type 2 diabetes (T2DM), cancer and death during follow-up until 2008-2010. In a Cox regression model with adjustment for age, gender, smoking and body mass index, subjects with serum calcium 2.50-2.60 mmol/L had a significantly increased risk of incident MI [n = 1,802, hazards ratio (HR) 1.40, 95 % confidence interval (CI) 1.18, 1.66] and T2DM (n = 705, HR 1.49, 95 % CI 1.15, 1.94) and a significantly reduced risk of cancer (n = 2,222, HR 0.73, 95 % CI 0.62, 0.86) as compared to subjects with serum calcium 2.20-2.29 mmol/L. For rs17251221 there was a mean difference in serum calcium of 0.05 mmol/L between major and minor homozygote genotypes. No consistent, significant relation between rs17251221 and risk factors or the major hard endpoints were found. The minor homozygote genotype (high serum calcium) had a significant twofold increased risk (HR 2.32, 95 % CI 1.24, 4.36) for prostate cancer, as compared to the major homozygote. This may be clinically important if confirmed in other cohorts.

The impact of risk factor trends on intracerebral hemorrhage incidence over the last two decades-The Tromsø Study.

BACKGROUND: Studies on the relationship between temporal trends in risk factors and incidence rates of intracerebral hemorrhage are scarce. AIMS: To analyze temporal trends in risk factors and incidence rates of intracerebral hemorrhage using individual data from a population-based study. METHODS: We included 28,167 participants of the Tromsø Study enrolled between 1994 and 2008. First-ever intracerebral hemorrhages were registered through 31 December 2013. Hazard ratios (HRs) for intracerebral hemorrhage were analyzed by Cox proportional hazards models, risk factor levels over time by generalized estimating equations, and incidence rate ratios (IRR) by Poisson regression. RESULTS: We registered 219 intracerebral hemorrhages. Age, male sex, systolic blood pressure (BP), diastolic BP, and hypertension were associated with intracerebral hemorrhage. Hypertension was more strongly associated with non-lobar intracerebral hemorrhage (HR 5.08, 95% CI 2.86-9.01) than lobar intracerebral hemorrhage (HR 1.91, 95% CI 1.12-3.25). In women, incidence decreased significantly (IRR 0.46, 95% CI 0.23-0.90), driven by a decrease in non-lobar intracerebral hemorrhage. Incidence rates in men remained stable (IRR 1.27, 95% CI 0.69-2.31). BP levels were lower and decreased more steeply in women than in men. The majority with hypertension were untreated, and a high proportion of those treated did not reach treatment goals. CONCLUSIONS: We observed a significant decrease in intracerebral hemorrhage incidence in women, but not in men. A steeper BP decrease in women may have contributed to the diverging trends. The high proportion of untreated and sub-optimally treated hypertension calls for improved strategies for prevention of intracerebral hemorrhage.

Endothelial dysfunction and systemic inflammation in persons with echolucent carotid plaques.

Echolucent carotid plaques are associated with high risk for future ischemic cerebrovascular events independent of the degree of stenosis. Elevated levels of markers of systemic inflammation and endothelial dysfunction are predictors for future myocardial infarction and stroke. The present study was undertaken to investigate the relations between plaque morphology, endothelial dysfunction assessed by tissue-plasminogen activator antigen (t-PA ag) and vonWillebrand factor (vWF), and systemic inflammation in persons with carotid stenosis. We conducted a crosssectional study including 133 persons with carotid stenosis and 138 controls without stenosis recruited from the populationbased Tromsø Study. High-resolution B-mode and colour Doppler/pulsed-wave Doppler ultrasonography of both carotid arteries was performed, and plaque morphology in terms of echogenicity was assessed. Persons with carotid stenosis had significantly higher plasma t-PA and vWF concentrations than controls. There was a significant inverse relationship between t-PA ag and plaque echogenicity (p = 0.034). The increased plasma t-PA ag in persons with carotid stenosis was not associated with increased plasminogen activator inhibitor-I (PAI-1). Persons with echolucent carotid plaques had higher degree of systemic inflammation, and plasma t-PA and vWF concentration increased significantly across quartiles of WBC, fibrinogen, and hs-CRP. Our findings may suggest that plasma t-PA may be superior to vWF as a marker for endothelial dysfunction due to its ability to discriminate between various plaque echogenicity, and that the predictive role of t-PA ag in cardiovascular disease is independent of inhibited fibrinolysis.

Burden of Cancer in a Large Consortium of Prospective Cohorts in Europe.

BACKGROUND: Disability-adjusted life-years (DALYs) are an indicator of mortality, morbidity, and disability. We calculated DALYs for cancer in middle-aged and older adults participating in the Consortium on Health and Ageing Network of Cohorts in Europe and the United States (CHANCES) consortium. METHODS: A total of 90 199 participants from five European cohorts with 10 455 incident cancers and 4399 deaths were included in this study. DALYs were calculated as the sum of the years of life lost because of premature mortality (YLLs) and the years lost because of disability (YLDs). Population-attributable fractions (PAFs) were also estimated for five cancer risk factors, ie, smoking, adiposity, physical inactivity, alcohol intake, and type II diabetes. RESULTS: After a median follow-up of 12 years, the total number of DALYs lost from cancer was 34 474 (382 per 1000 individuals) with a similar distribution by sex. Lung cancer was responsible for the largest number of lost DALYs (22.9%), followed by colorectal (15.3%), prostate (10.2%), and breast cancer (8.7%). Mortality (81.6% of DALYs) predominated over disability. Ever cigarette smoking was the risk factor responsible for the greatest total cancer burden (24.0%, 95% confidence interval [CI] = 22.2% to 26.0%), followed by physical inactivity (4.9%, 95% CI = 0.8% to 8.1%) and adiposity (1.8%, 95% CI = 0.2% to 2.8%). CONCLUSIONS: DALYs lost from cancer were substantial in this large European sample of middle-aged and older adults. Even if the burden of disease because of cancer is predominantly caused by mortality, some cancers have sizeable consequences for disability. Smoking remained the predominant risk factor for total cancer burden.

The DBP Phenotype Gc-1f/Gc-1f Is Associated with Reduced Risk of Cancer. The Tromsø Study.

BACKGROUND AND OBJECTIVE: In addition to its role as a transport protein, the vitamin D binding protein (DBP) may also affect lipid metabolism, inflammation and carcinogenesis. There are three common variants of the DBP, Gc1s (1s), Gc1f (1f), Gc2 (2) that result in six common phenotypes (1s/1s, 1s/1f, 1s/2, 1f/1f, 1f/2, and 2/2). These phenotypes can be identified by genotyping for the two single nucleotide polymorphisms rs7041 and rs4588 in the GC gene. The DBP variants have different binding coefficients for the vitamin D metabolites, and accordingly there may be important relations between DBP phenotypes and health. METHODS: DNA was prepared from subjects who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints myocardial infarction (MI), type 2 diabetes (T2DM), cancer or death as well as a randomly selected control group. The endpoint registers were complete up to 2010- 2013. Genotyping was performed for rs7041 and rs4588 and serum 25-hydroxyvitamin D (25(OH)D) was measured. RESULTS: Genotyping for rs7041 and rs4588 was performed successfully in 11 704 subjects. Among these, 1660 were registered with incident MI, 958 with T2DM, 2410 with cancer and 4318 had died. Subjects with the DBP phenotype 1f/1f had 23 - 26 % reduced risk of incident cancer compared to the 1s/1s and 2/2 phenotypes (P < 0.02, Cox regression with gender as covariate). Differences in serum 25(OH)D levels could not explain the apparent cancer protective effect of the DBP variant 1f. In addition to cancer and 25(OH)D, there were significant associations between DBP phenotype and body height, hip circumference and serum calcium. CONCLUSION: There are important biological differences between the common DBP phenotypes. If the relation between the DBP variant 1f and cancer is confirmed in other studies, determination of DBP phenotype may have clinical importance.