Leena Tenkanen

Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland).

AbstractObjectives:The aim was to evaluate the association between serum vitamin D (25-hydroxyvitamin D) level and risk of prostate cancer. Methods:The nested case–control study was based on a 13-year follow-up of about 19,000 middle-aged men who attended the first screening visit within the Helsinki Heart Study and were free of clinically verified prostate cancer at baseline. Through record linkage with the files of the Finnish Cancer Registry, 149 prostate cancer cases were identified in the cohort. They were matched (1:4) to probability density sampled controls for age, time of sample retrieval, and residence. Serum levels of 25-hydroxyvitamin D (25-VD) at entry were measured for cases and controls. The relative risks of prostate cancer were derived using conditional logistic regression analysis. Results:Prostate cancer risk, analyzed by quartiles of the 25-VD levels, was inversely related to 25-VD. Men with 25-VD concentration below the median had an adjusted relative risk (OR) of 1.7 compared to men with 25-VD level above the median. The prostate cancer risk was highest among younger men (<52 years) at entry and low serum 25-VD (OR 3.1 nonadjusted and 3.5 adjusted). Among those younger men (<52 years), low 25-VD entailed a higher risk of non-localized cancers (OR 6.3). The mean age at diagnosis of the patients with 25-VD concentration above the median was 1.8 years higher than that of patients with vitamin D below the median (63.1 vs 61.3 years). Conclusions: We conclude that low levels of 25-VD associated with an increased risk for subsequent earlier exposure and more aggressive development of prostate cancer, especially before the andropause.

Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: A longitudinal, nested case-control study in the Nordic countries

Vitamin D inhibits the development and growth of prostate cancer cells. Epidemiologic results on serum vitamin D levels and prostate cancer risk have, however, been inconsistent. We conducted a longitudinal nested case‐control study on Nordic men (Norway, Finland and Sweden) using serum banks of 200,000 samples. We studied serum 25(OH)‐vitamin D levels of 622 prostate cancer cases and 1,451 matched controls and found that both low (≤19 nmol/l) and high (≥80 nmol/l) 25(OH)‐vitamin D serum concentrations are associated with higher prostate cancer risk. The normal average serum concentration of 25(OH)‐vitamin D (40–60 nmol/l) comprises the lowest risk of prostate cancer. The U‐shaped risk of prostate cancer might be due to similar 1,25‐dihydroxyvitamin D3 availability within the prostate: low vitamin D serum concentration apparently leads to a low tissue concentration and to weakened mitotic control of target cells, whereas a high vitamin D level might lead to vitamin D resistance through increased inactivation by enhanced expression of 24‐hydroxylase. It is recommended that vitamin D deficiency be supplemented, but too high vitamin D serum level might also enhance cancer development.

High levels of circulating testosterone are not associated with increased prostate cancer risk: A pooled prospective study

Androgens stimulate prostate cancer in vitro and in vivo. However, evidence from epidemiologic studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent. We investigated the association of serum levels of testosterone, the principal androgen in circulation, and sex hormone‐binding globulin (SHBG) with risk in a case‐control study nested in cohorts in Finland, Norway and Sweden of 708 men who were diagnosed with prostate cancer after blood collection and among 2,242 men who were not. In conditional logistic regression analyses, modest but significant decreases in risk were seen for increasing levels of total testosterone down to odds ratio for top vs. bottom quintile of 0.80 (95% CI = 0.59–1.06; ptrend = 0.05); for SHBG, the corresponding odds ratio was 0.76 (95% CI = 0.57–1.01; ptrend = 0.07). For free testosterone, calculated from total testosterone and SHBG, a bell‐shaped risk pattern was seen with a decrease in odds ratio for top vs. bottom quintile of 0.82 (95% CI = 0.60–1.14; ptrend = 0.44). No support was found for the hypothesis that high levels of circulating androgens within a physiologic range stimulate development and growth of prostate cancer.

The sense of coherence, occupation and the risk of coronary heart disease in the Helsinki Heart Study

The risk of coronary heart disease (CHD) was studied in 4405 Finnish middle-aged working men in different occupations according to their sense of coherence (SOC). The study design was prospective and the follow-up time was eight years. Clinical findings such as total cholesterol, systolic blood pressure and body-mass index showed differences when comparing blue and white collar workers. Lifestyle factors such as smoking also differed, but leisure time physical activity depended on SOC. In the white collar work environment the low SOC tertile had a high CHD incidence of 20.1 per 1000 person-years; the incidences in the medium and high SOC tertiles were 10.9 and 12.3, respectively. A similar effect was not observed in the blue collar work environment. There, contrary to theoretical expectations, the low SOC tertile had the lowest incidence of CHD. The difference in the CHD incidence pattern depended on the blue and white collar dichotomy and not on the branch (state agencies vs. industry). The SOC had a salutogenic effect among white collar workers, but failed to have any consequent effect on the health of blue collar workers. Further study is needed to look at the psychosocial factors among blue collar workers.

Adrenal androgens and testosterone as coronary risk factors in the Helsinki Heart Study

We investigated the role of adrenal androgens, cortisol, testosterone and sex-hormone binding globulin (SHBG) as coronary risk factors using a nested case-control design. The study population consisted of 62 cases with cardiac end-points and 97 controls on placebo during the last 4 years in the Helsinki Heart Study. Serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, androstanediol glucuronide, cortisol, testosterone, and SHBG at the first annual visit of the 5-year study period were determined by radioimmunoassays. The only significant difference was found in DHEAS, with cases having higher levels than controls (P < 0.04). DHEAS levels were positively associated with smoking (P < 0.001), alcohol consumption (P < 0.04) and triglyceride levels (P < 0.002) and with systolic (P < 0.04) and diastolic (P < 0.006) blood pressures, and negatively associated with age (P < 0.01) and HDL-cholesterol (P < 0.03). The association between DHEAS and the CHD risk was studied using logistic regression analyses with the classical risk factors--age, smoking, blood pressure, and lipid levels--as covariates in the models. Studies of the joint effects of age and DHEAS disclosed that the risk associated with elevated DHEAS was confirmed to older men (odds ratio (OR) 7.3, 95%, CI 2.3-23.3). A similar analysis with smoking revealed that the DHEAS-related risk was mainly found in smokers (OR 3.4, 95% CI 1.5-8.2). One possible explanation for these results is that some form of mild steroid biosynthetic defect of the adrenals or functional adrenal hyperplasia associated with high DHEAS levels increases the CHD risk in this population.

Job stress and sleep disorders: findings from the Helsinki Heart Study

Sleep disorders and daytime fatigue are common health problems in middle-aged and elderly populations, and they vary greatly between occupational groups. There is widespread evidence that working hours and job stress may explain these differences. In this study the relationship of job demands and job control to sleep disorders was investigated. The subjects were 3079 middle-aged working men. The data were collected with a questionnaire including scales on sleep quality, job stress and lifestyle. The main effects of job demands and job control on insomnia, sleep deprivation and daytime fatigue were highly significant. Some interaction effects of the stressors were also noted. Lifestyle factors were not found as significant mediators or confounders of the effects. The associations between the stressors and sleep disorders were greater in the daytime workers than in the shift workers. The main conclusion is that job stressors have a direct relationship to sleep disorders, independent of working hours and lifestyle. Copyright

Circulating enterolactone and prostate cancer risk: A Nordic nested case‐control study

Enterolactone, a phytoestrogen belonging to the class of lignans, is produced by the intestinal microflora from precursors in plant foods and has been implicated in protection against cancer. We study the effect of enterolactone on the risk of a subsequent diagnosis of prostate cancer. We conducted a longitudinal, nested case‐control study by linkage of 3 biobanks to the cancer registries in Finland, Norway and Sweden, respectively. Enterolactone concentrations were measured by time‐resolved fluoroimmunoassay in serum from 794 men who had a diagnosis of prostate cancer at a mean follow‐up time of 14.2 years after blood collection and among 2,550 control men matched within each cohort for age (±2 years), date of blood collection (±2 months) and county. The median enterolactone concentrations did not differ between case and control subjects in the full study group (8.4 nmol/L [25th–75th percentile = 4.5–15.0] vs. 8.5 nmol/L [25th–75th percentile = 4.3–15.9]), nor in the national groups. Odds ratios of prostate cancer risk estimated by conditional logistic regression for increasing concentrations of enterolactone in quartiles in the full study group were 1.00 (referent), 1.21 (95% confidence interval [CI] = 0.96–1.52), 1.16 (95% CI = 0.91–1.47) and 1.08 (95% CI = 0.83–1.39). The OR estimate for the highest vs. the lowest quartile of enterolactone in separate analyses of the Norwegian, Finnish and Swedish cohort was 1.21 (95% CI = 0.91–1.60), 1.02 (95% CI = 0.59–1.76) and 0.87 (95% CI = 0.45–1.67), respectively. No support for the hypothesis that high circulating enterolactone is protective against prostate cancer was found.

Nordic biological specimen banks as basis for studies of cancer causes and control - More than 2 million sample donors, 25 million person years and 100 000 prospective cancers

The Nordic countries have a long tradition of large-scale biobanking and comprehensive, population-based health data registries linkable on unique personal identifiers, enabling follow-up studies spanning many decades. Joint Nordic biobank-based studies provide unique opportunities for longitudinal molecular epidemiological research. The purpose of the present paper is to describe the possibilities for such joint studies, by describing some of the major Nordic biobank cohorts with a standardised calculation of the cancer incidence in these cohorts. Altogether two million donors have since 1966 donated more than four million biological samples, stored at −20°C to −135°C, to 17 biobank cohorts in Finland, Iceland, Norway and Sweden. As a result of joint database handling principles, the accuracy of personal identifiers and completeness of follow-up for vital status in all participating biobanks was improved. Thereafter, the cancer incidence was determined using follow-up through the national cancer registries. Biobanks based on random samples of population typically showed slightly lower cancer incidence rates than the general population, presumably due to better participation rates among health-conscious subjects. On the other hand, biobanks including samples for viral screening or clinical testing showed 1.5 to 2.1 fold increased incidence of cancer. This excess was very high immediately after sampling, but for some cancer sites remained elevated for years after clinical sampling. So far, more than 100 000 malignant neoplasms have occurred after sample donation, and the annual increase of the cancer cases in these cohorts is about 10 000. The estimates on the population-representativity of the biobanks will assist in interpretation of generalizability of results of future studies based on these samples, and the systematic tabulations of numbers of cancer cases will serve in study power estimations. The present paper summarizes optimal study designs of biobank-based studies of cancer.

Testing equality of relative survival patterns based on aggregated data.

The relative survival rate is defined as the ratio of the survival rate observed in a patient group under consideration to the survival rate expected in a group of people similar to the patient group at the beginning of the follow-up interval, with respect to all possible factors (e.g., age and sex) affecting survival, except the disease under study. Survival from cancer and other chronic diseases is often measured by this quantity, which is adjusted for the effect of mortality attributable to competing risks of death. In this paper, maximum likelihood ratio tests are constructed on the basis of aggregated data for testing the equality of relative survival rates between patient groups against proportional hazards and general alternative hypotheses. The tests are applied to the Finnish nationwide data on colon cancer patients with nonlocalized tumors as reported to the Finnish Cancer Registry. Simulation studies show that the maximum likelihood ratio tests compare favorably with alternative methods proposed earlier. Moreover, the maximum likelihood ratio tests are more extensive in coverage and are based on more applicable alternative hypotheses than the other test statistics. Finally, an extension to proportional hazards regression models of the relative survival rates is suggested.

Joint Effects of an Aldosterone Synthase (CYP11B2) Gene Polymorphism and Classic Risk Factors on Risk of Myocardial Infarction

BACKGROUND The -344C allele of a 2-allele (C or T) polymorphism in the promoter of the gene encoding aldosterone synthase (CYP11B2) is associated with increased left ventricular size and mass and with decreased baroreflex sensitivity, known risk factors for morbidity and mortality associated with myocardial infarction (MI). We hypothesized that this polymorphism was a risk factor for MI. METHODS AND RESULTS We used a nested case-control design to investigate the relationships between this polymorphism and the risk of nonfatal MI in 141 cases and 270 matched controls from the Helsinki Heart Study, a coronary primary prevention trial in dyslipidemic, middle-aged men. There was a nonsignificant trend of increasing risk of MI with number of copies of the -344C allele. However, this allele was associated in a gene dosage-dependent manner with markedly increased MI risk conferred by classic risk factors. Whereas smoking conferred a relative risk of MI of 2.50 (P=0.0001) compared with nonsmokers in the entire study population, the relative risk increased to 4.67 in -344CC homozygous smokers (relative to nonsmokers with the same genotype, P=0.003) and decreased to 1.09 in -344TT homozygotes relative to nonsmokers with this genotype. Similar joint effects were noted with genotype and decreased HDL cholesterol level as combined risk factors. CONCLUSIONS Smoking and dyslipidemia are more potent risk factors for nonfatal MI in males who have the -344C allele of CYP11B2.