David Dynnes Ørsted

The link between benign prostatic hyperplasia and prostate cancer.

Benign prostatic hyperplasia (BPH) and prostate cancer are among the most common diseases of the prostate gland and represent significant burdens for patients and health-care systems in many countries. The two diseases share traits such as hormone-dependent growth and response to antiandrogen therapy. Furthermore, risk factors such as prostate inflammation and metabolic disruption have key roles in the development of both diseases. Despite these commonalities, BPH and prostate cancer exhibit important differences in terms of histology and localization. Although large-scale epidemiological studies have shown that men with BPH have an increased risk of prostate cancer and prostate-cancer-related mortality, it remains unclear whether this association reflects a causal link, shared risk factors or pathophysiological mechanisms, or detection bias upon statistical analysis. Establishing BPH as a causal factor for prostate cancer development could improve the accuracy of prognostication and expedite intervention, potentially reducing the number of men who die from prostate cancer.

Association of Clinical Benign Prostate Hyperplasia with Prostate Cancer Incidence and Mortality Revisited: A Nationwide Cohort Study of 3 009 258 Men

BACKGROUND Although benign prostate hyperplasia (BPH) and prostate cancer (PCa) share features such as hormone-dependent growth and response to treatment with antiandrogen therapy, BPH is generally not considered a premalignant lesion. OBJECTIVE To determine whether clinical BPH is associated with an increased risk of PCa incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS Using designs with individual participant data from five national registries, we studied the entire Danish male population from 1980 through 2006, a total of 3,009,258 Danish men. We collected PCa diagnoses (n=53,315), information on PCa mortality (n=25,459), and ascertained clinical BPH (not histologically proven BPH) through hospitalization (n=187,591) and/or surgery (n=77,698) from 1980 to 2006 and the use of α-adrenergic receptor antagonists (n=143,365) and/or the use of 5α-reductase inhibitors (5-ARIs) (n=47,465) from 1995 to 2006. MEASUREMENTS PCa incidence and mortality was assessed for each category of clinical BPH using Kaplan-Meier plots of cumulative incidence and Cox proportional hazard ratios (HRs) adjusted for potential confounders. RESULTS AND LIMITATIONS For the entire cohort studies, multivariate-adjusted HRs for PCa incidence were 2.22 (95% confidence interval, 2.13-2.31) in men hospitalized and 3.26 (3.03-3.50) in men operated on for clinical BPH versus general population controls. Corresponding HRs for PCa mortality were 2.00 (1.91-2.08) for hospitalization and 7.85 (7.40-8.32) for surgery. For age-matched cohort studies, corresponding HRs for PCa incidence were 3.04 (2.96-3.13) for hospitalization, 2.60 (2.47-2.73) for surgery, 4.49 (4.33-4.65) for α-adrenergic receptor antagonist use, and 2.54 (2.40-2.68) for 5-ARI use. Each category of clinical BPH has limitations, but limitations differ between the categories and therefore are unlikely to explain the results. CONCLUSIONS In Danish men followed for up to 27 yr, clinical BPH was associated with a two- to three-fold increased risk of PCa incidence and with a two- to eight-fold increased risk of PCa mortality. These data should not be used to infer causality.

Elevated C-Reactive Protein Associated With Late- and Very-Late-Onset Schizophrenia in the General Population: A Prospective Study

BACKGROUND Individuals with autoimmune diseases and severe infections have persistent or acutely elevated inflammatory biomarkers and increased risk of schizophrenia. We tested the hypothesis that baseline elevated plasma levels of the inflammatory biomarker, C-reactive protein (CRP), associate with increased risk of late- and very-late-onset schizophrenia in the general population, and if such an association possibly is causal. METHOD We analyzed data from 78 810 men and women, aged 20-100 years, from 2 large population studies. Endpoints were hospitalization with schizophrenia and schizophrenia and schizophrenia-like psychosis combined. We performed prospective and cross-sectional analyses adjusted for potential confounders with up to 20 years of follow-up. Furthermore, we used genetic variants influencing plasma CRP levels to perform a Mendelian randomization study. RESULTS Age- and gender-adjusted hazard ratios vs individuals in the first quartile of CRP were 1.7 (95% CI: 0.3-8.9) for second quartile, 2.1 (0.4-10) for third quartile, and 11 (2.8-40) for fourth quartile individuals. The corresponding hazard ratio for fourth quartile individuals after multifactorial adjustment was 5.9 (1.4-24). Furthermore, individuals with vs without schizophrenia had 63% increased plasma levels of CRP (P = 1 × 10(-4)). Finally, when CRP was on a continuous scale, a doubling in CRP yielded an age- and gender-adjusted observational OR of 1.5 (1.3-1.8) and a corresponding causal OR of 1.4 (0.5-4.3) (observed vs causal: P = .89). CONCLUSION Baseline elevated plasma CRP is associated with a 6- to 11-fold increased risk of late- and very-late-onset schizophrenia in the general population. We cannot exclude that this is a causal association. These are novel findings.

Elevated C-Reactive Protein, Depression, Somatic Diseases, and All-Cause Mortality: A Mendelian Randomization Study

BACKGROUND Elevated levels of plasma C-reactive protein (CRP) have been associated with many diseases including depression, but it remains unclear whether this association is causal. We tested the hypothesis that CRP is causally associated with depression, and compared these results to those for cancer, ischemic heart disease, chronic obstructive pulmonary disease, and all-cause mortality. METHODS We performed prospective and instrumental variable analyses using plasma CRP levels and four CRP genotypes on 78,809 randomly selected 20- to 100-year-old men and women from the Danish general population. End points included hospitalization or death with depression and somatic diseases, prescription antidepressant medication use, and all-cause mortality. RESULTS A doubling in plasma CRP yielded an observed odds ratio (OR) of 1.28 (95% confidence interval [CI]: 1.23-1.33) for hospitalization or death with depression, whereas for genetically elevated CRP, the causal OR was .79 (95% CI: .51-1.22; observed vs. causal estimate, p = .03). For prescription antidepressant medication use, corresponding ORs were 1.12 (1.11-1.15) and .98 (.83-1.15; p = .08). These results were similar to those for risk of cancer (p = .002), ischemic heart disease (p = 4 × 10(-99)), chronic obstructive pulmonary disease (p = 6 × 10(-86)), and all-cause mortality (p = .001) examined in the same individuals. CONCLUSIONS Elevated CRP was associated with increased risk of depression in individuals in the general population, but genetically elevated CRP was not. This indicates that CRP per se is not a causal risk factor for depression.

Prostate-Specific Antigen and Long-Term Prediction of Prostate Cancer Incidence and Mortality in the General Population

BACKGROUND It is largely unknown whether prostate-specific antigen (PSA) level at first date of testing predicts long-term risk of prostate cancer (PCa) incidence and mortality in the general population. OBJECTIVE Determine whether baseline PSA levels predict long-term risk of PCa incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS We examined 4383 men aged 20-94 yr from the Danish general population in the prospective Copenhagen City Heart Study. PSA was measured in plasma samples obtained in 1981-1983. MEASUREMENTS PCa incidence and mortality as a function of baseline PSA was assessed using Kaplan-Meier plots of cumulative incidence and competing risk subhazard ratios. RESULTS AND LIMITATIONS During 28 yr of follow-up, 170 men developed PCa, and 94 men died from PCa. Median follow-up was 18 yr (range: 0.5-28 yr). For PCa incidence, the subhazard ratio was 3.0 (95% confidence interval [CI], 1.9-4.6) for a PSA level of 1.01-2.00 ng/ml, 6.8 (95% CI, 4.2-11) for PSA 2.01-3.00 ng/ml, 6.6 (95% CI, 3.4-13) for PSA 3.01-4.00 ng/ml, 16 (95% CI, 10.4-25) for PSA 4.01-10.00 ng/ml, and 57 (95% CI, 32-104) for PSA >10.00 ng/ml versus 0.01-1.00 ng/ml. For PCa mortality, corresponding subhazard ratios were 2.2 (95% CI, 1.3-3.9), 5.1 (95% CI, 2.8-9.0), 4.2 (95% CI, 1.8-10), 7.0 (95% CI, 3.8-14), and 14 (95% CI, 6.0-32). For men with PSA levels of 0.01-1.00 ng/ml, the absolute 10-yr risk of PCa was 0.6% for ages <45 yr, 0.7% for ages 45-49 yr, 1.1% for ages 50-54 yr, 1.2% for ages 55-59 yr, 1.3% for ages 60-64 yr, 1.1% for ages 65-69 yr, 1.3% for ages 70-74 yr, and 1.5% for ages ≥75 yr; corresponding values for PSA levels >10.00 ng/ml were 35%, 41%, 63%, 71%, 77%, 69%, 75%, and 88%, respectively. CONCLUSIONS Stepwise increases in PSA at first date of testing predicted a 3-57-fold increased risk of PCa, a 2-16-fold increased risk of PCa mortality, and a 35-88% absolute 10-yr risk of PCa in men with PSA levels >10.00 ng/ml. Equally important, the absolute 10-yr risk of PCa in men with PSA levels 0.01-1.00 ng/ml was only 0.6-1.5%.

Tobacco smoking is causally associated with antipsychotic medication use and schizophrenia, but not with antidepressant medication use or depression

BACKGROUND Tobacco smoking is more common among patients with schizophrenia and depression than among healthy individuals. We tested the hypothesis that high tobacco smoking intensity is causally associated with antipsychotic medication use, schizophrenia, antidepressant medication use and/or depression in the general population, and compared results with those for chronic obstructive pulmonary disease. METHODS We used self-reported smoking intensity in cigarettes/day and a polymorphism in the CHRNA3 gene cluster (rs1051730) associated with smoking intensity, on 63,296 20-100-year-old individuals from the Danish general population; 23,282 were never-smokers and 40,014 ever-smokers. For schizophrenia, we compared our results with those in the Psychiatric Genomics Consortium. RESULTS In smokers, heterozygotes (CT) and homozygotes (TT) for rs1051730 genotype had higher smoking intensity compared with non-carriers (CC). Furthermore, in ever-smokers homozygotes had increased risk of antipsychotic medication with an odds ratio (OR) of 1.16 [95% confidence interval (CI) 1.02-1.31] compared with non-carriers, whereas in never-smokers the corresponding OR was 1.07 (0.87-1.31) (P-interaction: 0.60). Correspondingly, ORs were 1.60 (0.74-3.47) and 1.02 (0.11-9.10) for schizophrenia (P-interaction: 0.85), 1.02 (0.93-1.13) and 0.99 (0.85-1.15) for antidepressant medication (P-interaction: 0.87), 0.85 (0.66-1.10) and 1.26 (0.87-1.83) for depression (P-interaction: 0.30) and 1.31 (1.16-1.47) and 0.89 (0.58-1.36) for chronic obstructive pulmonary disease (P-interaction: 0.16). Odds ratios per rs1051730 allele for schizophrenia and antipsychotic medication use in ever-smokers in the general population were 1.22 (95% CI: 0.84-1.79) and 1.06 (1.00-1.12). In the Psychiatric Genomics Consortium, the corresponding OR for schizophrenia was 1.06 (1.04-1.08) in ever- and never-smokers combined. CONCLUSION Our data suggest that tobacco smoking could influence the development of psychotic conditions causally, whereas an influence on depression seems unlikely.

Elevated C-reactive protein and late-onset bipolar disorder in 78 809 individuals from the general population

BACKGROUND No prospective studies have examined the role of C-reactive protein (CRP) in late-onset bipolar disorder. AIMS We tested the hypothesis that elevated levels of CRP are associated cross-sectionally and prospectively with late-onset bipolar disorder, and that such an association possibly is causal. METHOD We performed cross-sectional and prospective analyses with a median follow-up time of 5.9 years (interquartile range: 4.4-7.6) in 78 809 individuals from the general population, and used genetic variants influencing CRP levels to perform a Mendelian randomisation study. RESULTS Elevated levels of CRP were associated both cross-sectionally and prospectively with late-onset bipolar disorder. When CRP was on a continuous scale, a doubling in CRP yielded an observational odds ratio for late-onset bipolar disorder of 1.28 (1.08-1.52) with a corresponding causal odds ratio of 4.66 (0.89-24.3). CONCLUSION Elevated CRP is associated with increased risk of late-onset bipolar disorder in the general population which was supported by the genetic analysis.

Plasma testosterone in the general population, cancer prognosis and cancer risk: a prospective cohort study

BACKGROUND Testosterone is an important anabolic hormone in humans and in vitro testosterone stimulates growth of lung and colon cancer cells. We tested the hypothesis that plasma testosterone associate with increased risk of cancer and with increased risk of early death after cancer. MATERIALS AND METHODS Plasma testosterone was measured in 8771 20- to 94-year-old men and women who participated in a prospective study of the general population. Participants were included in 1981-1983 and followed for a median of 22 years (range: 0-30 years). RESULTS During follow-up, 1140 men and 809 women developed cancer. For risk of early death after cancer, for men, after adjustment for age at diagnosis, tumour stage at diagnosis, and time since blood-sampling, the hazard ratio was 1.30 [95% confidence interval (CI) 1.03-1.65] for the 2nd quintile, 1.31 (1.02-1.67) for the 3rd quintile, 1.52 (1.19-1.93) for the 4th quintile, and 1.52 (1.20-1.91) for the 5th quintile, versus the 1st quintile. For women, corresponding hazard ratios were 1.09 (0.81-1.46), 1.17 (0.86-1.59), 1.03 (0.76-1.39), and 1.80 (1.32-2.46). For risk of cancer, multifactorially adjusted hazard ratios for risk of any cancer were 1.07 (95% CI 0.98-1.18) and 1.06 (0.93-1.22) for men and women, respectively, when testosterone doubled. For both men and women, a doubling of testosterone was not associated with risk of any cancer type. CONCLUSIONS In this prospective study of 8771 men and women from the general population followed for >30 years, increased levels of testosterone were associated with a 30%-80% increased risk of early death after cancer, but unchanged risk of incident cancer.BACKGROUND Testosterone is an important anabolic hormone in humans and in vitro testosterone stimulates growth of lung and colon cancer cells. We tested the hypothesis that plasma testosterone associate with increased risk of cancer and with increased risk of early death after cancer. MATERIALS AND METHODS Plasma testosterone was measured in 8771 20- to 94-year-old men and women who participated in a prospective study of the general population. Participants were included in 1981-1983 and followed for a median of 22 years (range: 0-30 years). RESULTS During follow-up, 1140 men and 809 women developed cancer. For risk of early death after cancer, for men, after adjustment for age at diagnosis, tumour stage at diagnosis, and time since blood-sampling, the hazard ratio was 1.30 [95% confidence interval (CI) 1.03-1.65] for the 2nd quintile, 1.31 (1.02-1.67) for the 3rd quintile, 1.52 (1.19-1.93) for the 4th quintile, and 1.52 (1.20-1.91) for the 5th quintile, versus the 1st quintile. For women, corresponding hazard ratios were 1.09 (0.81-1.46), 1.17 (0.86-1.59), 1.03 (0.76-1.39), and 1.80 (1.32-2.46). For risk of cancer, multifactorially adjusted hazard ratios for risk of any cancer were 1.07 (95% CI 0.98-1.18) and 1.06 (0.93-1.22) for men and women, respectively, when testosterone doubled. For both men and women, a doubling of testosterone was not associated with risk of any cancer type. CONCLUSIONS In this prospective study of 8771 men and women from the general population followed for >30 years, increased levels of testosterone were associated with a 30%-80% increased risk of early death after cancer, but unchanged risk of incident cancer.

Long-term Prostate-specific Antigen Velocity in Improved Classification of Prostate Cancer Risk and Mortality

BACKGROUND It remains unclear whether adding long-term prostate-specific antigen velocity (PSAV) to baseline PSA values improves classification of prostate cancer (PCa) risk and mortality in the general population. OBJECTIVE To determine whether long-term PSAV improves classification of PCa risk and mortality in the general population. DESIGN, SETTING, AND PARTICIPANTS We studied 503 men aged 30-80 yr, with and without PCa, who had repeated PSA measurements over 20 yr and up to 28 yr before PCa diagnosis. These were selected from among 7455 men in the Copenhagen City Heart Study, a prospective, general population study with follow-up from 1981 through 2010. Results were subsequently applied to all 1 351 441 men aged 40-80 yr living in Denmark from 1997 through 2006. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS PCa risk and mortality were assessed using Cox regression. Improvement in risk classification was assessed using the net reclassification index (NRI). RESULTS Age-adjusted hazard ratios for PCa risk and mortality were 2.7-5.3 and 2.3-3.4, respectively, for long-term PSAV when added to models already including baseline PSA values. For PCa risk and mortality, adding long-term PSAV to models already including baseline PSA values and age yielded continuous NRIs of 98-99% and 56-106%, respectively. Used on a nationwide scale (eg, for men aged 60-64 yr), long-term PSAV >0.35 versus ≤ 0.35 ng/ml per year appropriately reclassified 128 of 10 000 men with PCa and 8095 of 10 000 men with no PCa. Correspondingly, inappropriately reclassified were 49 of 10 000 men with PCa and 1658 of 10 000 men with no PCa. CONCLUSIONS Long-term PSAV in addition to baseline PSA value improves classification of PCa risk and mortality. Applying long-term PSAV nationwide, the ratio of appropriately to inappropriately classified men would typically be 5:1.

Alcohol consumption and risk of atrial fibrillation: Observational and genetic estimates of association

Background The aim of this study was to test the hypothesis that alcohol consumption, both observational (self-reported) and estimated by genetic instruments, is associated with a risk of atrial fibrillation and to determine whether people with high cardiovascular risk are more sensitive towards alcohol than people with low risk. Methods We used data for a total of 88,782 men and women from the Copenhagen City Heart Study 1991–1994 and 2001–2003 and the Copenhagen General Population Study 2003–2010. Information on incident cases of atrial fibrillation was obtained from a validated nationwide register. As a measure of alcohol exposure, both self-reported consumption and genetic variations in alcohol metabolizing genes (ADH1B/ADH1C) were used as instrumental variables. The endpoint was admission to hospital for atrial fibrillation as recorded in a validated hospital register. Results A total of 3493 cases of atrial fibrillation occurred during follow-up. High alcohol consumption was associated with a risk of atrial fibrillation among men, but not among women. Among the men who drank 28–35 and 35+ drinks/week, the hazards ratios were 1.40 (95% confidence interval 1.09–1.80) and 1.62 (95% confidence interval 1.27–2.05) compared with men who drank < 1 drink/week. Using genotypes as instrumental variables did not reveal a higher risk. Associations in those with high cardiovascular risk were similar to those at lower risk. Conclusions Observational alcohol consumption was associated with a higher risk of atrial fibrillation in men. In women, only a high alcohol intake (28+ drinks/week) was associated with a higher risk. Participants with a high cardiovascular risk were no more sensitive towards alcohol than those at low risk. Genetic analysis did not support a causal relationship of linear association between alcohol intake and atrial fibrillation.