Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort.

BACKGROUND AND OBJECTIVES: Inverse associations between caffeine intake and Parkinson disease (PD) have been frequently implicated in human studies. However, no studies have quantified biomarkers of caffeine intake years before PD onset and investigated whether and which caffeine metabolites are related to PD. METHODS: Associations between self-reported total coffee consumption and future PD risk were examined in the EPIC4PD study, a prospective population-based cohort including 6 European countries. Cases with PD were identified through medical records and reviewed by expert neurologists. Hazard ratios (HRs) and 95% CIs for coffee consumption and PD incidence were estimated using Cox proportional hazards models. A case-control study nested within the EPIC4PD was conducted, recruiting cases with incident PD and matching each case with a control by age, sex, study center, and fasting status at blood collection. Caffeine metabolites were quantified by high-resolution mass spectrometry in baseline collected plasma samples. Using conditional logistic regression models, odds ratios (ORs) and 95% CIs were estimated for caffeine metabolites and PD risk. RESULTS: In the EPIC4PD cohort (comprising 184,024 individuals), the multivariable-adjusted HR comparing the highest coffee intake with nonconsumers was 0.63 (95% CI 0.46-0.88, p = 0.006). In the nested case-control study, which included 351 cases with incident PD and 351 matched controls, prediagnostic caffeine and its primary metabolites, paraxanthine and theophylline, were inversely associated with PD risk. The ORs were 0.80 (95% CI 0.67-0.95, p = 0.009), 0.82 (95% CI 0.69-0.96, p = 0.015), and 0.78 (95% CI 0.65-0.93, p = 0.005), respectively. Adjusting for smoking and alcohol consumption did not substantially change these results. DISCUSSION: This study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine and its metabolites years before diagnosis.

Maternal anemia and childhood cancer: a population-based case-control study in Denmark.

BACKGROUND: Childhood cancer risk is associated with maternal health during pregnancy. Anemia in pregnancy is a common condition, especially in low-income countries, but a possible association between maternal anemia and childhood cancer has not been widely studied. METHODS: We examined the relation in a population-based study in Denmark (N = 6420 cancer cases, 160,485 controls). Cases were taken from the Danish Cancer Registry, and controls were selected from national records. We obtained maternal anemia diagnoses from the National Patient and Medical Births registries. In a separate analysis within the years available (births 1995-2014), we examined cancer risks among mothers taking prescribed vitamin supplements, using data from the National Prescription Register. We estimated the risks of childhood cancer using conditional logistic regression. RESULTS: The risks of neuroblastoma [odds ratio (OR= 1.83, 95% confidence interval (CI): 1.04, 3.22] and acute lymphoblastic leukemia (OR= 1.46, 95% CI 1.09, 1.97) were increased in children born to mothers with anemia in pregnancy. There was a two-fold increased risk for bone tumors (OR= 2.59, 95% CI: 1.42, 4.72), particularly osteosarcoma (OR= 3.54, 95% CI 1.60, 7.82). With regards to prescribed supplement use, mothers prescribed supplements for B12 and folate deficiency anemia (OR= 4.03, 95% CI 1.91, 8.50) had an increased risk for cancer in offspring. CONCLUSION: Our results suggest that screening for anemia in pregnancy and vitamin supplementation may be an actionable strategy to prevent some cases of childhood cancer.

Parental occupational exposure to solvents and heavy metals and risk of developing testicular germ cell tumors in sons (NORD-TEST Denmark).

Objective The present study aims to assess if parental occupational exposure to solvents or heavy metals is associated with risk of testicular germ cell tumors (TGCT) in sons in Denmark. Methods The NORD-TEST Denmark included 3421 cases diagnosed with TGCT at ages 14-49 years in Denmark between 1981 and 2014. Controls (N=14 024) selected from the central population registry were matched to cases on birth year. The Danish Supplementary Pension Fund provided parental occupational information. A job-exposure matrix was used to assign exposures, and conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results The overall analyses showed no significant associations except for paternal exposure to a sub-group of "heavy metal(s) and solvent(s)" (OR 1.50, 95% CI 1.01-2.24). Most fathers in this category had worked in wood related jobs and were assigned exposure to chromium VI and toluene. Other sub-group analyses suggested that maternal exposure to aromatic hydrocarbon were associated with TGCT risk, in sons born in 1970-1979, and to heavy metals (chromium, iron and nickel) in sons born in 1980-1998. Conclusion NORD-TEST Denmark provides no strong support for an association between parental exposures to solvents or heavy metals and TGCT in sons, and only weak support for an association between paternal exposure to chromium and toluene and TGCT risk in sons.

Gene-Environment Interaction in Parkinson's Disease: Coffee, ADORA2A, and CYP1A2.

BACKGROUND AND PURPOSE: Drinking caffeinated coffee has been reported to provide protection against Parkinson's disease (PD). Caffeine is an adenosine A2A receptor (encoded by the gene ADORA2A) antagonist that increases dopaminergic neurotransmission and Cytochrome P450 1A2 (gene: CYP1A2) metabolizes caffeine; thus, gene polymorphisms in ADORA2A and CYP1A2 may influence the effect coffee consumption has on PD risk. METHODS: In a population-based case-control study (PASIDA) in Denmark (1,556 PD patients and 1,606 birth year- and gender-matched controls), we assessed interactions between lifetime coffee consumption and 3 polymorphisms in ADORA2A and CYP1A2 for all subjects, and incident and prevalent PD cases separately using logistic regression models. We also conducted a meta-analysis combining our results with those from previous studies. RESULTS: We estimated statistically significant interactions for ADORA2A rs5760423 and heavy vs. light coffee consumption in incident (OR interaction = 0.66 [95% CI 0.46-0.94], p = 0.02) but not prevalent PD. We did not observe interactions for CYP1A2 rs762551 and rs2472304 in incident or prevalent PD. In meta-analyses, PD associations with daily coffee consumption were strongest among carriers of variant alleles in both ADORA2A and CYP1A2. CONCLUSION: We corroborated results from a previous report that described interactions between ADORA2A and CYP1A2 polymorphisms and coffee consumption. Our results also suggest that survivor bias may affect results of studies that enroll prevalent PD cases.

Outdoor work and risk for Parkinson's disease: a population-based case-control study.

OBJECTIVES: Sunlight is the main contributor to vitamin D in humans. Since inadequate levels of vitamin D have been linked to increased risks for neurodegenerative diseases, we examined whether outdoor work is associated with a reduced risk for Parkinson's disease in a population-based case-control study of Danish men. METHODS: We identified 3819 men with a primary diagnosis of Parkinson's disease in the period 1995-2006 in the Danish National Hospital Register and selected 19,282 age- and sex-matched population controls at random from the Central Population Register. Information on work history was ascertained from the Danish Supplementary Pension Fund and the Central Population Register. Based on trade grouping codes and job titles, we evaluated the extent of outdoor work of study subjects as a proxy of exposure to sunlight. RESULTS: Relying on trade grouping codes, we estimated ORs for study subjects with moderate, frequent and maximal outdoor work compared with exclusive indoor work of 0.90 (95% CI 0.78 to 1.02), 0.86 (95% CI 0.75 to 0.99) and 0.72 (95% CI 0.63 to 0.82), respectively, for Parkinson's disease. Reduced risks were also found for Parkinson's disease among outdoor workers based on study subjects' job titles. CONCLUSIONS: Our findings suggest that men working outdoors have a lower risk for Parkinson's disease. Further studies of measured vitamin D levels in outdoor workers are warranted to clarify a potential inverse association between vitamin D and the risk for Parkinson's disease.

Diurnal urinary 6-sulfatoxymelatonin levels among healthy Danish nurses during work and leisure time.

The present study aims to examine the influence of evening and night shift work, compared to day shift work, on melatonin secretion in nurses in a field setting. Effects were examined during a workday and during a day off. Both fixed schedules and mixed or rotating schedules were studied. In total, 170 nurses were studied: 89 nurses worked fixed schedules, 27 nurses worked the day shift, 12 nurses worked the evening shift, 50 nurses worked the night shift, and 82 nurses worked mixed schedules, with data collected during a day (n = 17), evening (n = 14), or night shift (n = 50). All spot urine samples were collected during 24 h from the participants on a work day and on a day off and were analyzed for 6-sulphatoxymelatonin. On the day of urine sampling, participants filled in the Karolinska Sleep Diary. Additional information was collected through a telephone interview. Data were analyzed using a mixed procedure with autoregressive covariance structure. The present study showed that shift work affected the concentrations of 6-sulphatoxymelatonin in the short term by lower excretion in urine from nurses working the night compared to day shift on a workday and on a day off as well. No significant differences were observed between a workday and a day off when doing day and evening shifts, irrespective of mixed and fixed schedules. Sleep length was reduced workdays (from 6.1-6.8 h) among all nurses, compared to days off (from 7.8-8.7 h).