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.

Lifestyle, family history, and risk of idiopathic Parkinson disease: a large Danish case-control study.

The relationship between Parkinson disease (PD) and smoking has been examined in several studies, but little is known about smoking in conjunction with other behaviors and a family history of PD. Using unconditional logistic regression analysis, we studied individual and joint associations of these factors with idiopathic PD among 1,808 Danish patients who were diagnosed in 1996-2009 and matched to 1,876 randomly selected population controls. Although there was a downward trend in duration of smoking, this was not observed for daily tobacco consumption. A moderate intake of caffeine (3.1-5 cups/day) was associated with a lower odds ratio for PD (0.45, 95% confidence interval: 0.34, 0.62), as was a moderate intake of alcohol (3.1-7 units/week) (odds ratio = 0.60, 95% confidence interval: 0.58, 0.84); a higher daily intake did not reduce the odds further. When these behaviors were studied in combination with smoking, the odds ratios were lower than those for each one alone. Compared with never smokers with no family history of PD, never smokers who did have a family history had an odds ratio of 2.81 (95% confidence interval: 1.91, 4.13); for smokers with a family history, the odds ratio was 1.60 (95% confidence interval: 1.15, 2.23). In conclusion, duration of smoking seems to be more important than intensity in the relationship between smoking and idiopathic PD. The finding of lower risk estimates for smoking in combination with caffeine or alcohol requires further confirmation.

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease.

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aß42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aß42 suggesting that TREM2's role in AD may involve tau dysfunction.

Nested case-control study of night shift work and breast cancer risk among women in the Danish military.

OBJECTIVES: Growing but limited evidence suggests that night shift work is associated with breast cancer. The authors conducted a nationwide case-control study nested within a cohort of 18,551 female military employees born in 1929-1968 to investigate the risk for breast cancer after night shift work and to explore the role of leisure time sun exposure and diurnal preference. METHODS: The authors documented 218 cases of breast cancer (1990-2003) and selected 899 age-matched controls from the cohort by incidence density sampling. Information on shift work, sun exposure habits, diurnal preference and other potential confounders was obtained from a structured questionnaire. ORs were estimated by multivariate conditional logistic regression. RESULTS: Overall, the authors observed an adjusted OR of 1.4 (95% CI 0.9 to 2.1) among women with ever compared with never night shifts. The RR for breast cancer tended to increase with increasing number of years of night shift work (p=0.03) and with cumulative number of shifts (p=0.02),with a neutral risk for fewer than three night shifts per week. The OR for the group with the highest tertile of cumulative exposure was 2.3 (95% CI 1.2 to 4.6). The most pronounced effect of night shift work on breast cancer risk was observed in women with morning chronotype preference and intense night shifts (OR=3.9, 95% CI 1.6 to 9.5). Night shift workers tended to sunbathe more frequently than day workers. CONCLUSIONS: The results indicate that frequent night shift work increases the risk for breast cancer and suggest a higher risk with longer duration of intense night shifts. Women with morning preference who worked on night shifts tended to have a higher risk than those with evening preference.

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.

Risk factors for persistent elbow, forearm and hand pain among computer workers.

OBJECTIVES: This study examined the influence of work-related and personal factors on the prognosis of "severe" elbow, forearm, and wrist-hand pain among computer users. METHODS: In a 1-year follow-up study of 6943 computer users, 673 (10%) participants reported "quite a lot" or more trouble due to elbow, forearm, or wrist-hand pain during the 12 months preceding the baseline questionnaire. Pain status (recovery versus persistence) at follow-up was examined in relation to computer work aspects and ergonomic, psychosocial, and personal factors by questionnaire. In addition, data on objectively recorded computer usage were available for 42% of the participants during the follow-up, measured by means of a program (WorkPaceRecorder) installed on their computers. RESULTS: During the follow-up, two-thirds of the baseline cases improved to some degree, but only one-third experienced substantial improvement. The prognosis was not influenced by mouse or keyboard work (time, speed, micropauses, and average activity periods) or ergonomic workplace conditions. Keyboard times, however, were very low. Pain in other regions was a predictor of persistent arm pain. Except for time pressure, female gender, and type-A behavior, the prognosis seemed independent of psychosocial workplace factors and personal factors. A few cases with severe pain were affected at a level which could be compared to clinical pain conditions. CONCLUSIONS: Our results do not support the hypothesis that computer work activity or ergonomic conditions influence the prognosis of severe arm pain. This result is somewhat surprising and should be tested in other studies. Pain in other regions implies a poorer prognosis for arm pain.

Head injury and risk for Parkinson disease: results from a Danish case-control study.

OBJECTIVE: To examine the association between head injuries throughout life and the risk for Parkinson disease (PD) in an interview-based case-control study. METHODS: We identified 1,705 patients diagnosed with PD at 10 neurologic centers in Denmark in 1996-2009 and verified their diagnoses in medical records. Patients were matched to 1,785 controls randomly selected from the Danish Central Population Register on sex and year of birth. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. RESULTS: We observed no association between any head injury before first cardinal symptom and PD (OR 1.02; 95% CI 0.88, 1.19). Examination of number of head injuries (1: OR 1.02; 95% CI 0.87, 1.20; ≥2: OR 1.03; 95% CI 0.72, 1.47) or hospitalization for a head injury (OR 0.89; 95% CI 0.70, 1.12) did not show an association with PD. For 954 study subjects with at least one head injury, there was no evidence of an association between loss of consciousness (OR 0.89; 95% CI 0.67, 1.17), duration of loss of consciousness (≤1 minute: OR 0.93; 95% CI 0.58, 1.49; 1-5 minutes: OR 0.74; 95% CI 0.51, 1.08; ≥5 minutes: OR 0.81; 95% CI 0.53, 1.24), or amnesia (OR 1.31; 95% CI 0.88, 1.95) and risk for PD. Application of a lag time of 10 years between head injury and first cardinal symptom resulted in similar risk estimates. CONCLUSIONS: The results do not support the hypothesis that head injury increases the risk for PD.

Occupational history of night shift work and Parkinson's disease in Denmark.

OBJECTIVES: We investigated whether working night shifts was associated with the risk of Parkinson's disease (PD). METHODS: Between January 2008 and December 2010, we recruited 1808 patients with a confirmed diagnosis of idiopathic PD from Denmark and 1876 population controls matched by year of birth and gender. Information on lifelong occupational history, including information on night work, smoking, caffeine and alcohol consumption habits, and family history of PD was collected through structured telephone interviews. RESULTS: Overall, there was no association between a history of night shift work and PD [odds ratio (OR) for any type of night work (ie, either permanent or rotating night work) 1.01, 95% confidence interval (95% CI) 0.86-1.21]. Compared with persons who never worked night shifts, risks of those with longer durations of night work did not appear to differ (OR <10 years=0.95, 95% CI 0.75-1.19, OR 10-19 years= 1.09, 95% CI 0.77-1.53, OR ≥20 years=1.05, 95% CI 0.81-1.37, P for trend=0.23). Associations were similar among men and women. CONCLUSIONS: These data suggest that working night shifts is not associated with PD or that low tolerance for night shift work is an early marker of PD. Due to the novel and exploratory nature of these findings, confirmation is needed.

Parkinson disease and smoking revisited: ease of quitting is an early sign of the disease.

OBJECTIVE: To assess whether being able to quit smoking is an early marker of Parkinson disease (PD) onset rather than tobacco being "neuroprotective," we analyzed information about ease of quitting and nicotine substitute use. METHODS: For this case-control study, we identified 1,808 patients with PD diagnosed between 1996 and 2009 from Danish registries, matched 1,876 population controls on sex and year of birth, and collected lifestyle information. We estimated odds ratios and 95% confidence intervals with logistic regression adjusting for matching factors and confounders. RESULTS: Fewer patients with PD than controls ever established a smoking habit. Among former smokers, those with greater difficulty quitting or using nicotine substitutes were less likely to develop PD, with the risk being lowest among those reporting "extremely difficult to quit" compared with "easy to quit." Nicotine substitute usage was strongly associated with quitting difficulty and duration of smoking, i.e., most strongly among current smokers, followed by former smokers who had used nicotine substitutes, and less strongly among former smokers who never used substitutes. CONCLUSIONS: Our data support the notion that patients with PD are able to quit smoking more easily than controls. These findings are compatible with a decreased responsiveness to nicotine during the prodromal phase of PD. We propose that ease of smoking cessation is an aspect of premanifest PD similar to olfactory dysfunction, REM sleep disorders, or constipation and suggests that the apparent "neuroprotective" effect of smoking observed in epidemiologic studies is due to reverse causation.