Abstract
Background
A pro-inflammatory gut microbiota was described in both Parkinson’s disease and colorectal cancer (CRC) and recently α-synuclein was demonstrated in the enteric nervous system. We sought to evaluate the association between Parkinson’s disease and CRC.
Methods
We conducted a nested case-control study using a large primary-care database. Cases were defined as all individuals with CRC. Up to 4 controls were matched with each case based on age, sex, practice-site and duration of follow-up. The primary exposure of interest was diagnosis of Parkinson’s disease prior to CRC as well as disease duration, and Parkinson’s specific therapies. The primary analysis was a conditional logistic-regression to estimate odds ratios (ORs) and 95% confidence interval (95%CI).
Results
The study included 22,093 CRC cases and 85,833 matched controls. Past medical history of Parkinson’s disease >1 year before index-date was associated with lower CRC risk (OR 0.74, 95%CI 0.59–0.94). The inverse association was more prominent among females compared to males (0.64, 95%CI 0.42–0.96 and 0.8, 95%CI 0.60–1.07, respectively). While patients who received no therapy or therapy with dopamine agonists had a non-significant decrease in cancer risk, patients who were treated with dopamine had a non-significant elevated cancer risk.
Conclusion
Parkinson’s disease is inversely associated with CRC risk.
Keywords: Parkinson’s disease, colorectal cancer, dopamine, age, risk, microbiota
Introduction
Parkinson’s disease is the second most common neurodegenerative disorder with a prevalence of 0.3% in the entire population and 1% in individuals above the age of 60 (1). The disease is slowly progressive with characteristic death of dopamine producing cells in the substantia nigra. Typical manifestations secondary to dopamine deficiency include both motor symptoms such as tremor, bradykinesia and muscle rigidity and neuropsychiatric symptoms such as depression and dementia (2). Most cases are sporadic and to date the exact etiology behind the dopaminergic cells death is unknown.
Parkinson’s disease and cancer share several common risk factors such as aging, DNA damage in response to oxidative stress, metabolic dysregulation, and environmental exposure to chemicals (i.e. pesticides) (3). In addition, a positive association between Parkinson’s disease and melanoma was described, possibly due to the role of L-Dopa in melanin synthesis (4). However, similar to other neuropsychiatric disorders, such as Alzheimer’s disease and schizophrenia, and some non-neurological diseases (5) epidemiological studies described an intriguing inverse comorbidity between Parkinson’s disease and cancer, mainly colorectal, lung, prostate and bladder cancers (4, 6–15) although some studies showed inconclusive results (16–18). Potential mechanisms explaining this association include: common genetic predispositions that are activated in opposite directions in neuronal compared to proliferating tissue (such as PIN1 and LRRK2) (19, 20); aberrations in the ubiquitin-proteasome system (21,22); low levels of melatonin that can improve Parkinson’s symptoms and appears to increase cancer risk (23); smoking status, a known cancer risk factor that was shown to reduce risk for Parkinson’s disease (24,25); diabetes (24) and high levels of cholesterol and fatty acids (26) that were described in association with lower risk for Parkinson’s disease; cancer promoting effect of anti-Parkinsonian medications, such as dopamine agonists (27); survival bias due to early mortality in patients with Parkinson’s disease; and detection bias secondary to different cancer screening practices among patients with neurodegenerative disorders due to disease severity or socioeconomic status.
Recently, several studies demonstrated α-synuclein accumulation, a known pathologic change in the Parkinsonian brain, in biopsies from the enteric nervous system of patients and suggested that the disease might actually result from a yet unknown pathogen or toxin that is able to penetrate the gastrointestinal mucosa and spread in a retrograde direction to the brain through the vagus nerve (28–33). Another study demonstrated a pro-inflammatory gut microbiota in Parkinson’s disease that might induce α-synuclein accumulation (34). A single epidemiological study in a Danish cohort demonstrated lower hazard for Parkinson’s disease in individuals after truncal vagotomy and more than 20 years of follow-up (35). Other studies demonstrated the significance of gut pathogens and changes in the composition and diversity of gut microbiota in the pathogenesis of colorectal cancer (CRC) (36–38). Thus, raising the possibility that gut microbiota might explain the reciprocal association between Parkinson’s disease and cancer, mainly colorectal cancer.
To date, epidemiological studies focused mainly on the association of specific groups of cancers, such as smoking related and non-smoking related, with Parkinson’s disease; evaluated patients with specific malignancies and relatively short surveillance time; lacked proper adjustment for specific cancer risk factors and previous cancer screening; and did not evaluate the effect of Parkinson’s therapy on cancer outcome.
The aim of the current study, is to evaluate the complex associations between the two conditions in a large population based dataset. In depth understanding of the protective effects of Parkinson’s disease on CRC in a well conducted epidemiological study might serve for future investigations of specific disease related pathways and possibly new therapies.
Methods
Study Design
We conducted a nested case control study with incidence density sampling using The Health Improvement Network (THIN), a population representative primary-care database from the United Kingdom (UK). This design was described in previous publications by our group (39). The study was approved by the Institutional Review Board at the University of Pennsylvania and by the Scientific Review Committee of THIN.
Data source
THIN contains data on approximately ten million patients treated by general practitioners (http://www.thin-uk.com/) including information on patient demographics, socioeconomic status, medical diagnoses, lab results, and drug prescriptions. Registration date is defined as the date when patients were first registered with a practice in THIN and Vision date is the date that a practice began using in-practice Vision software that collects information for the THIN database (40). Data quality is monitored through routine analysis of the entered data (41,42). THIN has been previously used for pharmaco-epidemiology studies, showing excellent quality of information (43).
Study cohort
All people receiving medical care from 1995–2013 from a THIN practitioner were eligible for inclusion. Exclusion criteria included: Patients without acceptable medical records (i.e., incomplete documentation or out of sequence date of birth, registration date, date of death, or date of exit from the database); subjects who were diagnosed with CRC before the age of 40, had inflammatory bowel disease or a family history of CRC (in order to focus on average risk population); Subjects who were diagnosed with CRC within the first 183 days after registration date in order to avoid prevalent cases (44)
Follow-up started at the later of either the Vision date or 183 days after the date on which the patient registered with the general practitioner (44), and ended on the earliest of cancer diagnosis date, date of death, transferring out of the database, or the end date of the database.
Case selection
Cases were defined as all individuals in the cohort with at least one medical Read code (the standard coding system used by general practices in the UK) for CRC during follow-up (45–47). The date of cancer diagnosis was regarded as the index-date for each case.
Selection of controls
Controls were selected using incidence-density sampling (48). The eligible control pool consisted of all individuals who remained at risk for CRC at the time when the case was diagnosed. Up to 4 controls were matched with each case based on age, sex, practice site and both duration and calendar period of follow-up. Controls were assigned the same index-date as their matched cases.
Exposures and Covariates
The primary exposure of interest was Parkinson’s disease defined as any medical codes for the disease before cancer diagnosis. We also used two additional definitions: incident Parkinson’s cases defined as patients that were diagnosed more than 183 days after registration with a THIN practitioner; and cases that were diagnosed more than 1 year before index date, in order to avoid possible detection bias. As a secondary exposure we evaluated duration of Parkinson’s disease (calculated as the difference between CRC index date and Parkinson’s diagnosis date and grouped as 0–1, >1–5,>5 years); age at Parkinson’s disease diagnosis (categorized as 40–49, 50–75 and >75 years old); and Parkinson’s specific therapies (grouped as no treatment, dopamine, dopamine agonists and combined therapy including MAO-B, COMT and cholinesterase inhibitors). Individuals without Parkinson’s disease served as the reference group for all the above variables. As potential confounders, we evaluated obesity (BMI>30), smoking history (ever/never), and alcohol consumption (non-users, any use and alcoholism/alcohol dependence); medical co-morbidities including diabetes mellitus; medications that may influence cancer risk such as chronic aspirin/NSAIDs use (more than 1 year in duration and last prescription within 6 months prior to cancer diagnosis) and hormone replacement therapy; and previous screening colonoscopy. All covariates were measured prior to index-date.
Statistical Analysis
Conditional logistic regression was used to estimate OR and 95% confidence intervals (CIs) for the association between Parkinson’s disease, as well as disease duration, therapy and age at disease onset and CRC risk. In a secondary analysis we performed stratification according to sex due to previous reports showing lower cumulative incidence of parkinson’s disease among females (49). Analyses were adjusted for all measured CRC risk factors. Finally, we assessed for interactions between variables (i.e older patients might be more likely to have longer disease duration and to receive treatment with dopamine) All analyses were performed using STATA 13 (Stata Corp., College Station, Tx, USA).
Results
The study population included 22,093 CRC cases and 85,833 matched controls with a median age of 72 (IQR 63–79) and a median duration of follow-up of 6 years (IQR 3–9). Characteristics of cases and controls are presented in table 1. Obesity, ever smoking, alcohol consumption, comorbidity with diabetes and recurrent antibiotic exposure were associated with higher CRC risk while previous screening colonoscopy was associated with lower risk.
Table 1.
Characteristics of cases and controls
| Parameter | Cases (n=22,093) | Controls (n=85,833) | P-value |
|---|---|---|---|
|
| |||
| Age at CRC diagnosis (median, IQR) | 72.3 (63.8–79.6) | 71.9 (63.3–79.3) | NA |
|
| |||
| Male sex (%) | 12,142 (55.1%) | 47,113 (55.1%) | NA |
|
| |||
| Duration of follow-up before CRC diagnosis (median IQR) | 6 (3–9) | 6 (3–9) | NA |
|
| |||
| Diabetes mellitus (%) | 2,844 (12.9%) | 8,551 (10.0%) | <0.0001 |
|
| |||
| Obesity (BMI >30) (%) | 4,580 (20.7%) | 15,807 (18.4%) | <0.0001 |
|
| |||
| Smoking (ever) (%) | 10,338 (46.8%) | 35,551 (41.4%) | <0.0001 |
|
| |||
| Alcohol use (%) | 11,319 (51.2%) | 41,374 (48.2%) | <0.0001 |
| Alcoholism (%) | 161 (0.7%) | 414 (0.5%) | <0.0001 |
|
| |||
| Chronic Aspirin/NSAIDs use (%) | 7,398 (33.5%) | 28,350 (33.0%) | 0.26 |
|
| |||
| Hormone replacement therapy (%) | 1,391 (6.3%) | 5,759 6.7%) | 0.04 |
|
| |||
| Previous screening colonoscopy (%) | 325 (1.5%) | 1,430 (1.7%) | 0.03 |
|
| |||
| Number of penicillin course: | |||
| No penicillin treatment | 10,054 (45.5%) | 41,739 (48.6%) | Ref. |
| 1 course | 9,052 (41.0%) | 33,636 (39.2%) | <0.0001 |
| 2–5 courses | 2,070 (9.4%) | 7,372 (8.6%) | <0.0001 |
| >5 courses | 917 (4.2%) | 3,086 (3.6%) | <0.0001 |
There were 117 patients with Parkinson’s disease among CRC cases (0.5%) compared to 541 among controls (0.5%). Past medical history of Parkinson’s disease was associated with lower CRC risk with a fully adjusted OR of 0.84 (95%CI 0.69–1.03) (Table 2). When only incident cases of Parkinson’s disease were included the OR was 0.77 (0.62–0.95). When the definition of Parkinson’s disease was limited to those who were diagnosed more than 1 year before index date, in order to avoid possible detection bias, the OR was 0.74 (95%CI 0.59–0.94) and after stratification according to gender the OR was 0.8 for males (95%CI 0.60–1.07) and 0.64 for females (95%CI 0.42–0.96). There was no change in CRC risk with Parkinson’s disease duration of 1–5 years and more than 5 years.
Table 2.
Association between Parkinson’s disease and CRC risk
| Parameter | Cases N (%) |
Controls N (%) |
Unadjusted OR (95% CI) |
Adjusted OR* (95% CI) |
Adjusted OR** (95% CI) |
|---|---|---|---|---|---|
| Parkinson’s disease | 117 (0.5%) | 541 (0.6%) | 0.81 (0.67–0.99) | 0.85 (0.69–1.04) | 0.84 (0.69–1.03) |
| Duration of Parkinson’s disease before CRC diagnosis | |||||
| No disease | 21,976 (99.5%) | 85,292 (99.4%) | Ref. | Ref. | Ref. |
| 0–1 years | 32 (0.1%) | 84 (0.1%) | 1.39 (0.92–2.10) | 1.36 (0.90–2.05) | 1.37 (0.91–2.08) |
| >1–5 years | 50 (0.2%) | 277 (0.3%) | 0.69 (0.51–0.93) | 0.73 (0.54–0.99) | 0.73 (0.54–0.98) |
| >5 years | 35 (0.2%) | 179 (0.2%) | 0.73 (0.51–1.06) | 0.77 (0.54–1.11) | 0.77 (0.53–1.10) |
| Age at diagnosis of Parkinson’s disease | |||||
| No disease | 21,976 (99.5%) | 85,292 (99.4%) | Ref. | Ref. | Ref. |
| 40–49 years | 3 (0.01%) | 4 (<0.01%) | 3.0 (0.67–13.40) | 3.26 (0.73–14.60) | 3.33 (0.74–14.95) |
| 50–75 years | 52 (0.2%) | 287 (0.3%) | 0.69 (0.52–0.93) | 0.73 (0.54–0.98) | 0.73 (0.54–0.98) |
| >75 years | 62 (0.3%) | 250 (0.3%) | 0.92 (0.69–1.22) | 0.94 (0.71–1.25) | 0.94 (0.71–1.25) |
| Therapy for Parkinson’s disease | |||||
| No disease | 21,976 (99.5%) | 85,292 (99.4%) | Ref. | Ref. | Ref. |
| No medical therapy | 63 (0.3%) | 299 (0.4%) | 0.81 (0.62–1.06) | 0.82 (0.62–1.08) | 0.82 (0.62–1.08) |
| Dopamine | 4 (0.02%) | 6 (0.01%) | 2.64 (0.74–9.36) | 2.95 (0.83–10.50) | 2.81 (0.79–10.00) |
| Dopamine agonists | 13 (0.06%) | 71 (0.08%) | 0.67 (0.37–1.21) | 0.73 (0.40–1.33) | 0.74 (0.40–1.34) |
| Other/combined therapy | 37 (0.2%) | 165 (0.2%) | 0.82 (0.58–1.18) | 0.87 (0.61–1.25) | 0.87 (0.61–1.25) |
Adjusted to obesity (BMI>30), smoking (ever), alcohol consumption, diabetes mellitus, chronic aspirin/NSAIDs use, hormone replacement therapy and previous screening colonoscopy.
In addition to the adjustment above, number of previous antibiotic courses with penicillin more than one year before cancer diagnosis (0,1,2–5,>5).
The inverse association between Parkinson’s disease and CRC was mainly seen in individuals at the main age group (50–75 years). Among the small group of individuals with a diagnosis of Parkinson’s disease at the age of 40–49 years there was a non-significant increase in CRC risk (the risk reached significance among males). In individuals who were diagnosed above the age of 75 there was no change in CRC risk (Table 2).
There was no association between anti-parkinsonian drugs and CRC risk. However while patients who received no medical therapy or therapy with dopamine agonists had a non-significant decrease in cancer risk, patients who were treated with dopamine showed a non-significant increase in risk (Table 2). When medication effect was evaluated only among cases and controls with Parkinson’s disease there was no change in results.
When the analyses for disease duration, age at onset and anti-Parkinsonian treatment was stratified according to sex there was no change in the above results (Table 3 and Table 4), however the inverse association between any medical code for Parkinson’s disease and CRC was more prominent among females compared to males, although not statistically significant.
Table 3.
Association between Parkinson’s disease and CRC risk among males (12,142 CRC cases and 47,113 matched controls)
| Parameter | Cases N (%) |
Controls N (%) |
Unadjusted OR (95% CI) |
Adjusted OR* (95% CI) |
Adjusted OR** (95% CI) |
|---|---|---|---|---|---|
| Parkinson’s disease | 79 (0.7%) | 343 (0.7%) | 0.86 (0.67–1.11) | 0.90 (0.70–1.16) | 0.90 (0.70–1.15) |
| Duration of Parkinson’s disease before CRC diagnosis | |||||
| No disease | 12,063 (99.4%) | 46,770 (99.3%) | Ref. | Ref. | Ref. |
| 0–1 years | 21 (0.2%) | 54 (0.1%) | 1.38 (0.83–2.31) | 1.34 (0.80–2.24) | 1.35 (0.81–2.26) |
| >1–5 years | 32 (0.3%) | 182 (0.4%) | 0.68 (0.47–0.99) | 0.73 (0.50–1.06) | 0.72 (0.49–1.05) |
| >5 years | 26 (0.2%) | 107 (0.2%) | 0.90 (0.59–1.39) | 0.95 (0.62–1.47) | 0.94 (0.61–1.45) |
| Age at diagnosis of Parkinson’s disease | |||||
| No disease | 12,063 (99.4%) | 46,770 (99.3%) | Ref. | Ref. | Ref. |
| 40–49 years | 3 (0.02%) | 2 (<0.01%) | 6.0 (1.00–35.91) | 6.77 (1.12–40.69) | 6.99 (1.15–42.15) |
| 50–75 years | 36 (0.3%) | 189 (0.4%) | 0.73 (0.51–1.05) | 0.77 (0.54–1.10) | 0.76 (0.53–1.09) |
| >75 years | 40 (0.3%) | 152 (0.3%) | 0.96 (0.67–1.37) | 0.99 (0.70–1.42) | 0.99 (0.69–1.42) |
| Therapy for Parkinson’s disease | |||||
| No disease | 12,063 (99.4%) | 46,770 (99.3%) | Ref. | Ref. | Ref. |
| No medical therapy | 37 (0.3%) | 188 (0.4%) | 0.76 (0.53–1.09) | 0.77 (0.54–1.11) | 0.77 (0.54–1.10) |
| Dopamine | 3 (0.02%) | 3 (0.01%) | 3.92 (0.79–19.42) | 4.31 (0.87–21.42) | 4.04 (0.81–20.12) |
| Dopamine agonists | 10 (0.08%) | 41 (0.09%) | 0.86 (0.43–1.73) | 0.94 (0.47–1.90) | 0.95 (0.47–1.92) |
| Other/combined therapy | 29 (0.2%) | 111 (0.2%) | 0.95 (0.63–1.44) | 1.03 (0.68–1.55) | 1.02 (0.68–1.55) |
Adjusted to obesity (BMI>30), smoking (ever), alcohol consumption, diabetes mellitus, chronic aspirin/NSAIDs use, hormone replacement therapy and previous screening colonoscopy.
In addition to the adjustment above, number of previous antibiotic courses with penicillin more than one year before cancer diagnosis (0,1,2–5,>5).
Table 4.
Association between Parkinson’s disease and CRC risk among females (9,951 CRC cases and 38,720 matched controls)
| Parameter | Cases N (%) | Controls N (%) | Unadjusted OR (95% CI) | Adjusted OR* (95% CI) | Adjusted OR** (95% CI) |
|---|---|---|---|---|---|
| Parkinson’s disease | 38 (0.4%) | 198 (0.5%) | 0.73 (0.51–1.03) | 0.75 (0.53–1.07) | 0.75 (0.53–1.06) |
| Duration of Parkinson’s disease before CRC diagnosis | |||||
| No disease | 9,913 (99.6%) | 38,522 (99.5%) | Ref. | Ref. | Ref. |
| 0–1 years | 11 (0.1%) | 30 (0.1%) | 1.41 (0.70–2.82) | 1.39 (0.69–2.80) | 1.41 (0.70–2.83) |
| >1–5 years | 18 (0.2%) | 95 (0.3%) | 0.71 (0.43–1.18) | 0.74 (0.44–1.23) | 0.73 (0.44–1.22) |
| >5 years | 9 (0.1%) | 72 (0.2%) | 0.48 (0.24–0.96) | 0.50 (0.25–1.01) | 0.50 (0.25–1.01) |
| Age at diagnosis of Parkinson’s disease | |||||
| No disease | 9,913 (99.6%) | 38,522 (99.5%) | Ref. | Ref. | Ref. |
| 40–49 years | 0 (0%) | 2 (0.01%) | NA | NA | NA |
| 50–75 years | 16 (0.2%) | 98 (0.3%) | 0.62 (0.37–1.06) | 0.66 (0.39–1.12) | 0.66 (0.39–1.13) |
| >75 years | 22 (0.2%) | 97 (0.3%) | 0.86 (0.54–1.37) | 0.86 (0.54–1.37) | 0.86 (0.54–1.37) |
| Therapy for Parkinson’s disease | |||||
| No disease | 9,913 (99.6%) | 38,522 (99.5%) | Ref. | Ref. | Ref. |
| No medical therapy | 26 (0.3%) | 111 (0.3%) | 0.89 (0.58–1.37) | 0.90 (0.58–1.39) | 0.90 (0.59–1.39) |
| Dopamine | 1 (0.01%) | 3 (0.01%) | 1.33 (0.14–12.82) | 1.50 (0.16–14.44) | 1.46 (0.15–14.11) |
| Dopamine agonists | 3 (0.03%) | 30 (0.08%) | 0.39 (0.12–1.26) | 0.43 (0.13–1.40) | 0.43 (0.13–1.40) |
| Other/combined therapy | 8 (0.1%) | 54 (0.1%) | 0.55 (0.26–1.16) | 0.57 (0.27–1.21) | 0.57 (0.27–1.20) |
Adjusted to obesity (BMI>30), smoking (ever), alcohol consumption, diabetes mellitus, chronic aspirin/NSAIDs use, hormone replacement therapy and previous screening colonoscopy.
In addition to the adjustment above, number of previous antibiotic courses with penicillin more than one year before cancer diagnosis (0,1,2–5,>5).
Of note, there were no interaction between age at diagnosis of Parkinson’s disease, anti-parkinsonian medications used and duration of Parkinson’s disease before CRC diagnosis.
Discussion
The current large population based study provide further support to the inverse association between Parkinson’s disease and CRC (with an adjusted OR of 0.74 and 95%CI 0.59–0.94) and enhance our understanding of the possible biological mechanisms behind this association.
Our first goal was to exclude bias as a possible explanation to the inverse comorbidity. By using a nested case control study design with matching on duration of follow up we were able to prevent possible survival bias if patients with Parkinson’s disease had worse survival, and as a result lower opportunity for CRC diagnosis. We were also able to adjust for previous screening colonoscopies in order to exclude different screening frequencies among Parkinson’s patients, either lower screening due to poor medical status or increased screening due to better medical surveillance, thus avoiding detection bias. Since patients who undergo medical evaluation are at higher risk for incidental comorbidities, excluding Parkinson’s diagnosis in the year prior to cancer diagnosis prevented this additional type of detection bias in the secondary analysis.
We further evaluated possible biological explanations for the observed inverse comorbidity. While factors such as smoking, diabetes and obesity were previously described as having differential effect on Parkinson’s disease and CRC risk (24–26) including these variables in the multivariate model did not change the association between the two diseases. The gut microbiota and bacterial dysbiosis might also serve as a common pathway in the pathogenesis of both Parkinson’s disease and CRC, and recurrent antibiotic exposure was shown to increase CRC risk by 20% (39). However adjusting to recurrent antibiotic exposure that can change the composition of the microbiota, did not influence the inverse association.
The anti-Parkinsonian drug dopamine was recently reported to inhibit vascular endothelial growth factor A (VEGFA) and tumor angiogenesis (50), thus possibly lowering cancer risk. In the current study only a small number of patients were treated solely with dopamine, however patients that were treated with dopamine agonists or other medical combinations that contain dopamine did not have statistically significant lower CRC risk. These results are similar to data from one previous epidemiological study focusing on any cancer incidence following Parkinson’s diagnosis (16). In addition, if the association between Parkinson’s disease and CRC risk was secondary to drug effects we would expect to see a more prominent association with disease duration and duration of therapy, an effect that was not seen in the current study.
Furthermore, our analysis did not show a significant association between age at Parkinson’s disease onset and CRC risk. The above results points toward a genetic explanation that is not affected by age, disease duration or therapy and remain stable during follow-up. Since CRC risk was lower among women (OR 0.64, 95%CI 0.42–0.96) compared to males (OR 0.8, 95%CI 0.60–1.07) for cases that were diagnosed more than 1 year before cancer diagnosis, it is possible that the association is related to estrogenic influence on dopaminergic pathways. It was previously shown that estrogen deprivation might lead to death of dopamine neurons (51).
The current study had several limitations. Sample size was small for some of the subgroup analyses, mainly for anti-parkinsonian medications and for subjects diagnosed before the age of 50, thus the study might be underpowered for these analyses. Since THIN database lacks information regarding cancer stage, location and histopathology we were not able to test possible association of Parkinson’s disease with these variables. Future studies are needed in order to evaluate whether the protective effect differ in early compared to advanced disease and in proximal compared to distal lesions (that are known to differ in their genetic landscape). The database did not include information regarding symptoms of Parkinson’s disease, mainly neurologic symptoms such as constipation or bacterial overgrowth that might be related to CRC risk. However those manifestations are associated with higher cancer risk and would not explain the inverse association. Additionally, although Parkinson’s disease is associated with several genetic mutations, mainly in familial cases (such as the SNCA, PARKIN, PIN and LRRK gene mutations), we did not have genetic information of the subjects and could not differentiate between familial and sporadic Parkinson’s disease.
The use of a large primary care population representative database with detailed Cinformation regarding CRC risk factors, anti-parkinsonian medications and lifestyle habits allowed us to provide the most extensive analysis to date of the inverse comorbidity between CRC and Parkinson’s disease. We were able to focus on average risk CRC patients without family history of cancer or personal history of inflammatory bowel disease. By using such an electronic medical database we were also able to focus on incident cancer cases. The THIN database was previously shown to be valid for CRC studies (45).
In summary, our current study demonstrated lower CRC risk among patients with a previous diagnosis of Parkinson’s disease. The association was independent of age of Parkinson’s diagnosis, disease duration or therapy used and did not change after adjustment to known CRC risk factors and recurrent antibiotic exposure. Of note, the observed effect was more prominent among females compared to males, although not statistically significant. Future studies should focus on the role of genetic pathways, such as those involved in apoptosis and cellular metabolism, that might explain cellular proliferation in CRC on the one hand and dopaminergic cell death in Parkinson’s disease on the other hand.
Acknowledgments
Funding: This study was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000003. Dr. Mamtani was supported by NIH K23 grant CA187185.
Footnotes
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Conflict of interest: None of the authors has any relevant conflict of interest to declare.
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