Identification of Drugs Associated with Lower Risk of Parkinson’s Disease Using a Systematic Screening Approach in a Nationwide Nested Case–Control Study

Koponen, Marjaana; Paakinaho, Anne; Lin, Julian; Hartikainen, Sirpa; Tolppanen, Anna‐Maija

doi:10.2147/clep.s381289

Cited by 6 publications

(7 citation statements)

References 44 publications

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“…CYP2W1 is expressed in a cancer-specific way and converts pro-dugs as well as fatty acids like arachidonic acid ( Pan and Ong, 2017 ). CYP20A1 is highly expressed in the brain, especially in the Substantia nigra ( Stark et al, 2008 ; Lemaire et al, 2016 ) , and a connection to methotrexate toxicity has been found ( Papapetropoulos et al, 2004 ; Aslibekyan et al, 2014 ) although this finding is controversial ( Koponen et al, 2022 ). Interestingly, for CYPs of the CYP4 family (CYP4A22, CYP4X1 and CYP4Z1) a participation in fatty acid conversion and epoxide formation of eicosatrienoic acids has been described ( Zöllner et al, 2009 ; Carver et al, 2014 ; McDonald et al, 2017 ; Durairaj et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

A CYPome-wide study reveals new potential players in the pathogenesis of Parkinson’s disease

Hartz

Fehlmann²,

Wagenpfeil³

et al. 2023

Front. Pharmacol.

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Genetic and environmental factors lead to the manifestation of Parkinson’s disease (PD) but related mechanisms are only rudimentarily understood. Cytochromes P450 (P450s) are involved in the biotransformation of toxic compounds and in many physiological processes and thus predestinated to be involved in PD. However, so far only SNPs (single nucleotide polymorphisms) in CYP2D6 and CYP2E1 have been associated with the susceptibility of PD. Our aim was to evaluate the role of all 57 human P450s and their redox partners for the etiology and pathophysiology of PD and to identify novel potential players which may lead to the identification of new biomarkers and to a causative treatment of PD. The PPMI (Parkinson’s Progression Markers Initiative) database was used to extract the gene sequences of all 57 P450s and their three redox partners to analyze the association of SNPs with the occurrence of PD. Applying statistical analyses of the data, corresponding odds ratios (OR) and confidence intervals (CI) were calculated. We identified SNPs significantly over-represented in patients with a genetic predisposition for PD (GPD patients) or in idiopathic PD (IPD patients) compared to HC (healthy controls). Xenobiotic-metabolizing P450s show a significant accumulation of SNPs in PD patients compared with HC supporting the role of toxic compounds in the pathogenesis of PD. Moreover, SNPs with high OR values (>5) in P450s catalyzing the degradation of cholesterol (CYP46A1, CY7B1, CYP39A1) indicate a prominent role of cholesterol metabolism in the brain for PD risk. Finally, P450s participating in the metabolism of eicosanoids show a strong over-representation of SNPs in PD patients underlining the effect of inflammation on the pathogenesis of PD. Also, the redox partners of P450 show SNPs with OR > 5 in PD patients. Taken together, we demonstrate that SNPs in 26 out of 57 P450s are at least 5-fold over-represented in PD patients suggesting these P450s as new potential players in the pathogenesis of PD. For the first time exceptionally high OR values (up to 12.9) were found. This will lead to deeper insight into the origin and development of PD and may be applied to develop novel strategies for a causative treatment of this disease.

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Section: Resultsmentioning

confidence: 99%

A CYPome-wide study reveals new potential players in the pathogenesis of Parkinson’s disease

Hartz

Fehlmann²,

Wagenpfeil³

et al. 2023

Front. Pharmacol.

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“…The association with a reduced PD risk for drugs acting on RAS (C09) has previously been described among others in an early review of experimental data and clinical observations, 17 2 retrospective cohort studies of the risk for PD among 107,207 patients treated for hypertension 18 and among 62,228 patients with ischemic heart disease, 19 and 1 nationwide screening using a nested case-control study of 10,183 PD cases and 67,849 controls. 20 Furthermore, a clinical prospective study of 107 patients with PD found that treatment with ARB improved cognitive function. 21 The 3 epidemiologic studies found that the use of the ARBs was associated with a reduced PD risk, whereas no association was found for the ACEIs.…”

Section: Discussionmentioning

confidence: 99%

“…The drugs for obstructive airway diseases (R03, including β2-agonists) were shown to be related to reduced PD risk in newly published studies on French national health data 39 and Finnish health data. 20 Specifically, β2-agonists have been previously investigated for a role in PD. Mechanistically, selective β2AR activation suppresses the degeneration of nigral dopamine neurons, prevents loss of striatal dopamine, and rescues movements in multiple rodent models of PD.…”

Section: Discussionmentioning

confidence: 99%

Association Between Use of Any of the Drugs Prescribed in Norway and the Subsequent Risk of Parkinson Disease

Romanowska,

Bjornevik,

Cortese

et al. 2023

Neurology

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Background and objectives: The incidence rate of Parkinson’s disease (PD) has been increasing rapidly during the last years. Yet, no treatments exist to prevent or slow the progression of the disease. Moreover, we are unable to detect early disease stages during which intervention with disease-modifying therapies is most likely to succeed. The objective of this study was to perform an agnostic drug-wide association study (DWAS) estimating the association between use of any of the drugs prescribed in Norway and the subsequent risk of PD. Methods: This registry-based cohort study use data from the entire Norwegian population between 2004–2019 linked to the Norwegian Prescription Registry, with more than 600 million individual prescriptions. Drug classes were screened according to ATC codes at level 2, corresponding to therapeutic subgroups. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for the associations between drug classes and PD risk. All p-values were corrected for multiple testing using the false discovery rate. Additionally, we conducted sensitivity analyses of exposure definition, as well as time-lag and dose-response analyses. Results: The study population comprised 3,223,672 individuals, 15,849 of whom developed PD during the follow-up. We identified thirty-one drug classes that were statistically significantly associated with PD risk in Norway during the follow-up. Drugs acting on the renin-angiotensin system (HR = 0.92, 95% CI: 0.89–0.95), corticosteroids for systemic use (0.88, 95% CI: 0.84–0.93), and vaccines (0.89, 95% CI: 0.82–0.96) were associated with a decreased risk of PD even up to 10 years prior to PD onset. Drug classes used to treat symptoms related to prodromal signs of PD such as constipation, urological issues, and depression were associated with an increased risk of subsequent diagnosis of PD with HRs of 1.6 (95% CI: 1.49–1.73), 1.48 (1.42–1.53), and 1.94 (1.87–2.01), respectively. Discussion: This drug-wide study identified thirty-one drug classes that were associated with the PD risk change. It reveals links of renin-angiotensin system medications, vaccines, and corticosteroids with PD risk and suggests that monitoring drug usage using pharmacoepidemiology may allow identifying individuals with prodromal PD.

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“…We previously found no evidence of confounding by indication for an inverse methotrexate-PD association in our population [ 37 ]. Another study found a stronger inverse methotrexate-PD association [ 30 ], but did not observe the association when restricting to rheumatoid arthritis patients [ 38 ]. Still, another study restricted to rheumatoid arthritis patients did find an inverse methotrexate-dementia association very similar to our association for AD [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries

et al. 2023

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Objective To identify prescription medications associated with a lower risk of three neurodegenerative diseases: Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. Methods We conducted a population-based, case-control study of U.S. Medicare beneficiaries in 2009 (42,885 incident neurodegenerative disease cases, 334,387 randomly selected controls). Using medication data from 2006–2007, we categorized all filled medications according to their biological targets and mechanisms of action on those targets. We used multinomial logistic regression models, while accounting for demographics, indicators of smoking, and health care utilization, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 141 target-action pairs and each neurodegenerative disease. For target-action pairs inversely associated with all three diseases, we attempted replication in a cohort study that included an active comparator group. We constructed the cohort by following controls forward for incident neurodegenerative disease from the beginning of 2010 until death or end of 2014, i.e., up to five years after the two-year exposure lag. We used Cox proportional hazards regression while accounting for the same covariates. Results The most consistent inverse association across both studies and all three neurodegenerative diseases was for xanthine dehydrogenase/oxidase blockers, represented by the gout medication, allopurinol. Allopurinol was associated with a 13–34% lower risk for each neurodegenerative disease group in multinomial regression, and a mean reduction of 23% overall, as compared to individuals who did not use allopurinol. In the replication cohort we observed a significant 23% reduction for neurodegenerative disease in the fifth year of follow-up, when comparing allopurinol users to non-users, and more marked associations with an active comparator group. We observed parallel associations for a related target-action pair unique to carvedilol. Discussion/Conclusion Xanthine dehydrogenase/oxidase blockade might reduce risk of neurodegenerative disease. However, further research will be necessary to confirm that the associations related to this pathway are causal or to examine whether this mechanism slows progression.

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Identification of Drugs Associated with Lower Risk of Parkinson’s Disease Using a Systematic Screening Approach in a Nationwide Nested Case–Control Study

Cited by 6 publications

References 44 publications

A CYPome-wide study reveals new potential players in the pathogenesis of Parkinson’s disease

A CYPome-wide study reveals new potential players in the pathogenesis of Parkinson’s disease

Association Between Use of Any of the Drugs Prescribed in Norway and the Subsequent Risk of Parkinson Disease

Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries

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