Increased Risk Of Parkinson's Disease Research Articles

Lifestyle Factors and Parkinson Disease Risk: Korean Nationwide Cohort Study With Repeated Health Screening Data.

Many previous studies, mostly performed in Western countries, on the effects of lifestyle factors on Parkinson disease (PD) used baseline lifestyle characteristics without directly accounting for changes in covariate values over time. The objective of this study was to evaluate the association of repeatedly measured lifestyle factors with PD risk in a Korean population. We conducted a nationwide population-based cohort study. Among 512,836 Koreans in the national health checkup database, we selected individuals who underwent health screening ≥3 times between 2002 and 2015 and followed up until December 31, 2015. PD was defined using the ICD-10 code G20 (with ≥3 times clinic visits for PD, to increase the diagnostic validity). Data on lifestyle factors such as smoking, alcohol consumption, and physical activity were collected using self-reported questionnaires. Logistic regression analysis with time-dependent covariates using generalized estimation equation models was performed to determine PD development. During the 14-year follow-up, 2,665 patients developed PD. Smoking showed a dose-response inverse association with PD only in men (ex-smoker, odds ratio [OR] 0.782, 95% confidence interval [CI] 0.713-0.858; current smoker, OR 0.556, 95% CI 0.488-0.632). Alcohol consumption and regular physical activity were related to reduced PD development in both sexes; however, alcohol consumption in men (≤3 per week, OR 0.717, 95% CI 0.658-0.780; ≥4 per week, OR 0.745, 95% CI 0.644-0.861) and physical activity in women (moderate, OR 0.792, 95% CI 0.748-0.840; vigorous, OR 0.830, 95% CI 0.756-0.911) had more consistent associations with PD development compared to those of the other sex. Participants with regular health screening showed a consistent relationship between lifestyle factors and PD development, whereas lifestyle factors in those without regular health screening had a decreased relationship with PD, even smoking habit. Analysis using repeatedly measured lifestyle factors showed an association between lifestyle factors and PD development. Characteristics of lifestyle data including repeated measurements, timing, or regularity might influence results, and future studies with appropriate lifestyle factors could increase PD risk prediction. This study provides Class II evidence that smoking, alcohol use, and physical activity are associated with reduced risk of PD in a Korean population.

Irritable bowel syndrome and subsequent risk of Parkinson's disease: a nationwide population-based matched-cohort study.

Gastrointestinal dysfunction (GI) is the most prevalent non-motor symptom of Parkinson's disease (PD), and its role in the risk of PD has been studied. In this study, we tried to evaluate whether irritable bowel syndrome (IBS) increased the risk of PD development stratified by sex, age, and IBS duration using a large nationwide cohort in Korea. Patients aged ≥ 20years with a primary diagnosis of IBS (ICD-10 codes: G56) more than three times were selected. A randomly matched cohort without IBS was enrolled by exact matching patients for sex, age, socioeconomic status, comorbidities, and year of enrollment to the IBS group with a ratio of 1:3. Cause-specific Cox regression models were used to identify hazards associated with PD development depending on the presence of IBS during the 11-year follow-up period. In total, 285,064 patients were enrolled in the study: 71,806 in the IBS cohort and 213,258 in the comparison cohort. Cause-specific Cox regression model showed a hazard ratio of 1.436 (95% CI, 1.226-1.682) for PD development in the IBS cohort, which is consistent in both male and female sexes. Subgroup analyses according to age groups showed that IBS increased PD risk only in individuals ≥ 65years (HR = 1.449, 95% CI, 1.207-1.741). We found temporal relationship between IBS and PD at aged ≥ 65years. There might be a possibility that IBS was an early manifestation of PD, and future studies for causal link between the two diseases to elucidate biomechanism are warranted.

Association between inflammatory bowel diseases and Parkinson's disease: systematic review and meta-analysis.

Growing evidence suggests that there are similar pathological mechanisms and closely related pathogenic risk factors for inflammatory bowel disease (IBD) and Parkinson's disease (PD). However, the epidemiological features of these two diseases are different. This review systematically evaluated the relationship between inflammatory bowel diseases and Parkinson's disease risk. We searched PubMed, Embase, and Cochrane databases to retrieve observational studies of IBD and PD published from inception to October 2019. Nine observational studies, involving 12,177,520 patients, were included in the final analysis. None of the studies had Newcastle–Ottawa Scale scores that suggested a high risk of bias. After adjusting for confounders and excluding heterogeneous studies, the overall risk of PD was significantly higher in IBD patients than in the general population (adjusted risk ratio [RR] = 1.24, 95% confidence interval [CI]: 1.15–1.34, P < 0.001). A meta-analysis of the temporal relationship revealed that the incidence of IBD was significantly increased before (adjusted hazard ratio [HR] = 1.26, 95% CI: 1.18–1.35, P < 0.001) and after (adjusted RR = 1.40, 95% CI: 1.20–1.80, P < 0.001) PD diagnosis. After excluding a heterogeneous study, the pooled risk of PD development in patients with ulcerative colitis (adjusted HR = 1.25, 95% CI: 1.13–1.38, P < 0.001) or Crohn's disease (adjusted HR = 1.33, 95% CI: 1.21–1.45, P < 0.01) was significantly increased. Subgroup analysis revealed no significant differences in risk between men (adjusted HR = 1.23, 95% CI: 1.10–1.39) and women (adjusted HR = 1.26, 95% CI: 1.10–1.43); however, older (> 65 years old) IBD patients (adjusted HR = 1.32, 95% CI: 1.17–1.48) may have a higher risk than younger (≤ 65 years old) patients (adjusted HR = 1.24, 95% CI: 1.08–1.42). Patients with IBD who were not treated with anti-tumor necrosis factor-α or azathioprine had significantly higher PD risk (adjusted HR = 1.6, 95% CI: 1.2–2.2). Thus, our meta-analysis indicates a certain correlation between IBD and PD, and suggests that IBD may moderately increase PD risk regardless of sex, especially in patients over 65 years of age. Moreover, early anti-inflammatory therapies for IBD might reduce the risk of developing PD. Our findings suggest an urgent need for an individualized screening strategy for patients with IBD. However, most studies included in this paper were observational, and more randomized controlled trials are needed to confirm the precise association between IBD and PD.

Parkinson disease risks: correctly identifying environmental factors for a chronic disease.

Parkinson disease (PD) is now the world's fastest growing brain disease; however, the factors underlying this rise are unclear. The past 25 years has witnessed a vast expansion in our understanding of the genetics of PD, but few individuals with PD carry one of the major known genetic risk factors. Environmental factors, including individual (e.g., medications) and ambient (e.g., pollutants), may contribute to this rise. In this issue of the JCI, Sasane et al. examined the risk of PD associated with medications commonly used to treat benign prostatic hypertrophy. In contrast with previous studies, certain α1 receptor antagonists failed to lower PD risk. Rather, the commonly used comparator drug, tamsulosin, increased PD risk. This finding highlights the importance of selecting comparator groups to correctly identify risk factors. Future studies to address the rise of PD with emphasis on both individual as well as the understudied ambient environmental factors are warranted.

Increased prevalence of Parkinson's disease in soils with high arsenic levels

IntroductionExposure to arsenic (As)-containing pesticides was associated with an increased risk for Parkinson's disease (PD). Arsenic also induced in murine brains α-synuclein aggregates, a pathognomic feature of PD. ObjectivesPeople living on farms irrigated with high As water in Taiwan are likely exposed to increased As. We addressed whether increased farm soil As levels correlate with an increased PD risk. MethodsWe used the information from several national surveys (1983–1986) on soil metal contents to study the relationships between soil metal contents and PD prevalence in Taiwan. PD prevalence (2009–2013) was calculated with a database from Taiwan's compulsory national health insurance. A patient is defined by a PD diagnosis and prescriptions of Levodopa in three or more office visits in twelve months. We used regression models to study the correlation between PD prevalence and soil metal contents. ResultsThe PD prevalence ranged from 83 to 213 per one hundred thousand persons in different regions of Taiwan. Among the studied heavy metals, we found only As was significantly associated with the PD prevalence. The top three regions (Yunlin, Chiayi, Tainan) in the PD prevalence list correspond exactly with the top three in soil As levels. Soil As levels and PD prevalence had a strong correlation (r = 0.75). ConclusionPD prevalence is statistically correlated with farm soil As levels in Taiwan.

Association of NO2 and Other Air Pollution Exposures With the Risk of Parkinson Disease

The development of Parkinson disease (PD) may be promoted by exposure to air pollution. To investigate the potential association between exposure to particulate matters (PM2.5 and PM10), nitrogen dioxide (NO2), ozone (O3), sulfur dioxide (SO2), and carbon monoxide (CO) and the risk of incident PD. This retrospective cohort study used data from the Korean National Health Insurance Service. Among the 1 021 208 Korean individuals in the database, those who had lived in Seoul from January 2002 to December 2006 (n = 176 875) were screened for eligibility. A total of 78 830 adults older than 40 years without PD and who lived in Seoul between January 2002 and December 2006 were included in this study. Individuals diagnosed with PD before 2006 (n = 159) and individuals 40 years or younger (n = 97 886) were excluded. Each participant was followed up with annually from January 2007 to December 2015, thereby adding up to 757 704 total person-years of follow-up. Data were analyzed from January to September 2020. Individual exposure levels to PM2.5, PM10, NO2, O3, SO2, and CO were estimated based on the participants' residential address at the district level. To evaluate long-term exposure to air pollution, time-varying 5-year mean air pollutant exposure was calculated for each participant. The outcome measure was the association between air pollution and the risk of incident PD measured as hazard ratios after adjusting for demographic factors, socioeconomic factors, and medical comorbidities. At baseline, the mean (SD) age of the 78 830 participants was 54.4 (10.7) years, and 41 070 (52.1%) were female. A total of 338 individuals with newly diagnosed PD were identified during the study period. Exposure to NO2 was associated with an increase in risk of PD (hazard ratio for highest vs lowest quartile, 1.41; 95% CI, 1.02-1.95; P for trend = .045). No statistically significant associations between exposure to PM2.5, PM10, O3, SO2, or CO and PD incidence were found. In this large cohort study, a statistically significant association between NO2 exposure and PD risk was identified. This finding suggests the role of air pollutants in PD development, advocating for the need to implement a targeted public health policy.

Plasma Lipopolysaccharide-Binding Protein Reflects Risk and Progression of Parkinson’s Disease

Lipopolysaccharide-binding protein (LBP) presents bacterial endotoxin, lipopolysaccharides, to cellular surface pattern receptors for immune responses in the gut-brain axis of Parkinson's disease (PD). We investigated whether plasma LBP levels were associated with PD severity and progression. This study included 397 participants (248 PD patients and 149 controls). We measured participants' plasma levels of LBP and pro-inflammatory cytokines, including TNF-α, IL-6, andIL-17A. PD patients underwent motor and cognition evaluations at baseline and at a mean follow-up interval of 4.7±2.3 years. We assessed the progression of motor and cognition symptoms based on changes in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III motor score and Mini-Mental State Examination (MMSE) score, respectively. Plasma LBP levels were lower in PD patients than controls (9.08±2.91 vs. 10.10±3.00μg/ml, p < 0.01). A multiple logistic regression model with adjustment for age, sex, and plasma cytokine levels revealed that reduced plasma LBP levels were associated with increased PD risk (odds ratio 0.816, [95% CI 0.717-0.929], p = 0.002). Among PD patients, LBP levels were correlated with MDS-UPDRS part III motor score after adjustment for confounders (coefficient = 0.636, p = 0.017), but not with MMSE score. Adjusted Cox regression analysis showed that higher plasma LBP levels associated with faster motor progression (adjusted hazard ratio 1.084 [95% CI 1.011-1.163], p = 0.024) during follow-up. Our results demonstrated that plasma LBP levels reflect risk, motor symptom severity and progression in patients with PD.

Nigral MRI features of asymptomatic welders

IntroductionManganese (Mn)-induced parkinsonism involves motor symptoms similar to those observed in Parkinson's disease (PD). Previous literature suggests that chronic Mn- exposure may increase PD risk, although Mn-induced clinical syndromes are considered atypical for PD. This study investigated whether asymptomatic welders display differences in the substantia nigra (SN), the key pathological locus of PD. MethodBrain MRI data and occupational exposure history were obtained in welders (N = 43) and matched controls (N = 31). Diffusion tensor imaging fractional anisotropy (FA; estimate of microstructural integrity) and R2* (estimate of iron and other PD-related brain differences) values in the SN pars compacta (SNc), SN reticulata (SNr), and globus pallidus (GP) were compared between the two groups. The MRI markers of the SN and GP within welders were related to exposure estimates. ResultsCompared to controls, welders who had chronic, but low-level, Mn-exposure had similar FA and R2* values in both SN regions (p's > 0.082), but significantly lower FA (p = 0.0013), although not R2* (p = 0.553), in the GP. In welders, FA values in the SN and GP showed a second-order polynomial relationship with cumulative lifetime welding exposure (p's < 0.03). ConclusionNeurotoxic processes associated with Mn-exposure may be different from those in PD when the exposure-level is relatively low. Greater welding duration and level, however, were associated with FA differences in the GP and SN, indicating that welding exposures above a certain level may induce neurotoxicity in the SN, a finding that should be explored further in future studies.

GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson's Disease.

Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal–lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD.

Lower Lymphocyte Count is Associated With Increased Risk of Parkinson's Disease.

Objectives:Patients with established Parkinson’s disease (PD) display differences in peripheral blood markers of immune function, including leukocyte differential counts, compared with controls. These differences may be useful biomarkers to predict PD and may shed light on pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with increased risk of subsequent PD diagnosis.Methods:We examined the relationship between incident PD, baseline differential leukocyte count and other blood markers of acute inflammation in UK Biobank (UKB), a longitudinal cohort with ~500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations.Results:After excluding individuals with comorbidities which could influence biomarkers of inflammation, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of subsequent PD diagnosis (per 1-SD decrease in lymphocyte count odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.07–1.32, padjusted = 0.01). There was some evidence that reductions in eosinophil counts, monocyte counts and C-reactive protein (CRP) were associated with increased PD risk, and that higher neutrophil count was also associated. Only the association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1-SD decrease in lymphocyte count; ORMR = 1.09, 95% CI = 1.01–1.18, p = 0.02).Interpretation:We provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD.

Ferritinophagy-Mediated Ferroptosis Involved in Paraquat-Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD.

Parkinson's disease (PD) is a progressive nervous system disorder. Until now, the molecular mechanism of its occurrence is not fully understood. Paraquat (PQ) was identified as a neurotoxicant and is linked to increased PD risk and PD-like neuropathology. Ferroptosis is recognized as a new form of regulated cell death. Here, we revealed a new underlying mechanism by which ferritinophagy-mediated ferroptosis is involved in PD induced by PQ. The effect of PQ on movement injury in mice was investigated by the bar fatigue and pole-climbing test. SH-SY5Y human neuroblastoma cells were used to evaluate the mechanism of ferroptosis. Our results showed that PQ induced movement injury by causing the decrease in tyrosine hydroxylase in mice. In vitro, PQ significantly caused the iron accumulation in cytoplasm and mitochondria through ferritinophagy pathway induced by NCOA4. Iron overload initiated lipid peroxidation through 12Lox, further inducing ferroptosis by producing lipid ROS. PQ downregulated SLC7A11 and GPX4 expression and upregulated Cox2 expression significantly, which were important markers in ferroptosis. Fer-1, an inhibitor of ferroptosis, could significantly ameliorate the ferroptosis induced by PQ. Meanwhile, Bcl2, Bax, and p-38 were involved in apoptosis induced by PQ. In conclusion, ferritinophagy-mediated ferroptosis pathway played an important role in PD occurrence. Bcl2/Bax and P-p38/p38 pathways mediated the cross-talk between ferroptosis and apoptosis induced by PQ. These data further demonstrated the complexity of PD occurrence. The inhibition of the ferroptosis and apoptosis together may be a new strategy for the prevention of neurotoxicity or PD in the future.

Pesticide use and incident Parkinson's disease in a cohort of farmers and their spouses

BackgroundExtensive literature suggests an association between general pesticide use and Parkinson's disease (PD). However, with few exceptions, little is known about associations between specific pesticides and PD. ObjectiveWe evaluated use of pesticides and incident PD in 38,274 pesticide applicators and 27,836 of their spouses in the Agricultural Health Study cohort followed over 20 years. MethodsWe used self-reported information on ever-use of 50 specific pesticides as of enrollment for both applicators and spouses, and considered intensity-weighted lifetime days (IWLD) reported at enrollment and through the first 5-year follow-up among applicators. We estimated covariate-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression. We also examined heterogeneity in associations by history of head injury and chemical resistant glove use. ResultsA total of 373 applicators and 118 spouses self-reported incident doctor-diagnosed PD. Ever-use of the insecticide terbufos (HR:1.31, 95%CI:1.02–1.68) and the herbicides trifluralin (HR:1.29, 95%CI: 0.99–1.70) and 2,4,5-T (HR:1.57, 95%CI:1.21–2.04) was associated with elevated PD risk. On the other hand, diazinon (HR:0.73, 95%CI: 0.58–0.94) and 2,4,5-TP (HR:0.39, 95%CI:0.25–0.62) were associated with reduced risk. We observed heterogeneity in ever-use associations by head injury and chemical-resistant glove use for some pesticides, with higher risk among those who reported a history of head injury, or who did not use gloves. PD risk was also elevated for applicators in the highest category of IWLD for dichlorvos, permethrin (animal use), and benomyl. ConclusionsWe found evidence of increased PD risk for some pesticides. Our results also suggest higher susceptibility for pesticide-associated PD among individuals with head injury as well as protection with use of chemical resistant gloves, although further research is needed to understand the impact of head injury. Research on current and newer pesticides, including mechanisms relevant to PD, is important given widespread pesticide use.

Evaluating Lipid-Lowering Drug Targets for Parkinson's Disease Prevention with Mendelian Randomization.

Long‐term exposure to lipid‐lowering drugs might affect Parkinson's disease (PD) risk. We conducted Mendelian randomization analyses where genetic variants indexed expected effects of modulating lipid‐lowering drug targets on PD. Statin exposure was not predicted to increase PD risk, although results were not precise enough to support benefits for prevention clearly (odds ratio [OR] = 0.83; 95% confidence interval [CI] = 0.65, 1.07). Other target results were null, except for variants indicating Apolipoprotein‐A5 or Apolipoprotein‐C3 inhibition might confer protection. These findings suggest peripheral lipid variation may not have a prominent role in PD etiology, but some related drug targets could influence PD via alternate pathways. ANN NEUROL 2020;88:1043–1047

Clostridium difficile infection and risk of Parkinson's disease: a Swedish population-based cohort study.

Gastrointestinal inflammation has been implicated in Parkinson's disease (PD). The aim of this study was to examine whether individuals with a history of Clostridium difficile infection (CDI) are at elevated risk of PD. We performed a population-based cohort study using Swedish national register data. Adults aged ≥35years were identified from the Swedish Population and Housing Census 1990 and followed during the period 1997-2013. Diagnoses of CDI and PD were extracted from the National Patient Register. Associations of CDI history with PD risk were estimated using Cox proportional hazards regression. We also explored whether the association differed by the source of CDI diagnosis (inpatient vs. outpatient), presence of recurrent infections, and pre-infection use of antibiotics. Amongst the study population (N=4670423), 34868 (0.75%) had a history of CDI. A total of 165 and 47035 incident PD cases were identified from individuals with and without CDI history, respectively. Across the entire follow-up, a 16% elevation of PD risk was observed among the CDI group [hazard ratio 1.16, 95% confidence interval (CI)1.00-1.36], which was mainly driven by increased PD risk within the first 2years after CDI diagnosis (hazard ratio 1.38, 95% CI 1.12-1.69). In longer follow-up, CDI was not associated with subsequent PD occurrence. This temporal pattern of CDI-PD associations was generally observed across all CDI subgroups. Clostridium difficile may be associated with an increased short-term PD risk, but this might be explained by reverse causation and/or surveillance bias. Our results do not imply that CDI history affects long-term PD risk.

Interaction between SNCA gene polymorphisms and T2DM with Parkinson's disease.

To investigate the association of several single nucleotide polymorphisms (SNPs) within alpha-synuclein (SNCA) gene and additional gene-environment interaction with Parkinson's disease (PD) risk. Hardy-Weinberg equilibrium (HWE) is tested for controls using SNPstats (http://bioinfo.iconcologia.net/SNPstats). Logistic regression is used to calculate the ORs (95% CI) for relations between the four SNPs and PD risk. The generalized multifactor dimensionality reduction (GMDR) model is used to evaluate the synergy between gene and environment. A total of 1161 people were included in this study, including 386 cases of PD and 775 normal controls. In this study, the genotype frequency of the control group was consistent with HWE distribution. Rs356219-G allele frequency was 30.0% in patients and 19.8% in control group. The rs356221-T allele frequency was 29.7% in the patients and 20.8% in the control group. Rs356219-G and rs356221-T alleles were associated with increased PD risk, with adjusted ORs (95% CI) of 1.92 (1.28-2.52) and 1.52 (1.05-2.02), respectively. We also found no significant correlation between rs2301134 and rs2301135 and susceptibility to PD. The best gene-environment interaction models were determined by GMDR analysis, which shown a significant gene-T2DM interaction combinations, but the gene-alcohol drinking interaction combinations were all not significant. We also conducted stratified analysis for interaction effect using logistic regression. We found that T2DM patients with rs356221-AT/ TT genotype have the highest PD risk, compared to subjects with rs356219-AA genotype, OR (95%CI) = 2.67 (1.83-3.46). The rs356219-G and rs356221-T, gene-environment interaction between rs356221 and T2DM were all associated with increased PD risk.

The association between the C-reactive protein gene +1444C/T polymorphism and Parkinson's disease susceptibility in a Chinese population.

C-reactive protein (CRP) is increased in Parkinson's disease (PD). The CRP +1444C/T (rs1130864) polymorphism is located in the 3' untranslated region (3'-UTR) and is associated with serum CRP concentrations. We explored the relationship between the CRP +1444C/T polymorphism and susceptibility to PD. A total of 1000 subjects from a Chinese population were recruited into this case-control study, including 500 PD patients and 500 healthy controls. The genotype of the CRP +1444C/T polymorphism was tested by Sanger sequencing, and the Hardy-Weinberg equilibrium (HWE) was assessed in the groups. The odds ratios and 95% confidence intervals were calculated to evaluate the strength of any correlations in allelic, dominant, recessive, and additive genetic models. The genotypic distribution of the CRP +1444C/T polymorphism was consistent with HWE in controls, and markedly different with cases. The CRP +1444C/T polymorphism was associated with increased PD risk in allelic and dominant models in the overall and male population, but not the female subgroup. The presence of a CRP +1444C/T polymorphism may be associated with an increased risk of PD in our Chinese population. Given the missing support for a role of this SNP in PD in the pre-existing GWAS, the SNP may not be genuinely associated with PD despite some positive candidate gene studies.

Reader response: Use of β2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease.

This Danish study1 “confirmed (β2-adrenoreceptor [β2AR]) agonist use to be associated with reduced Parkinson disease (PD) risk…,” replicating larger studies in Israel2 and Norway.3 However, the authors' speculations regarding causality, and that smoking may confound the association, conflict with their own study. First, they did not collect smoking data. In Israel,2 the association remained significant after directly adjusting for smoking (which was collected) and smoking-related covariates. Second, even after adjusting for COPD diagnosis, inhaled corticosteroids, and inhaled anticholinergics (their “markers of smoking”), β2AR agonists were significantly associated with reduced PD risk with an OR of 0.64 (0.42–0.98) compared with 0.66 (0.52–0.85) without adjusting (table 4).1 Adjusting for the smoking markers did not attenuate the OR. Once these covariates are statistically controlled, any remaining significant relation between β2AR agonists and reduced PD risk cannot be due to their mediating effects. Whether covariates themselves are related to PD risk is not directly relevant. Third, the beta-blocker propranolol, which increased neuronal SNCA,3 was associated with increased PD risk in Denmark (excluding essential tremor),1 Norway (restricted to cardiovascular indications),3 and Israel (5–8 years lag).2 Finally, β2AR agonists, associated with reduced PD risk after adjusting for smoking-related covariates in Norway,3 Israel,2 and Denmark,1 offered neuroprotection in 3 rodent models.3–5 Thankfully, rodents don't smoke.

Bacterial, viral, and fungal infection-related risk of Parkinson's disease: Meta-analysis of cohort and case-control studies.

AimsRecent studies showed that patients with various bacterial, viral, and fungal infections might be at increased risk of Parkinson's disease (PD). However, the risk of PD in patients with each specific infection varied. This meta‐analysis estimated the association between various infections and PD risk.MethodsLiterature published from January 1965 to October 2019 in PubMed and EMBASE databases was searched. Data were extracted and pooled using random/fixed effects model. Sensitivity analysis and meta‐regression were also performed to analyze the source of heterogeneity. Publication bias was estimated by the trim and fill.ResultsTwenty‐three out of 6,609 studies were included. Helicobacter pylori (HP; pooled OR = 1.653, 1.426–1.915, p < .001), hepatitis C virus (HCV; pooled OR = 1.195, 1.012–1.410, p = .035), Malassezia (pooled OR = 1.694, 1.367–2.100, p < .001), and pneumoniae (pooled OR = 1.595, 1.020–2.493, p = .041) infection were associated with increased PD risk. Influenza virus, herpes virus, hepatitis B virus, scarlet fever, mumps virus, chicken pox, pertussis, German measles, and measles were not associated with PD risk. After antiviral treatment against HCV reduced the risk of PD in patients with HCV infection (OR = 0.672, 0.571–0.791, p < .001). Significant heterogeneity exists among the included studies.ConclusionPatients with infection of HP, HCV, Malassezia, pneumoniae might be an increased risk of PD. Antiviral treatment of HCV could reduce the risk of PD.

Single nucleotide polymorphisms in the non-coding region of STIM1 gene are associated with Parkinson disease risk in Chinese Han population.

The stromal interaction molecule 1 (STIM1) gene contributes essentially to Ca2+ transport, thus it is functionally related to neurodegenerative disorders. The objective of this study was to investigate the correlation between single nucleotide polymorphisms (SNP) in the non-coding region of STIM1 gene and the risk for Parkinson disease (PD) in a Chinese Han population.In a cohort composed of 300 PD patients and 300 healthy individuals from a Chinese Han population, we analyzed genotypes for five novel SNPs, rs7934581, rs3794050, rs1561876, rs3750994 and rs3750996 in the non-coding region of STIM1 gene. The levels of STIM1 protein in plasma of these subjects were also assessed by enzyme-linked immunosorbent assay (ELISA).We found that the SNPs of STIM1 gene rs7934581, rs3794050, rs1561876, and rs3750996 were associated with increased PD risk, while rs3750994 SNP was not. An increased risk of PD was observed in subjects with the TAAG and TGAG haplotypes of rs7934581, rs3794050, rs1561876, rs3750996. Moreover, PD risk was significantly elevated only in subjects with age ≥60 years or females who carry the STIM1 rs3794050 minor allele. There was a significant difference in plasma STIM1 protein levels between subjects with different genotypes of STIM1 rs7934581, rs3794050, rs1561876, and rs3750996.STIM1 gene rs7934581, rs3794050, rs1561876, rs3750996 SNPs are associated with increased PD risk, and its mechanism may be related to abnormal STIM1 gene expression.

Association of RIT2 and RAB7L1 with Parkinson's disease: a case-control study in a Taiwanese cohort and a meta-analysis in Asian populations

Several genome-wide association studies and meta-analyses on Parkinson's disease (PD)-related genes have identified several risk foci in Ras-related genes, particularly among Caucasian individuals. However, the corresponding results have been controversial among Asian individuals. We investigated whether 2 single-nucleotide polymorphisms of Ras-related genes, RIT2 (rs12456492) and RAB7L1 (rs823118), are associated with PD risk in Taiwanese individuals. In addition, we conducted a meta-analysis of all studies related to rs12456492 in Asian populations to resolve inconsistency in this locus. In total, 1103 Taiwanese individuals (588 patients with PD and 515 controls) and 1111 Taiwanese individuals (594 patients with PD and 517 controls) were genotyped for rs12456492 and rs823118. However, we could not confirm the association of rs12456492 and rs823118 with PD. Our current meta-analysis involving the rs12456492(A/G) variant demonstrated that the GG + GA genotypes, GG genotypes, and G allele may be risk factors for PD. RIT2 may increase PD risk in Asian individuals. The discrepancies between Caucasian and Asian populations may be due to differences in geographic region–specific genetic backgrounds and gene-environmental interactions.