Re: 파킨슨 환자.. 녹차 마시면 호전된다 .. Mendelian Randomization Study ..

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Front Nutr. 2022; 9: 848223.

Published online 2022 May 26. doi: 10.3389/fnut.2022.848223

PMCID: PMC9199515

PMID: 35719152

Green Tea Intake and Parkinson's Disease Progression: A Mendelian Randomization Study

Chunyu Li, Junyu Lin, Tianmi Yang, and Huifang Shang

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Abstract

Epidemiological studies have suggested green tea intake was associated with a reduced risk of Parkinson's disease (PD). However, whether green tea intake has an effect on PD progression is unknown. To eval‎uate the role of green tea intake in PD progression, we conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of green tea intake (N = 64,949), age at onset (N = 28,568) and progression (N = 4,093) of PD. One standard deviation increase in genetically determined green tea intake was significantly associated with slower progression to dementia (OR: 0.87, 95% CI: 0.81–0.94, P: 3.48E−04) after the Bonferroni correction. Meanwhile, higher green tea intake was nominally associated with slower progression to depression, and lower risk of dementia, depression, hyposmia and insomnia at baseline. The results were robust under all sensitivity analyses. These results might facilitate novel therapeutic targets to slow down the progression of PD in clinical trials, and have clinical implications for patients with PD.

초록

역학 연구에 따르면 

녹차 섭취는 

파킨슨병(PD) 위험 감소와 관련이 있는 것으로 나타났습니다. 

그러나 

녹차 섭취가 

PD 진행에 영향을 미치는지 여부는 알려지지 않았습니다. 

녹차 섭취가 

PD 진행에 미치는 영향을 평가하기 위해 

녹차 섭취량(N = 64,949), 

발병 연령(N = 28,568), 

PD 진행(N = 4,093)에 대한 

게놈 전체 연관성 연구의 요약 통계를 사용하여 

두 가지 샘플 멘델 무작위 분석을 실시했습니다. 

본페로니 보정 후 

유전적으로 결정된 녹차 섭취량이 

1 표준편차 증가하면 치

매로의 진행이 느려지는 것과 유의미한 관련이 있었습니다(OR: 0.87, 95% CI: 0.81-0.94, P: 3.48E-04). 

한편, 

녹차 섭취량이 많을수록 

우울증으로의 진행 속도가 느려지고 

기준치에서 치매, 우울증, 후각소실 및 불면증 위험이 낮아지는 것으로 나타났습니다.

이 결과는 모든 민감도 분석에서 견고하게 나타났습니다. 이러한 결과는 임상시험에서 파킨슨병의 진행을 늦추는 새로운 치료 표적을 촉진하고 파킨슨병 환자에게 임상적 영향을 미칠 수 있습니다.

Keywords: green tea intake, Parkinson's disease, Mendelian randomization, age at onset, progression

Introduction

Parkinson's disease (PD) is a complex progressive neurodegenerative disorder with a wide range of phenotypes like motor, cognitive and affective manifestations (1, 2), which is further entangled by heterogeneous age at onset (AAO) and symptom progression between individuals (3). The interplay of multiple factors like aging, genetics and environmental factors might contribute to such heterogeneity (4). Identifying risk factors for PD progression could help better understand the pathogenesis of the disease, and provide care and therapeutic strategies for patients and clinicians.

Green tea, a widely-consumed beverage, was suggested to have health benefits against cancer, cardiovascular diseases, diabetes and several neurodegenerative disorders including PD (5). Previous case-control designed studies have identified an inverse association between tea intake and risk of PD (6, 7). Pathologically, several potential mechanisms for the protective role of green tea against PD have also been proposed, like the antioxidant potential of green tea in combating oxidative stress and alleviating mitochondrial dysfunction (8). As for the progression of PD, a previous study among 278 patients with PD found that consumption of tea more than 3 cups per day could delay the onset age of motor symptoms (9). However, a recent prospective cohort study investigating lifestyle factors and the progression of PD found that caffeinated tea was associated with reduced mortality but not progression (10). Similarly, a systematic review of prospective longitudinal studies found evidence for a protective role of tea intake against the risk for PD, but not progression of PD (11). Therefore, whether green tea intake has a beneficial role in the progression of PD is still unknown. Meanwhile, the observational studies might be biased by unavoidable confounding factors and relatively small sample size, and cannot determine causation.

In this context, we performed a two-sample Mendelian randomization (MR) analysis to explore the causal role of green tea intake in the progression of PD (Supplementary Figure 1). The MR approach is not susceptible to reverse causation or confounding factors which may distort interpretations of conventional observational studies. As a result, we found that green tea intake was causally associated with a lower risk of dementia in PD.

소개

파킨슨병(PD)은 운동, 인지 및 정서 증상(1, 2)과 같은 다양한 표현형을 가진 복잡한 진행성 신경 퇴행성 질환으로, 개인 간의 이질적인 발병 연령(AAO)과 증상 진행으로 인해 더욱 복잡하게 얽혀 있습니다(3). 노화, 유전, 환경적 요인 등 여러 요인의 상호 작용이 이러한 이질성에 기여할 수 있습니다(4).

PD 진행의 위험 요인을 파악하면

질병의 발병 기전을 더 잘 이해하고

환자와 임상의에게 치료 및 치료 전략을 제공하는 데 도움이 될 수 있습니다.

널리 소비되는 음료인 녹차는

암, 심혈관 질환, 당뇨병 및 PD를 포함한

여러 신경 퇴행성 질환에 대한 건강상의 이점이 있는 것으로 제안되었습니다(5).

이전의 사례 대조군 연구에서는

차 섭취와 PD의 위험 사이에

역의 상관관계가 있는 것으로 나타났습니다(6, 7).

병리학적으로도

산화 스트레스에 대항하고

미토콘드리아 기능 장애를 완화하는 녹차의 항산화 잠재력과 같은

녹차의 PD 보호 역할에 대한 몇 가지 잠재적 메커니즘이 제안되었습니다(8).

파킨슨병의 진행과 관련하여,

278명의 파킨슨병 환자를 대상으로 한 이전 연구에서는

하루에 3잔 이상의 차를 마시면

운동 증상의 발병 연령을 늦출 수 있다는 사실이 밝혀졌습니다(9).

그러나

최근 생활 습관 요인과

파킨슨병의 진행을 조사한 전향적 코호트 연구에서는

카페인이 함유된 차가 사망률 감소와 관련이 있지만

진행과는 관련이 없는 것으로 나타났습니다(10).

마찬가지로,

전향적 종단 연구에 대한 체계적인 검토에서는

녹차 섭취가 PD의 위험에 대한 보호 역할을 하지만

PD의 진행에는 영향을 미치지 않는다는 증거를 발견했습니다(11).

따라서

녹차 섭취가 PD의 진행에 유익한 역할을 하는지 여부는

아직 밝혀지지 않았습니다.

한편,

관찰 연구는 피할 수 없는 교란 요인과

상대적으로 작은 표본 크기로 인해 편향될 수 있으며

인과 관계를 단정할 수 없습니다.

이러한 맥락에서

녹차 섭취가 PD 진행에 미치는 인과적 역할을 탐구하기 위해

2샘플 멘델 무작위 배정(MR) 분석을 수행했습니다(보충 그림 1).

MR 접근법은

기존 관찰 연구의 해석을 왜곡할 수 있는

역 인과관계나 교란 요인에 영향을 받지 않습니다.

그 결과,

녹차 섭취가 파킨슨 치매 위험 감소와

인과관계가 있다는 사실을 발견했습니다.

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Methods

Datasets

We obtained summary statistics of green tea intake from a genome-wide association study (GWAS) based on the UK Biobank data (N = 64,949). Green tea intake was measured by “How many cups/mugs of green tea did you drink yesterday?” in the UK Biobank (data field: 100420). The summary statistics were generated from regression on green tea intake adjusting for sex and principal components after excluding poor quality samples. The detailed design like quality control procedures and statistical analyses could be found at http://www.nealelab.is/uk-biobank/. Single nucleotide polymorphisms (SNP) that passed the genome-wide significance threshold (P < 5E−08) were chosen as instrumental variables, which were then clumped based on the 1,000 Genomes Project linkage disequilibrium (LD) structure. Index SNPs (R2 < 0.001 with any other associated SNP within 10 Mb) with the minimum P value were kept. Furthermore, we used the PhenoScanner v2 tool to check for variants associated with other phenotypes (P < 5E−08) which might affect the progression of PD independent of green tea intake (12).

Summary statistics of AAO of PD were from GWAS based on 28,568 PD patients of European ancestry (13). For the progression of PD, we obtained summary data from a large GWAS on clinical biomarkers of PD such as the Hoehn-Yahr (HY) stage in 12 longitudinal PD cohorts (N = 4,093) (14). A total of 28 clinical progression phenotypes were analyzed. Harmonization was undertaken to rule out strand mismatches and ensure alignment of SNP effect sizes.

메소드
데이터 세트
영국 바이오뱅크 데이터(N = 64,949)를 기반으로 한 전장 유전체 연관성 연구(GWAS)에서 녹차 섭취량에 대한 요약 통계를 얻었습니다. 녹차 섭취량은 영국 바이오뱅크(데이터 필드: 100420)에서 “어제 몇 잔/잔의 녹차를 마셨습니까?”라는 질문으로 측정했습니다. 요약 통계는 품질이 낮은 샘플을 제외한 후 성별과 주성분을 조정하여 녹차 섭취량에 대한 회귀분석을 통해 생성되었습니다. 품질 관리 절차 및 통계 분석과 같은 자세한 설계는 http://www.nealelab.is/uk-biobank/ 에서 확인할 수 있습니다 . 게놈 전체 유의성 임계값(P < 5E-08)을 통과한 단일염기다형성(SNP)을 도구 변수로 선택한 다음, 1,000 게놈 프로젝트 연결 불균형(LD) 구조에 따라 묶어냈습니다. 최소 P값을 가진 인덱스 SNP(10Mb 이내의 다른 연관 SNP와 R2 <0.001)는 유지했습니다. 또한, 녹차 섭취와 무관하게 PD 진행에 영향을 미칠 수 있는 다른 표현형(P < 5E-08)과 관련된 변이를 확인하기 위해 PhenoScanner v2 도구를 사용했습니다(12).
PD의 AAO에 대한 요약 통계는 유럽 혈통의 PD 환자 28,568명을 대상으로 한 GWAS에서 얻은 것입니다(13). PD의 진행에 대해서는 12개의 종단적 PD 코호트(N = 4,093)에서 Hoehn-Yahr(HY) 단계와 같은 PD의 임상 바이오마커에 대한 대규모 GWAS의 요약 데이터를 얻었습니다(14). 총 28개의 임상 진행 표현형을 분석했습니다. 가닥 불일치를 배제하고 SNP 효과 크기의 정렬을 보장하기 위해 조화가 수행되었습니다.

Mendelian Randomization Analysis

We hypothesized that green tea intake as a protective factor could causally decrease the risk of specific symptom progression in PD, and the following assumptions were satisfied: the genetic variants used as instrumental variables are associated with green tea intake; the genetic variants are not associated with confounders; the genetic variants are associated with PD progression through green tea intake (namely horizontal pleiotropy should not be present) (Supplementary Figure 2).

To eval‎uate the causative effect of green tea intake on the progression of PD, we performed a two-sample MR analysis using the random effects inverse variance weighted (IVW) method, which is most widely used in MR studies and could provide robust causal estimates under the absence of directional pleiotropy. A P value below 1.79E−03 (0.05/28) was considered statistically significant after the Bonferroni correction. For the significant association, we further verified the results using another three MR methods, namely MR Egger regression, weighted median and weighted mode. In addition, we conducted comprehensive sensitivity analyses to estimate potential violation of the model assumptions in the MR analysis. We conducted Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) analysis and leave-one-out analysis to detect outlier instrumental variables (15). Outlier instrumental variables identified by the MR-PRESSO analysis were removed step-by-step to reduce the effect of horizontal pleiotropy. Cochran's Q test was executed to check heterogeneity across the individual causal effects. MR-Egger regression was performed to eval‎uate the pleiotropy of instrumental variables (16). To eval‎uate the strongness of each instrumental variable, we computed the F-statistic of each SNP as described earlier (17). The statistical analyses were conducted using the R package TwoSampleMR 0.5.5 (18).

멘델 무작위 분석
우리는 보호 인자로서 녹차 섭취가 PD의 특정 증상 진행 위험을 인과적으로 감소시킬 수 있다는 가설을 세웠으며, 도구 변수로 사용된 유전적 변이가 녹차 섭취와 관련이 있고, 유전적 변이가 교란 변수와 관련이 없으며, 유전적 변이가 녹차 섭취를 통해 PD 진행과 관련이 있다는 가정이 충족되었습니다(즉, 수평 다형성이 존재하지 않아야 함)(보충 그림 2).

녹차 섭취가 PD 진행에 미치는 인과적 영향을 평가하기 위해 MR 연구에서 가장 널리 사용되고 방향성 플레오트로피가 없을 때 강력한 인과 추정치를 제공할 수 있는 무작위 효과 역분산 가중(IVW) 방법을 사용하여 두 개의 샘플 MR 분석을 수행했습니다. 본페로니 보정 후 1.79E-03(0.05/28) 미만의 P값은 통계적으로 유의미한 것으로 간주했습니다. 유의미한 연관성을 확인하기 위해 MR 에거 회귀, 가중 중앙값, 가중 모드 등 다른 세 가지 MR 방법을 사용하여 결과를 추가로 검증했습니다. 또한 포괄적인 민감도 분석을 수행하여 MR 분석에서 모델 가정에 대한 잠재적인 위반 가능성을 추정했습니다. 이상값 도구 변수(15개)를 탐지하기 위해 멘델식 랜덤화 플리오트로피 잔여 합 및 이상값(MR-PRESSO) 분석과 이탈 원 아웃 분석을 수행했습니다. MR-PRESSO 분석으로 식별된 이상값 도구 변수는 수평적 플리트로피의 영향을 줄이기 위해 단계적으로 제거했습니다. 개별 인과 효과의 이질성을 확인하기 위해 코크란의 Q 테스트를 실행했습니다. 도구 변수의 플리오트로피를 평가하기 위해 MR-에거 회귀를 수행했습니다(16). 각 도구 변수의 강도를 평가하기 위해 앞서 설명한 대로 각 SNP의 F-통계량을 계산했습니다(17). 통계 분석은 R 패키지 TwoSampleMR 0.5.5를 사용하여 수행했습니다(18).

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Results

We analyzed the role of green tea intake in the progression of PD using the two-sample MR approach. Results showed that each standard deviation increase in green tea intake was significantly associated with slower progression to dementia (OR: 0.87, 95% CI: 0.81–0.94, P: 3.48E−04) after the Bonferroni correction (Figure 1). Such association was further verified using the other three MR methods (Figure 2). Consistently, green tea intake was nominally associated with a lower risk of dementia at baseline, suggesting a protective role of green tea against cognitive impairment in PD. In addition, nominal association was observed between green tea intake and slower progression to depression, and lower risk of depression, hyposmia and insomnia at baseline (Figure 1).

Figure 1

Forest plot showing Mendelian randomization analysis results to eval‎uate the causal association between green tea intake and progression of PD. Results above the dashed line are for symptoms collected at baseline, while results below the dashed line are from survival analysis on symptom progression during follow-up. SEADL, Schwab and England Activities of Daily Living Scale; UPDRS, Unified Parkinson Disease Rating Scale; HY-3, Hoehn Yahr scale 3 or greater; RBD, REM sleep behavior disorder; SEADL70, SEADL of 70 or less. aDenotes statistical significance, while bdenotes nominal significance.

Figure 2

Mendelian randomization analysis results for green tea intake and dementia of PD. (A) Forest plot showing Mendelian randomization (MR) analysis results to eval‎uate the causal association between green tea intake and progression to dementia using four methods. (B) Scatter plot of single nucleotide polymorphism (SNP) potential effects on green tea intake and dementia of PD. The 95% CI for the effect size on green tea intake is shown as vertical lines, while the 95% CI for the effect size on dementia of PD is shown as horizontal lines. The slope of fitted lines represents the estimated MR effect per method. (C) Funnel plot for green tea intake shows the estimation using the inverse of the standard error of the causal estimate with each individual SNP as a tool. The vertical line represents the estimated causal effect obtained using IVW and MR-Egger methods.

Next, we performed sensitivity analyses to validate the causal association between green tea intake and the progression of PD. No heterogeneity of effects was detected by Cochran's Q test (Table 1). The F statistics of all the instrumental variables were above 10 (ranging from 30 to 44), indicating absence of weakness in the selected instrumental variables. No apparent horizontal pleiotropy was observed as the intercept of MR-Egger was not significantly deviated from zero (Table 1). Meanwhile, no potential instrumental outlier was detected at the nominal significance level of 0.05 by the MR-PRESSO analysis (Table 1). The leave-one-out results suggested that the causal effect was not driven by a single instrumental variable (Supplementary Figures 3–7). Lastly, we used the PhenoScanner tool to check if the SNPs used in the MR analysis were associated with other phenotypes. As a result, no instrumental variable was associated with other phenotypes which might affect the progression of PD independent of green tea intake (Supplementary Table 1).

Table 1

Heterogeneity and horizontal pleiotropy analyses between green tea intake and PD progression.

TraitHeterogeneityHorizontal pleiotropyMR-PRESSOIVW QIVW Q dfIVW P valueEgger interceptSEP valueP value

Constipation	8.51	12	0.74	0.12	0.2	0.55	0.78
Dementia	7.96	17	0.97	0.13	0.2	0.51	0.96
Depression	4.38	10	0.93	−0.62	0.81	0.47	0.92
Dyskinesia	7.2	10	0.71	0.32	0.42	0.47	0.7
HY-3	9.28	10	0.51	0.70	0.33	0.06	0.49
Hyposmia	6.33	14	0.96	0.13	0.18	0.48	0.97
Insomnia	7.26	14	0.92	0.09	0.17	0.63	0.94
Motor fluctuation	8.46	10	0.58	−0.07	0.36	0.86	0.56
RBD	11.06	12	0.52	0.31	0.28	0.29	0.53
Daytime sleepiness	10.11	10	0.43	0.48	0.61	0.45	0.45
Age at onset	2.63	4	0.62	0.03	0.32	0.92	0.64
HY	8.93	19	0.98	−0.02	0.02	0.26	0.98
SEADL	18.17	16	0.31	0.69	0.6	0.27	0.33
UPDRS1	15.04	12	0.24	2.75E−03	0.12	0.98	0.28
UPDRS2	13.95	12	0.3	−0.24	0.11	0.05	0.3
UPDRS3	12.23	16	0.73	−0.06	0.07	0.38	0.79
UPDRS4	11.01	9	0.28	0.1	0.15	0.51	0.3
UPDRS	9	17	0.94	−0.07	0.06	0.27	0.94
Constipation	8.87	8	0.35	0.25	0.16	0.17	0.34
Dementia	10.72	13	0.63	0.12	0.17	0.51	0.67
Depression	2.61	6	0.86	0.11	0.27	0.7	0.88
Dyskinesia	5.72	11	0.89	0.01	0.18	0.97	0.9
HY-3	13.71	17	0.69	−0.002	0.12	0.99	0.67
Insomnia	9.19	13	0.76	0.13	0.15	0.4	0.76
Motor fluctuation	10.98	14	0.69	0.01	0.13	0.92	70
RBD	14.12	13	0.37	0.54	0.24	0.04	0.36
SEADL70	7.45	14	0.92	−0.07	0.23	0.76	0.94
Daytime sleepiness	15.15	12	0.23	−0.06	0.2	0.78	0.17

Open in a separate window

IVW, Inverse variance weighted; Q, Cochran's Q test estimate; df, Cochran's Q test degrees of freedom; SE, standard error.

Results above the dashed line were for symptoms collected at baseline, while results below the dashed line were from survival analysis on symptom progression during follow-up.

Discussion

Previous epidemiological studies have suggested green tea intake has a protective effect against risk of PD, but whether it could slow down the progression of PD is less explored. Meanwhile, unmeasured confounding factors in clinical studies might potentially bias the association evidence, as is a common criticism inherent to observational studies. Therefore, we investigated the role of green tea intake in the progression of PD using the MR approach. The results demonstrated a protective role of great tea intake against the risk of dementia and depression in PD. Meanwhile, green tea intake was nominally associated with a lower risk of hyposmia and insomnia for patients with PD at baseline. These findings provided a better understanding of the role of green tea intake in the progression of PD, and provided novel targets to explore the pathogenesis of PD.

Previous observational studies have suggested that green tea intake might reduce the risk of dementia, Alzheimer's disease, and cognitive impairment in the elderly (19). However, whether the effect applies to dementia in other disorders was less explored. From a genetic perspective, our results demonstrated the protective role of green tea intake applied to dementia in PD as well, suggesting a universal favorable role of green tea against cognitive impairment. Though how green tea exerts this effect is still unknown, several potential mechanisms have been proposed (19). The first mechanism is the antioxidant activity of green tea catechins in the brain. Oxidative stress has been demonstrated to be involved in the pathogenesis of dementia, while catechins in green tea could chelate bivalent metal ions and prevent oxidation caused by reactive hydroxyl radicals (20).

Secondly, several brain inflammatory markers are associated with the risk of all-cause dementia (21), while the anti-inflammatory effects of green tea polyphenols through the inhibition of nuclear factor kappa-beta activation could reduce brain inflammation. Thirdly, epigallocatechin gallate (EGCG), the main component of green tea catechins, has neuroprotective effects due to its inhibition of amyloid-beta aggregation which is closely related to the pathogenesis of dementia (22). Meanwhile, in vitro experiments suggested that green tea polyphenols (GTP) could protect dopamine neurons and thus might be beneficial to cognitive function (23). And EGCG was suggested to reduce neuronal cell death and induce nitric oxide synthase (NOS) expression‎ in an MPTP mouse model of PD, which provided further evidence for the neuroprotective role of green tea (24). Additionally, our results also suggested a nominal protective role of green tea intake against depression of PD. Depression is closely related to dementia, and depressive symptoms are considered as the first glimpse of the brain failure that will lead to dementia. The role of green tea against depression in the elderly has been reported by previous observational studies (25). Our results further strengthened this protective effect and broadened the spectrum of this effect to PD. Though the exact mechanism remains elusive, the main components of green tea, namely L-theanine and EGCG might play a role (26, 27). Future clinical or functional studies could attach importance to this in exploring how green tea intake protects against dementia and depression in PD.

Besides, we noticed a nominal protective role of green tea against hyposmia and insomnia at baseline. A previous cohort study found that lower lifetime caffeine consumption was associated with abnormal olfaction in relatives of patients with PD (28). Since caffeine was a major component of green tea, green tea might protect against hyposmia as well. Additionally, daily ingestion of low-caffeine green tea might be beneficial for improving the sleep quality of the elderly via the suppression of stress (29). However, contradictory results have also been reported. For example, one study found that caffeine administration had little or no effect on hyposmia in a group of 76 hyposmic individuals (30). Meanwhile, the caffeine within green tea might also increase the risk of insomnia. Since only nominal association was detected in the current study, further exploration was still necessary to explore the role of green tea intake in hyposmia and insomnia.

In addition, we also noticed an association with borderline significance between green tea intake and progression to HY-3 stage (OR = 0.94, 95 % CI: 0.89–1.00, P = 0.054), which described the overall motor symptom progression of PD. Green tea might exert this effect by modulating microglia activation and decreasing the production of inflammatory mediators (31). Similarly, a previous clinical study found that drinking green tea could improve antioxidant status and reduce oxidative damage (32), suggesting the potential beneficial role of green tea in the progression of PD. Pathologically, a previous study has shown that EGCG strongly inhibited the aggregation of α-synuclein and prevented toxicity in PC12 cells (33). Meanwhile, EGCG could also bind to the native unfolded α-synuclein polypeptide chain and prevent the formation of toxic β structures by mediating the formation of the unstructured oligomer. Previous study has shown that EGCG could reduce interaction between α-synuclein oligomers and cell membranes and thus protect rat neuronal cells from toxicity (34). However, a previous epidemiological study did not find an association between tea intake and the time to reach the HY-3 stage of PD (35). Therefore, more evidence was necessary to better understand whether and how green tea was involved in the overall progression of PD.

In contrast, for other symptoms like the Unified Parkinson's Disease Rating Scale (UPDRS) which was shown to benefit from green tea intake, we did not identify a significant association in the current study. This might be due to the different pathogenesis of various symptoms in PD. However, we cannot exclude the possibility that we failed to detect the association due to the insufficiency of the sample sizes. The moderate variance explained by the instrumental variables of the exposure limited the power to detect weaker causal associations. Further validations in larger cohorts were still necessary.

In conclusion, based on results from the MR analysis, we demonstrated a protective effect of green tea intake against dementia and depression of PD. These results could help better understand the role of green tea in the progression of PD, will facilitate therapeutic drugs in the future clinical trials, and also provide some lifestyle recommendation for the patients with PD.

토론
이전의 역학 연구에 따르면 녹차 섭취가 pd의 위험에 대한 보호 효과가 있다고 하지만, 녹차가 pd의 진행을 늦출 수 있는지에 대해서는 아직 연구가 덜 진행되었습니다. 한편, 임상 연구에서 측정되지 않은 교란 요인은 관찰 연구에 내재된 일반적인 비판처럼 연관성 증거를 편향시킬 수 있습니다. 따라서 저희는 MR 접근법을 사용하여 녹차 섭취가 PD 진행에 미치는 역할을 조사했습니다.

그 결과

다량의 녹차 섭취가

치매와 우울증의 위험에 대한 보호 역할을 하는 것으로 나타났습니다.

한편, 녹차 섭취는

명목상 PD 환자의 후각소실 및 불면증 위험을 낮추는 것과 관련이 있는 것으로 나타났습니다.

이러한 연구 결과는

파킨슨병 진행에 있어 녹차 섭취의 역할에 대한 이해를 높이고

파킨슨병의 발병 기전을 탐구할 수 있는 새로운 표적을 제공했습니다.

이전의 관찰 연구에 따르면

녹차 섭취가 노인의 치매, 알츠하이머병, 인지 장애의 위험을 감소시킬 수 있다고 합니다(19).

그러나 이러한 효과가 다른 질환의 치매에도 적용되는지에 대해서는 연구가 덜 진행되었습니다. 유전적 관점에서 본 연구 결과는 녹차 섭취가 알츠하이머 치매에도 적용되는 보호 역할을 입증하여 녹차가 인지 장애에 대해 보편적으로 유리한 역할을 한다는 것을 시사합니다. 녹차가 어떻게 이러한 효과를 발휘하는지는 아직 밝혀지지 않았지만 몇 가지 잠재적인 메커니즘이 제안되었습니다(19).

첫 번째 메커니즘은

뇌에서 녹차 카테킨의 항산화 작용입니다.

산화 스트레스는 치매 발병에 관여하는 것으로 입증되었으며,

녹차의 카테킨은 2가 금속 이온을 킬레이트화하여 반응성 수산기 라디칼로 인한 산화를 방지할 수 있습니다(20).

치매는 노인에게 흔한 질환이지만 현재 치매를 예방하거나 치료할 수 있는 효과적인 치료법은 없습니다. 지난 10년 동안 폴리페놀(특히 커큐민, 레스베라트롤, 차 카테킨)은 신경 퇴행성 질환, 당뇨병, 염증성 질환 및 노화에 대한 잠재적 치료제로서 매우 면밀히 조사되어 왔습니다. '치매' 및 '커큐민', '레스베라트롤', 'EGCG', '차 카테킨' 키워드를 검색하여 2000년부터 2015년까지 Web of Science(ISI Web of Knowledge), Pubmed 및 Medline에서 데이터를 수집했습니다. 동일한 키워드를 사용하여 NIH clinicaltrials.gov 레지스트리에 기록된 임상시험 현황을 조사했습니다. 화합물의 본질적인 특성부터 시작하여 알츠하이머 치매 환자 및 가장 일반적인 치매 유형에 대한 구체적인 작용을 설명합니다. 커큐민, 레스베라트롤, 차 카테킨의 약리 작용은 주로 항산화 작용, 세포 신호 전달 경로와의 상호작용, 항염증 효과, 금속 이온의 킬레이트화, 신경 보호에 기인하는 것으로 알려져 있습니다. 폴리페놀에 대한 시험관 및 생체 내 연구를 통해 폴리페놀이 신경 퇴행과 관련된 질병을 예방하고 치료하는 데 필수적인 역할을 할 수 있음이 입증되었습니다. 또한 이러한 화합물의 실제 약리 작용과 가능한 부작용을 조사하는 임상시험을 비판적으로 분석합니다. 이 리뷰에서는 치매 예방/치료에 있어 폴리페놀의 잠재적 역할을 강조하고 현재 이 분야 연구의 한계에 대해 설명합니다.

킬레이션 요법은 금속의 독성 영향을 줄이기 위해 선호되는 치료법입니다. 킬레이트제는 독성 금속 이온과 결합하여 복잡한 구조를 형성하여 체내에서 쉽게 배출되어 세포 내 또는 세포 외 공간에서 제거할 수 있습니다. 2,3-디메르카프롤은 오랫동안 납 또는 비소 중독에 대한 킬레이션 치료의 주류를 차지해 왔지만, 심각한 부작용으로 인해 연구자들은 독성이 덜한 유사체를 개발하기 위해 노력해 왔습니다. 메소-2 ,3-디메르캅토숙신산과 같은 친수성 킬레이트는 신장의 금속 배설을 효과적으로 촉진하지만 세포 내 금속에 접근하는 능력은 약합니다. 이러한 단점을 해결하기 위한 병용 요법(구조적으로 다른 킬레이트제의 사용) 또는 항산화제의 병용 투여와 같은 새로운 전략이 최근 보고되고 있습니다. 이 리뷰에서는 기존의 킬레이트제와 중금속

둘째,

여러 뇌 염증 표지자는 모든 원인 치매의 위험과 관련이 있으며(21),

녹차 폴리페놀의 항염증 효과는 Nfkb 활성화 억제를 통해 뇌 염증을 줄일 수 있습니다.

셋째,

녹차 카테킨의 주성분인 에피갈로카테킨 갈레이트(EGCG)는

치매 발병과 밀접한 관련이 있는 아밀로이드 베타 응집을 억제하여

신경 보호 효과가 있습니다(22).

한편, 시험관 실험에서는 녹차 폴리페놀(GTP)이 도파민 뉴런을 보호하여 인지 기능에 도움이 될 수 있다고 제안했습니다(23). 또한 EGCG는 신경세포 사멸을 감소시키고 파킨슨병의 MPTP 마우스 모델에서 산화질소 합성효소(NOS) 발현을 유도하는 것으로 나타나 녹차의 신경 보호 역할에 대한 추가적인 증거를 제공했습니다(24). 또한, 녹차 섭취가 PD의 우울증에 대해 명목상 보호 역할을 한다는 결과도 제시했습니다. 우울증은 치매와 밀접한 관련이 있으며, 우울 증상은 치매로 이어질 뇌 기능 장애의 첫 징후로 간주됩니다. 노인의 우울증에 대한 녹차의 역할은 이전의 관찰 연구(25)에서 보고된 바 있습니다. 우리의 연구 결과는 이러한 보호 효과를 더욱 강화하고 이 효과의 스펙트럼을 PD로 확대했습니다. 정확한 메커니즘은 아직 밝혀지지 않았지만 녹차의 주요 성분인 L-테아닌과 EGCG가 중요한 역할을 할 수 있습니다(26, 27). 향후 임상 또는 기능적 연구를 통해 녹차 섭취가 치매와 치매성 우울증을 예방하는 방법을 알아보는 데 중요한 역할을 할 수 있습니다.

또한,

녹차가 후각소실과 불면증에 대해

명목상 보호 역할을 하는 것으로 나타났습니다.

이전 코호트 연구에 따르면

평생 카페인 섭취량이 적을수록

파킨슨병 환자의 친척에서 후각 이상과 관련이 있는 것으로 나타났습니다(28).

카페인은

녹차의 주요 성분이므로

녹차가 후각소실을 예방할 수도 있습니다.

또한 저카페인 녹차를 매일 섭취하면 스트레스 억제를 통해 노인의 수면의 질을 개선하는 데 도움이 될 수 있습니다(29). 그러나 상반된 결과도 보고되었습니다. 예를 들어, 한 연구에서는 카페인 투여가 76명의 저체온증 환자 그룹에서 저체온증에 거의 또는 전혀 영향을 미치지 않는 것으로 나타났습니다(30). 한편 녹차에 함유된 카페인은 불면증의 위험을 증가시킬 수도 있습니다. 이번 연구에서는 명목상의 연관성만 발견되었기 때문에 저산소증과 불면증에서 녹차 섭취의 역할을 탐구하기 위해서는 더 많은 연구가 필요합니다.

또한 녹차 섭취와 파킨슨병의 전반적인 운동 증상 진행을 설명하는 HY-3 단계(OR = 0.94, 95% CI: 0.89-1.00, P = 0.054)로의 진행 사이에 경계선 수준의 유의미한 연관성이 있는 것으로 나타났습니다(녹차 섭취와 파킨슨병의 전반적인 운동 증상 진행). 녹차는 미세아교세포 활성화를 조절하고 염증 매개체의 생성을 감소시킴으로써 이러한 효과를 발휘할 수 있습니다(31). 마찬가지로, 이전 임상 연구에 따르면 녹차를 마시면 항산화 상태를 개선하고 산화 손상을 줄일 수 있으며(32), 이는 녹차가 파킨슨병의 진행에 잠재적으로 유익한 역할을 할 수 있음을 시사합니다. 병리학적으로, 이전 연구에 따르면 EGCG는 α-시누클레인의 응집을 강력하게 억제하고 PC12 세포에서 독성을 예방하는 것으로 나타났습니다(33). 한편, EGCG는 또한 자연적으로 펼쳐진 α-시누클레인 폴리펩티드 사슬에 결합하여 비정형 올리고머의 형성을 매개하여 독성 β 구조의 형성을 방지할 수 있습니다. 이전 연구에 따르면 EGCG는 α-시누클레인 올리고머와 세포막 사이의 상호작용을 감소시켜 쥐 신경세포를 독성으로부터 보호할 수 있는 것으로 나타났습니다(34). 그러나 이전의 역학 연구에서는 차 섭취와 파킨슨병의 HY-3 단계에 도달하는 시간 사이의 연관성을 찾지 못했습니다(35). 따라서 녹차가 PD의 전반적인 진행에 관여하는지 여부와 그 방법을 더 잘 이해하기 위해서는 더 많은 증거가 필요했습니다.

반면, 녹차 섭취가 도움이 되는 것으로 나타난 통합 파킨슨병 평가 척도(UPDRS)와 같은 다른 증상의 경우, 이번 연구에서는 유의미한 연관성을 확인하지 못했습니다. 이는 파킨슨병의 다양한 증상의 발병 기전이 다르기 때문일 수 있습니다. 그러나 표본 크기가 충분하지 않아 연관성을 발견하지 못했을 가능성도 배제할 수 없습니다. 노출의 도구 변수에 의해 설명되는 중간 정도의 분산은 약한 인과 관계를 감지하는 힘을 제한했습니다. 더 큰 규모의 코호트를 대상으로 한 추가 검증이 여전히 필요했습니다.
결론적으로, MR 분석 결과를 바탕으로 녹차 섭취가 치매와 치매성 우울증에 대한 보호 효과를 입증했습니다. 이러한 결과는 치매 진행에서 녹차의 역할을 더 잘 이해하고 향후 임상 시험에서 치료제를 촉진하는 데 도움이 될 수 있으며, 치매 환자를위한 생활 습관 권장 사항을 제공 할 수도 있습니다.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

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Author Contributions

CL: research project—conception and execution, statistical analysis—design, execution, review and critique, and manuscript—writing of the first draft. JL: statistical analysis—execution, manuscript—writing of the first draft, and review and critique. TY: manuscript—review and critique. HS: research project—organization, statistical analysis—review and critique, and manuscript—review and critique. All authors contributed to the article and approved the submitted version.

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Funding

This research was supported by the funding of the National Key Research and Development Program of China (Grant Nos. 2021YFC2501203, and 2021YFC2501205), the Sichuan Science and Technology Program (Grant Nos. 2022ZDZX0023 and 2021YJ0415), and the National Natural Science Foundation of China (Grant Nos. 81901294 and 81871000). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript.

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Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be eval‎uated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Glossary

Abbreviations

AAO	age at onset
ADL	activities of daily living
GWAS	genome-wide association study
HY	Hoehn and Yahr score
IVW	inverse variance weighted
LD	linkage disequilibrium
MR	Mendelian randomization
SEADL	the Schwab and England ADL
PD	Parkinson's disease
SNP	single nucleotide polymorphism
UPDRS	the Unified Parkinson's Disease Rating Scale.

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Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnut.2022.848223/full#supplementary-material

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References

Front Nutr. 2022; 9: 848223.

Published online 2022 May 26. doi: 10.3389/fnut.2022.848223

PMCID: PMC9199515

PMID: 35719152

Green Tea Intake and Parkinson's Disease Progression: A Mendelian Randomization Study

Chunyu Li, Junyu Lin, Tianmi Yang, and Huifang Shang

 *

Author information Article notes Copyright and License information PMC Disclaimer

Associated DataSupplementary MaterialsData Availability Statement

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Abstract

Epidemiological studies have suggested green tea intake was associated with a reduced risk of Parkinson's disease (PD). However, whether green tea intake has an effect on PD progression is unknown. To eval‎uate the role of green tea intake in PD progression, we conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of green tea intake (N = 64,949), age at onset (N = 28,568) and progression (N = 4,093) of PD. One standard deviation increase in genetically determined green tea intake was significantly associated with slower progression to dementia (OR: 0.87, 95% CI: 0.81–0.94, P: 3.48E−04) after the Bonferroni correction. Meanwhile, higher green tea intake was nominally associated with slower progression to depression, and lower risk of dementia, depression, hyposmia and insomnia at baseline. The results were robust under all sensitivity analyses. These results might facilitate novel therapeutic targets to slow down the progression of PD in clinical trials, and have clinical implications for patients with PD.

Keywords: green tea intake, Parkinson's disease, Mendelian randomization, age at onset, progression

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Introduction

Parkinson's disease (PD) is a complex progressive neurodegenerative disorder with a wide range of phenotypes like motor, cognitive and affective manifestations (1, 2), which is further entangled by heterogeneous age at onset (AAO) and symptom progression between individuals (3). The interplay of multiple factors like aging, genetics and environmental factors might contribute to such heterogeneity (4). Identifying risk factors for PD progression could help better understand the pathogenesis of the disease, and provide care and therapeutic strategies for patients and clinicians.

Green tea, a widely-consumed beverage, was suggested to have health benefits against cancer, cardiovascular diseases, diabetes and several neurodegenerative disorders including PD (5). Previous case-control designed studies have identified an inverse association between tea intake and risk of PD (6, 7). Pathologically, several potential mechanisms for the protective role of green tea against PD have also been proposed, like the antioxidant potential of green tea in combating oxidative stress and alleviating mitochondrial dysfunction (8). As for the progression of PD, a previous study among 278 patients with PD found that consumption of tea more than 3 cups per day could delay the onset age of motor symptoms (9). However, a recent prospective cohort study investigating lifestyle factors and the progression of PD found that caffeinated tea was associated with reduced mortality but not progression (10). Similarly, a systematic review of prospective longitudinal studies found evidence for a protective role of tea intake against the risk for PD, but not progression of PD (11). Therefore, whether green tea intake has a beneficial role in the progression of PD is still unknown. Meanwhile, the observational studies might be biased by unavoidable confounding factors and relatively small sample size, and cannot determine causation.

In this context, we performed a two-sample Mendelian randomization (MR) analysis to explore the causal role of green tea intake in the progression of PD (Supplementary Figure 1). The MR approach is not susceptible to reverse causation or confounding factors which may distort interpretations of conventional observational studies. As a result, we found that green tea intake was causally associated with a lower risk of dementia in PD.

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Methods

Datasets

We obtained summary statistics of green tea intake from a genome-wide association study (GWAS) based on the UK Biobank data (N = 64,949). Green tea intake was measured by “How many cups/mugs of green tea did you drink yesterday?” in the UK Biobank (data field: 100420). The summary statistics were generated from regression on green tea intake adjusting for sex and principal components after excluding poor quality samples. The detailed design like quality control procedures and statistical analyses could be found at http://www.nealelab.is/uk-biobank/. Single nucleotide polymorphisms (SNP) that passed the genome-wide significance threshold (P < 5E−08) were chosen as instrumental variables, which were then clumped based on the 1,000 Genomes Project linkage disequilibrium (LD) structure. Index SNPs (R2 < 0.001 with any other associated SNP within 10 Mb) with the minimum P value were kept. Furthermore, we used the PhenoScanner v2 tool to check for variants associated with other phenotypes (P < 5E−08) which might affect the progression of PD independent of green tea intake (12).

Summary statistics of AAO of PD were from GWAS based on 28,568 PD patients of European ancestry (13). For the progression of PD, we obtained summary data from a large GWAS on clinical biomarkers of PD such as the Hoehn-Yahr (HY) stage in 12 longitudinal PD cohorts (N = 4,093) (14). A total of 28 clinical progression phenotypes were analyzed. Harmonization was undertaken to rule out strand mismatches and ensure alignment of SNP effect sizes.

Mendelian Randomization Analysis

We hypothesized that green tea intake as a protective factor could causally decrease the risk of specific symptom progression in PD, and the following assumptions were satisfied: the genetic variants used as instrumental variables are associated with green tea intake; the genetic variants are not associated with confounders; the genetic variants are associated with PD progression through green tea intake (namely horizontal pleiotropy should not be present) (Supplementary Figure 2).

To eval‎uate the causative effect of green tea intake on the progression of PD, we performed a two-sample MR analysis using the random effects inverse variance weighted (IVW) method, which is most widely used in MR studies and could provide robust causal estimates under the absence of directional pleiotropy. A P value below 1.79E−03 (0.05/28) was considered statistically significant after the Bonferroni correction. For the significant association, we further verified the results using another three MR methods, namely MR Egger regression, weighted median and weighted mode. In addition, we conducted comprehensive sensitivity analyses to estimate potential violation of the model assumptions in the MR analysis. We conducted Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) analysis and leave-one-out analysis to detect outlier instrumental variables (15). Outlier instrumental variables identified by the MR-PRESSO analysis were removed step-by-step to reduce the effect of horizontal pleiotropy. Cochran's Q test was executed to check heterogeneity across the individual causal effects. MR-Egger regression was performed to eval‎uate the pleiotropy of instrumental variables (16). To eval‎uate the strongness of each instrumental variable, we computed the F-statistic of each SNP as described earlier (17). The statistical analyses were conducted using the R package TwoSampleMR 0.5.5 (18).

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Results

We analyzed the role of green tea intake in the progression of PD using the two-sample MR approach. Results showed that each standard deviation increase in green tea intake was significantly associated with slower progression to dementia (OR: 0.87, 95% CI: 0.81–0.94, P: 3.48E−04) after the Bonferroni correction (Figure 1). Such association was further verified using the other three MR methods (Figure 2). Consistently, green tea intake was nominally associated with a lower risk of dementia at baseline, suggesting a protective role of green tea against cognitive impairment in PD. In addition, nominal association was observed between green tea intake and slower progression to depression, and lower risk of depression, hyposmia and insomnia at baseline (Figure 1).

Figure 1

Forest plot showing Mendelian randomization analysis results to eval‎uate the causal association between green tea intake and progression of PD. Results above the dashed line are for symptoms collected at baseline, while results below the dashed line are from survival analysis on symptom progression during follow-up. SEADL, Schwab and England Activities of Daily Living Scale; UPDRS, Unified Parkinson Disease Rating Scale; HY-3, Hoehn Yahr scale 3 or greater; RBD, REM sleep behavior disorder; SEADL70, SEADL of 70 or less. aDenotes statistical significance, while bdenotes nominal significance.

Figure 2

Mendelian randomization analysis results for green tea intake and dementia of PD. (A) Forest plot showing Mendelian randomization (MR) analysis results to eval‎uate the causal association between green tea intake and progression to dementia using four methods. (B) Scatter plot of single nucleotide polymorphism (SNP) potential effects on green tea intake and dementia of PD. The 95% CI for the effect size on green tea intake is shown as vertical lines, while the 95% CI for the effect size on dementia of PD is shown as horizontal lines. The slope of fitted lines represents the estimated MR effect per method. (C) Funnel plot for green tea intake shows the estimation using the inverse of the standard error of the causal estimate with each individual SNP as a tool. The vertical line represents the estimated causal effect obtained using IVW and MR-Egger methods.

Next, we performed sensitivity analyses to validate the causal association between green tea intake and the progression of PD. No heterogeneity of effects was detected by Cochran's Q test (Table 1). The F statistics of all the instrumental variables were above 10 (ranging from 30 to 44), indicating absence of weakness in the selected instrumental variables. No apparent horizontal pleiotropy was observed as the intercept of MR-Egger was not significantly deviated from zero (Table 1). Meanwhile, no potential instrumental outlier was detected at the nominal significance level of 0.05 by the MR-PRESSO analysis (Table 1). The leave-one-out results suggested that the causal effect was not driven by a single instrumental variable (Supplementary Figures 3–7). Lastly, we used the PhenoScanner tool to check if the SNPs used in the MR analysis were associated with other phenotypes. As a result, no instrumental variable was associated with other phenotypes which might affect the progression of PD independent of green tea intake (Supplementary Table 1).

Table 1

Heterogeneity and horizontal pleiotropy analyses between green tea intake and PD progression.

TraitHeterogeneityHorizontal pleiotropyMR-PRESSOIVW QIVW Q dfIVW P valueEgger interceptSEP valueP value

Constipation	8.51	12	0.74	0.12	0.2	0.55	0.78
Dementia	7.96	17	0.97	0.13	0.2	0.51	0.96
Depression	4.38	10	0.93	−0.62	0.81	0.47	0.92
Dyskinesia	7.2	10	0.71	0.32	0.42	0.47	0.7
HY-3	9.28	10	0.51	0.70	0.33	0.06	0.49
Hyposmia	6.33	14	0.96	0.13	0.18	0.48	0.97
Insomnia	7.26	14	0.92	0.09	0.17	0.63	0.94
Motor fluctuation	8.46	10	0.58	−0.07	0.36	0.86	0.56
RBD	11.06	12	0.52	0.31	0.28	0.29	0.53
Daytime sleepiness	10.11	10	0.43	0.48	0.61	0.45	0.45
Age at onset	2.63	4	0.62	0.03	0.32	0.92	0.64
HY	8.93	19	0.98	−0.02	0.02	0.26	0.98
SEADL	18.17	16	0.31	0.69	0.6	0.27	0.33
UPDRS1	15.04	12	0.24	2.75E−03	0.12	0.98	0.28
UPDRS2	13.95	12	0.3	−0.24	0.11	0.05	0.3
UPDRS3	12.23	16	0.73	−0.06	0.07	0.38	0.79
UPDRS4	11.01	9	0.28	0.1	0.15	0.51	0.3
UPDRS	9	17	0.94	−0.07	0.06	0.27	0.94
Constipation	8.87	8	0.35	0.25	0.16	0.17	0.34
Dementia	10.72	13	0.63	0.12	0.17	0.51	0.67
Depression	2.61	6	0.86	0.11	0.27	0.7	0.88
Dyskinesia	5.72	11	0.89	0.01	0.18	0.97	0.9
HY-3	13.71	17	0.69	−0.002	0.12	0.99	0.67
Insomnia	9.19	13	0.76	0.13	0.15	0.4	0.76
Motor fluctuation	10.98	14	0.69	0.01	0.13	0.92	70
RBD	14.12	13	0.37	0.54	0.24	0.04	0.36
SEADL70	7.45	14	0.92	−0.07	0.23	0.76	0.94
Daytime sleepiness	15.15	12	0.23	−0.06	0.2	0.78	0.17

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IVW, Inverse variance weighted; Q, Cochran's Q test estimate; df, Cochran's Q test degrees of freedom; SE, standard error.

Results above the dashed line were for symptoms collected at baseline, while results below the dashed line were from survival analysis on symptom progression during follow-up.

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Discussion

Previous epidemiological studies have suggested green tea intake has a protective effect against risk of PD, but whether it could slow down the progression of PD is less explored. Meanwhile, unmeasured confounding factors in clinical studies might potentially bias the association evidence, as is a common criticism inherent to observational studies. Therefore, we investigated the role of green tea intake in the progression of PD using the MR approach. The results demonstrated a protective role of great tea intake against the risk of dementia and depression in PD. Meanwhile, green tea intake was nominally associated with a lower risk of hyposmia and insomnia for patients with PD at baseline. These findings provided a better understanding of the role of green tea intake in the progression of PD, and provided novel targets to explore the pathogenesis of PD.

Previous observational studies have suggested that green tea intake might reduce the risk of dementia, Alzheimer's disease, and cognitive impairment in the elderly (19). However, whether the effect applies to dementia in other disorders was less explored. From a genetic perspective, our results demonstrated the protective role of green tea intake applied to dementia in PD as well, suggesting a universal favorable role of green tea against cognitive impairment. Though how green tea exerts this effect is still unknown, several potential mechanisms have been proposed (19). The first mechanism is the antioxidant activity of green tea catechins in the brain. Oxidative stress has been demonstrated to be involved in the pathogenesis of dementia, while catechins in green tea could chelate bivalent metal ions and prevent oxidation caused by reactive hydroxyl radicals (20). Secondly, several brain inflammatory markers are associated with the risk of all-cause dementia (21), while the anti-inflammatory effects of green tea polyphenols through the inhibition of nuclear factor kappa-beta activation could reduce brain inflammation. Thirdly, epigallocatechin gallate (EGCG), the main component of green tea catechins, has neuroprotective effects due to its inhibition of amyloid-beta aggregation which is closely related to the pathogenesis of dementia (22). Meanwhile, in vitro experiments suggested that green tea polyphenols (GTP) could protect dopamine neurons and thus might be beneficial to cognitive function (23). And EGCG was suggested to reduce neuronal cell death and induce nitric oxide synthase (NOS) expression‎ in an MPTP mouse model of PD, which provided further evidence for the neuroprotective role of green tea (24). Additionally, our results also suggested a nominal protective role of green tea intake against depression of PD. Depression is closely related to dementia, and depressive symptoms are considered as the first glimpse of the brain failure that will lead to dementia. The role of green tea against depression in the elderly has been reported by previous observational studies (25). Our results further strengthened this protective effect and broadened the spectrum of this effect to PD. Though the exact mechanism remains elusive, the main components of green tea, namely L-theanine and EGCG might play a role (26, 27). Future clinical or functional studies could attach importance to this in exploring how green tea intake protects against dementia and depression in PD.

Besides, we noticed a nominal protective role of green tea against hyposmia and insomnia at baseline. A previous cohort study found that lower lifetime caffeine consumption was associated with abnormal olfaction in relatives of patients with PD (28). Since caffeine was a major component of green tea, green tea might protect against hyposmia as well. Additionally, daily ingestion of low-caffeine green tea might be beneficial for improving the sleep quality of the elderly via the suppression of stress (29). However, contradictory results have also been reported. For example, one study found that caffeine administration had little or no effect on hyposmia in a group of 76 hyposmic individuals (30). Meanwhile, the caffeine within green tea might also increase the risk of insomnia. Since only nominal association was detected in the current study, further exploration was still necessary to explore the role of green tea intake in hyposmia and insomnia.

In addition, we also noticed an association with borderline significance between green tea intake and progression to HY-3 stage (OR = 0.94, 95 % CI: 0.89–1.00, P = 0.054), which described the overall motor symptom progression of PD. Green tea might exert this effect by modulating microglia activation and decreasing the production of inflammatory mediators (31). Similarly, a previous clinical study found that drinking green tea could improve antioxidant status and reduce oxidative damage (32), suggesting the potential beneficial role of green tea in the progression of PD. Pathologically, a previous study has shown that EGCG strongly inhibited the aggregation of α-synuclein and prevented toxicity in PC12 cells (33). Meanwhile, EGCG could also bind to the native unfolded α-synuclein polypeptide chain and prevent the formation of toxic β structures by mediating the formation of the unstructured oligomer. Previous study has shown that EGCG could reduce interaction between α-synuclein oligomers and cell membranes and thus protect rat neuronal cells from toxicity (34). However, a previous epidemiological study did not find an association between tea intake and the time to reach the HY-3 stage of PD (35). Therefore, more evidence was necessary to better understand whether and how green tea was involved in the overall progression of PD.

In contrast, for other symptoms like the Unified Parkinson's Disease Rating Scale (UPDRS) which was shown to benefit from green tea intake, we did not identify a significant association in the current study. This might be due to the different pathogenesis of various symptoms in PD. However, we cannot exclude the possibility that we failed to detect the association due to the insufficiency of the sample sizes. The moderate variance explained by the instrumental variables of the exposure limited the power to detect weaker causal associations. Further validations in larger cohorts were still necessary.

In conclusion, based on results from the MR analysis, we demonstrated a protective effect of green tea intake against dementia and depression of PD. These results could help better understand the role of green tea in the progression of PD, will facilitate therapeutic drugs in the future clinical trials, and also provide some lifestyle recommendation for the patients with PD.

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Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

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Author Contributions

CL: research project—conception and execution, statistical analysis—design, execution, review and critique, and manuscript—writing of the first draft. JL: statistical analysis—execution, manuscript—writing of the first draft, and review and critique. TY: manuscript—review and critique. HS: research project—organization, statistical analysis—review and critique, and manuscript—review and critique. All authors contributed to the article and approved the submitted version.

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Funding

This research was supported by the funding of the National Key Research and Development Program of China (Grant Nos. 2021YFC2501203, and 2021YFC2501205), the Sichuan Science and Technology Program (Grant Nos. 2022ZDZX0023 and 2021YJ0415), and the National Natural Science Foundation of China (Grant Nos. 81901294 and 81871000). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript.

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Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be eval‎uated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Glossary

Abbreviations

AAO	age at onset
ADL	activities of daily living
GWAS	genome-wide association study
HY	Hoehn and Yahr score
IVW	inverse variance weighted
LD	linkage disequilibrium
MR	Mendelian randomization
SEADL	the Schwab and England ADL
PD	Parkinson's disease
SNP	single nucleotide polymorphism
UPDRS	the Unified Parkinson's Disease Rating Scale.

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Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnut.2022.848223/full#supplementary-material

Click here for additional data file.(538K, PDF)

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References