上海交通大学学报（医学版）

上海交通大学学报（医学版） >

2025 , Vol. 45 >Issue 1: 87 - 94

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.01.010

论著 · 公共卫生

空气污染与阿尔茨海默病因果关联的两样本孟德尔随机化研究

  • 张迎迎 ,
  • 张俊瑶 ,
  • 宋际伟 ,
  • 王声杰 ,
  • 姚俊岩
展开
  • 1.上海交通大学医学院附属第一人民医院麻醉科，上海 200080
    2.同济大学附属东方医院麻醉科，上海 200120
张迎迎（1999—），女，硕士生；电子信箱：yingying1232022@163.com。
姚俊岩，博士，主任医师；电子信箱：sunshineyao@163.com。

收稿日期: 2024-06-10

  录用日期: 2024-10-02

  网络出版日期: 2025-01-17

基金资助

国家自然科学基金(82171183);上海市浦东新区卫生健康委员会医学人才培养项目(PWR12023-01)

收起

Two-sample Mendelian randomization study on the causal association between air pollution and Alzheimer′s disease

  • ZHANG Yingying ,
  • ZHANG Junyao ,
  • SONG Jiwei ,
  • WANG Shengjie ,
  • YAO Junyan
Expand
  • 1.Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
    2.Department of Anesthesiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
YAO Junyan, E-mail: sunshineyao@163.com.

Received date: 2024-06-10

  Accepted date: 2024-10-02

  Online published: 2025-01-17

Supported by

National Natural Science Foundation of China(82171183);Medical Talent Training Program of Shanghai Pudong New Area Health Commission(PWR12023-01)

Fold

摘要

目的·利用两样本孟德尔随机化（Mendelian randomization，MR）的方法探究空气污染与阿尔茨海默病（Alzheimer′s disease，AD）发病风险之间的因果关系。方法·基于全基因组关联研究（genome-wide association study，GWAS）的数据，采用两样本MR分析评估空气污染与AD发病风险的因果关系。以空气污染指标包括细颗粒物（particulate matter 2.5，PM2.5）、粗颗粒物（particulate matter 2.5-10，PM2.5-10）、可吸入颗粒物（particulate matter 10，PM10）、二氧化氮以及氮氧化物为暴露因素，从英国生物银行（UK Biobank）数据库中获得其汇总数据。PM2.5的数据集包括暴露人群423 796例，包含9 851 867个单核苷酸多态性（single nucleotide polymorphisms，SNPs）的关联分析；PM2.5-10的数据集包括暴露人群423 796例，包含9 851 867个SNPs的关联分析；PM10的数据集包括暴露人群455 314例，包含9 851 867个SNPs的关联分析；二氧化氮的数据集包括暴露人群456 380例，包含9 851 867个SNPs的关联分析；氮氧化物的数据集包括暴露人群456 380例，包含9 851 867个SNPs的关联分析。以AD为结局因素，从国际阿尔茨海默病基因组学项目（International Genomics of Alzheimer′s Project，IGAP）中获得AD的数据。AD的数据集包括患者25 580例和对照人群48 466例，包含7 067 513个SNPs的关联分析。以与AD显著相关的SNPs作为工具变量，以逆方差加权（inverse variance weighted，IVW）法为主要分析方法，选择加权中位数法、MR-Egger回归、基于众数的简单估计和基于众数的加权估计4种方法进行质量控制，并通过异质性检验、基因多效性检验和敏感性分析来评估研究结果的可靠性。结果·异质性检验（IVW法和MR-Egger回归）显示，空气污染指标与AD的SNP之间不存在异质性（均P>0.05）。基因多效性检验（MR-Egger回归）显示，未检测到多效性（P>0.05）。敏感性分析显示，PM2.5的研究结果稳定。IVW法的分析结果发现，在欧洲人群中PM2.5（P<0.001）与AD之间存在统计学关联，而PM2.5-10（P=0.664）、PM10（P=0.664）、二氧化氮（P=0.284）、氮氧化物（P=0.567）这4种因素与AD之间不存在统计学关联。结论·PM2.5暴露与AD发病风险之间存在显著的因果关系，PM2.5的暴露会增加AD的发病风险，但尚未发现PM2.5-10、PM10、二氧化氮和氮氧化物暴露导致AD发病风险增加的证据。

关键词： 阿尔茨海默病; 空气污染; 孟德尔随机化; 因果推断

本文引用格式

张迎迎 , 张俊瑶 , 宋际伟 , 王声杰 , 姚俊岩 . 空气污染与阿尔茨海默病因果关联的两样本孟德尔随机化研究[J]. 上海交通大学学报（医学版）, 2025 , 45(1) : 87 -94 . DOI: 10.3969/j.issn.1674-8115.2025.01.010

Abstract

Objective ·To explore the causal relationship between air pollution and the risk of Alzheimer′s disease (AD) by using two-sample Mendelian randomization (MR). Methods ·Based on the data from the genome-wide association study (GWAS), a two-sample MR analysis was conducted to evaluate the causal relationship between air pollution and the risk of AD. Air pollution indicators, including particulate matter 2.5 (PM2.5), particulate matter 2.5-10 (PM2.5-10), particulate matter 10 (PM10), nitrogen dioxide and nitrogen oxides, were used as exposure factors, and summarized data were aggregated from the UK Biobank database. The PM2.5 dataset included 423 796 cases, with correlation analysis conducted on 9 851 867 single nucleotide polymorphisms (SNPs); the PM2.5-10 dataset included 423 796 cases, with correlation analysis conducted on 9 851 867 SNPs; the PM10 dataset included 455 314 cases, with correlation analysis conducted on 9 851 867 SNPs; the nitrogen dioxide dataset included 456 380 cases, with correlation analysis conducted on 9 851 867 SNPs; the nitrogen oxides dataset included 456 380 cases, with correlation analysis conducted on 9 851 867 SNPs. AD was used as the outcome factor, and data were obtained from the International Genomics of Alzheimer′s Project (IGAP). The AD dataset included 25 580 cases and 48 466 controls, with correlation analysis of 7 067 513 SNPs. SNPs significantly associated with AD were used as instrumental variables. The main analysis was conducted by using the inverse variance weighted (IVW) method, and four methods including weighted median, MR-Egger regression, mode-based simple estimation and mode-based weighted estimation were used for quality control. Heterogeneity testing, gene pleiotropy testing and sensitivity analysis were conducted to assess the reliability of the study results. Results ·Heterogeneity testing indicated no evidence of heterogeneity among SNPs associated with air pollution indicators and AD (both IVW and MR-Egger results, P>0.05). Gene pleiotropy testing did not detect any pleiotropic effects (MR-Egger results, P>0.05). Sensitivity analysis confirmed the stability of the PM2.5 results. IVW analysis revealed a statistically significant association between PM2.5 and AD in European populations (P<0.001), while no statistically significant associations were observed between PM2.5-10 (P=0.664), PM10 (P=0.664), nitrogen dioxide (P=0.284), nitrogen oxides (P=0.567) and AD. Conclusion ·There is a significant causal relationship between PM2.5 exposure and the risk of AD, with PM2.5 exposure increasing the incidence of AD. However, no evidence has been found to suggest that PM2.5-10, PM10, nitrogen dioxide or nitrogen oxides cause an increased risk of AD.

Key words： Alzheimer′s disease (AD); air pollution; Mendelian randomization (MR); causal inference

参考文献

1 THIANKHAW K, CHATTIPAKORN N, CHATTIPAKORN S C. PM2.5 exposure in association with AD-related neuropathology and cognitive outcomes[J]. Environ Pollut, 2022, 292(Pt A): 118320.
2 SCHELTENS P, DE STROOPER B, KIVIPELTO M, et al. Alzheimer′s disease[J]. Lancet, 2021, 397(10284): 1577-1590.
3 CHOI J, OH J Y, LEE Y S, et al. Harmful impact of air pollution on severe acute exacerbation of chronic obstructive pulmonary disease: particulate matter is hazardous[J]. Int J Chron Obstruct Pulmon Dis, 2018, 13: 1053-1059.
4 AKIMOTO H. Global air quality and pollution[J]. Science, 2003, 302(5651): 1716-1719.
5 SHOU Y K, HUANG Y L, ZHU X Z, et al. A review of the possible associations between ambient PM2.5 exposures and the development of Alzheimer′s disease[J]. Ecotoxicol Environ Saf, 2019, 174: 344-352.
6 CHEN J C, SCHWARTZ J. Neurobehavioral effects of ambient air pollution on cognitive performance in US adults[J]. Neurotoxicology, 2009, 30(2): 231-239.
7 LIU X Q, HUANG J, SONG C, et al. Neurodevelopmental toxicity induced by PM2.5 exposure and its possible role in neurodegenerative and mental disorders[J]. Hum Exp Toxicol, 2023, 42: 9603271231191436.
8 KATIKIREDDI S V, GREEN M J, TAYLOR A E, et al. Assessing causal relationships using genetic proxies for exposures: an introduction to Mendelian randomization[J]. Addiction, 2018, 113(4): 764-774.
9 CHANG L, ZHOU G Y, XIA J G. mGWAS-explorer 2.0: causal analysis and interpretation of metabolite-phenotype associations[J]. Metabolites, 2023, 13(7): 826.
10 LAMBERT J C, IBRAHIM-VERBAAS C A, HAROLD D, et al. Meta-analysis of 74 046 individuals identifies 11 new susceptibility loci for Alzheimer′s disease[J]. Nat Genet, 2013, 45(12): 1452-1458.
11 SANDERSON E, DAVEY SMITH G, WINDMEIJER F, et al. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings[J]. Int J Epidemiol, 2019, 48(3): 713-727.
12 ZENG Y J, CAO S, YANG H. The causal role of gastroesophageal reflux disease in anxiety disorders and depression: a bidirectional Mendelian randomization study[J]. Front Psychiatry, 2023, 14: 1135923.
13 BOWDEN J, DAVEY SMITH G, HAYCOCK P C, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted Median estimator[J]. Genet Epidemiol, 2016, 40(4): 304-314.
14 BOWDEN J, DAVEY SMITH G, BURGESS S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression[J]. Int J Epidemiol, 2015, 44(2): 512-525.
15 YAVORSKA O O, BURGESS S. MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data[J]. Int J Epidemiol, 2017, 46(6): 1734-1739.
16 HAYREH S S. Ocular vascular occlusive disorders: natural history of visual outcome[J]. Prog Retin Eye Res, 2014, 41: 1-25.
17 PIERCE B L, BURGESS S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators[J]. Am J Epidemiol, 2013, 178(7): 1177-1184.
18 WU J, GRANDE G, STAFOGGIA M, et al. Air pollution as a risk factor for Cognitive Impairment no Dementia (CIND) and its progression to dementia: a longitudinal study[J]. Environ Int, 2022, 160: 107067.
19 SHI L H, WU X, DANESH YAZDI M, et al. Long-term effects of PM2.5 on neurological disorders in the American Medicare population: a longitudinal cohort study[J]. Lancet Planet Health, 2020, 4(12): e557-e565.
20 URBANO T, CHIARI A, MALAGOLI C, et al. Particulate matter exposure from motorized traffic and risk of conversion from mild cognitive impairment to dementia: an Italian prospective cohort study[J]. Environ Res, 2023, 222: 115425.
21 TZIVIAN L, DLUGAJ M, WINKLER A, et al. Long-term air pollution and traffic noise exposures and mild cognitive impairment in older adults: a cross-sectional analysis of the heinz nixdorf recall study[J]. Environ Health Perspect, 2016, 124(9): 1361-1368.
22 JUNG C R, LIN Y T, HWANG B F. Ozone, particulate matter, and newly diagnosed Alzheimer′s disease: a population-based cohort study in Taiwan[J]. J Alzheimers Dis, 2015, 44(2): 573-584.
23 POWER M C, WEISSKOPF M G, ALEXEEFF S E, et al. Traffic-related air pollution and cognitive function in a cohort of older men[J]. Environ Health Perspect, 2011, 119(5): 682-687.
24 OUDIN A, FORSBERG B, ADOLFSSON A N, et al. Traffic-related air pollution and dementia incidence in northern Sweden: a longitudinal study[J]. Environ Health Perspect, 2016, 124(3): 306-312.
25 WEUVE J, PUETT R C, SCHWARTZ J, et al. Exposure to particulate air pollution and cognitive decline in older women[J]. Arch Intern Med, 2012, 172(3): 219-227.
26 AILSHIRE J A, CRIMMINS E M. Fine particulate matter air pollution and cognitive function among older US adults[J]. Am J Epidemiol, 2014, 180(4): 359-366.
27 LI W, LIN G H, XIAO Z X, et al. A review of respirable fine particulate matter (PM2.5)-induced brain damage[J]. Front Mol Neurosci, 2022, 15: 967174.
28 HUANG W J, ZHANG X, CHEN W W. Role of oxidative stress in Alzheimer′s disease[J]. Biomed Rep, 2016, 4(5): 519-522.
29 BLOCK M L, CALDERóN-GARCIDUE?AS L. Air pollution: mechanisms of neuroinflammation and CNS disease[J]. Trends Neurosci, 2009, 32(9): 506-516.
30 CACCIOTTOLO M, WANG X, DRISCOLL I, et al. Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models[J]. Transl Psychiatry, 2017, 7(1): e1022.
31 KILIAN J, KITAZAWA M. The emerging risk of exposure to air pollution on cognitive decline and Alzheimer′s disease: evidence from epidemiological and animal studies[J]. Biomed J, 2018, 41(3): 141-162.
32 COSTA L G, COLE T B, DAO K, et al. Effects of air pollution on the nervous system and its possible role in neurodevelopmental and neurodegenerative disorders[J]. Pharmacol Ther, 2020, 210: 107523.
33 CALDERóN-GARCIDUE?AS L, REED W, MARONPOT R R, et al. Brain inflammation and Alzheimer′s-like pathology in individuals exposed to severe air pollution[J]. Toxicol Pathol, 2004, 32(6): 650-658.
34 CASEY E, LI Z J, LIANG D H, et al. Association between fine particulate matter exposure and cerebrospinal fluid biomarkers of Alzheimer′s disease among a cognitively healthy population-based cohort[J]. Environ Health Perspect, 2024, 132(4): 47001.
35 KU T T, LI B, GAO R, et al. NF-κB-regulated microRNA-574-5p underlies synaptic and cognitive impairment in response to atmospheric PM2.5 aspiration[J]. Part Fibre Toxicol, 2017, 14(1): 34.
36 FROST B. Alzheimer′s disease and related tauopathies: disorders of disrupted neuronal identity[J]. Trends Neurosci, 2023, 46(10): 797-813.
37 CALDERóN-GARCIDUE?AS L, AVILA-RAMíREZ J, CALDERóN-GARCIDUE?AS A, et al. Cerebrospinal fluid biomarkers in highly exposed PM2.5 urbanites: the risk of Alzheimer′s and Parkinson′s diseases in young Mexico city residents[J]. J Alzheimers Dis, 2016, 54(2): 597-613.
38 CALDERóN-GARCIDUE?AS L, MUKHERJEE P S, WANIEK K, et al. Non-phosphorylated tau in cerebrospinal fluid is a marker of Alzheimer′s disease continuum in young urbanites exposed to air pollution[J]. J Alzheimers Dis, 2018, 66(4): 1437-1451.
39 SCHEFF S W, PRICE D A, SCHMITT F A, et al. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment[J]. Neurology, 2007, 68(18): 1501-1508.
Options
文章导航

/

〈 〉