Inflammatory Diseases, Inflammatory Biomarkers, and Alzheimer Disease: An Observational Analysis and Mendelian Randomization.
Inflammatory Diseases, Inflammatory Biomarkers, and Alzheimer Disease: An Observational Analysis and Mendelian Randomization.
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DOI：
10.1212/wnl.0000000000201489
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发表时间：
2023-02-07
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影响因子：
9.9
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中科院分区：
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慢性自身免疫性炎症性疾病是否会影响阿尔茨海默病（AD）的发病风险仍存在争议。我们描述了炎性疾病和AD风险之间的关系，并探讨了循环炎性生物标志物在炎性疾病和AD之间关系中的作用。我们使用英国临床实践研究数据链（CPRD）中确定的2，047，513名参与者的数据对慢性自身免疫性炎症性疾病和AD风险进行了观察性分析。使用来自15个大规模全基因组关联研究数据集的总计超过1，100，000人的数据，我们进行了2样本孟德尔随机化（MR），以研究慢性自身免疫性炎症性疾病，循环炎症生物标志物水平和AD风险之间的关系。使用CPRD数据的考克斯回归模型显示，炎症性肠病患者中AD的总体发病率较高（风险比[HR] 1.17; 95% CI 1.15-1.19; p = 2.1 × 10−4），其他炎性多关节病和系统性结缔组织疾病（HR 1.13; 95% CI 1.12-1.14; p = 8.6 × 10−5），银屑病（HR 1.13; 95% CI 1.10-1.16; p = 2.6 × 10−4），类风湿性关节炎（HR 1.08; 95% CI 1.06-1.11; p = 4.0 × 10−4）和多发性硬化症（HR 1.06; 95% CI 1.04-1.07; p = 2.8 × 10−4）与年龄（±5岁）和性别匹配的对照组相比，无研究中的所有炎性疾病。双向MR分析确定了慢性自身免疫性炎性疾病和循环炎性生物标志物之间的关系。特别是，γ干扰素（IFN）水平诱导的循环单核因子与AD的高风险（逆方差加权比值比[ORIVW] 1.23; 95% CI 1.06-1.42; pIVW = 0.007）和克罗恩病的低风险（ORIVW 0.73; 95% CI −0.62至0.86; pIVW = 1.3 × 10−4）相关。共定位支持共同的因果单核苷酸多态性的克罗恩病和克罗恩病（后验概率= 0.74），但不是AD（后验概率= 0.03）。使用双样本MR方法，炎症性疾病的遗传预测风险与较高的AD风险无关。我们的数据表明，炎症性疾病和AD风险之间的关联不太可能是因果关系，可能是混杂的结果。作为支持，尽管炎症生物标志物显示与炎症性疾病存在因果关系的证据，但它们影响炎症性疾病和AD的证据很弱。
Whether chronic autoimmune inflammatory diseases causally affect the risk of Alzheimer disease (AD) is controversial. We characterized the relationship between inflammatory diseases and risk of AD and explored the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large-scale genome-wide association study data sets, we performed 2-sample Mendelian randomizations (MRs) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. Cox regression models using CPRD data showed that the overall incidence of AD was higher among patients with inflammatory bowel disease (hazard ratio [HR] 1.17; 95% CI 1.15–1.19; p = 2.1 × 10−4), other inflammatory polyarthropathies and systematic connective tissue disorders (HR 1.13; 95% CI 1.12–1.14; p = 8.6 × 10−5), psoriasis (HR 1.13; 95% CI 1.10–1.16; p = 2.6 × 10−4), rheumatoid arthritis (HR 1.08; 95% CI 1.06–1.11; p = 4.0 × 10−4), and multiple sclerosis (HR 1.06; 95% CI 1.04–1.07; p = 2.8 × 10−4) compared with the age (±5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted [ORIVW] 1.23; 95% CI 1.06–1.42; pIVW = 0.007) and lower risk of Crohn disease (ORIVW 0.73; 95% CI −0.62 to 0.86; pIVW = 1.3 × 10−4). Colocalization supported a common causal single nucleotide polymorphism for MIG and Crohn disease (posterior probability = 0.74), but not AD (posterior probability = 0.03). Using a 2-sample MR approach, genetically predicted risks of inflammatory diseases were not associated with higher AD risk. Our data suggest that the association between inflammatory diseases and risk of AD is unlikely to be causal and may be a result of confounding. In support, although inflammatory biomarkers showed evidence for causal associations with inflammatory diseases, evidence was weak that they affected both inflammatory disease and AD.