The impact of increasing levels of blood C-reactive protein on the inflammatory loci SPI1 and CD33 in Alzheimer's disease.
The impact of increasing levels of blood C-reactive protein on the inflammatory loci SPI1 and CD33 in Alzheimer's disease.
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DOI：
10.1038/s41398-022-02281-6
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发表时间：
2022-12-22
影响因子：
6.8
通讯作者：
Zhang, Xiaoling
中科院分区：
文献类型：
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作者：
Huang, Jinghan;Tao, Qiushan;Ang, Ting Fang Alvin;Farrell, John;Zhu, Congcong;Wang, Yixuan;Stein, Thor D.;Lunetta, Kathryn L.;Massaro, Joseph;Mez, Jesse;Au, Rhoda;Farrer, Lindsay A.;Qiu, Wei Qiao;Zhang, Xiaoling
载脂蛋白ε4(ApoEε4)是晚发性阿尔茨海默病(AD)最重要的遗传危险因素。血C反应蛋白升高进一步增加了携带载脂蛋白ε4等位基因的人患AD的风险。我们假设，CRP作为一种关键的炎症因素，可以调节其他基因变异对AD风险的影响。我们在已报道的AD风险基因座上选择了10个单核苷酸多态(SNPs)，编码与炎症相关的蛋白。然后，我们使用英国生物库中的COX比例风险模型(n = 279,176名白人参与者，803例AD发病病例)测试了这些SNPs和血液C反应蛋白水平之间的交互作用对AD发病率的影响。在弗雷明翰心脏研究第二代队列(n = 3009，事件AD = 156)中，测试了前五个SNP与AD发病率的不同C反应蛋白截止点的相互作用。我们发现，血清CRP浓度越高，3个AD相关基因(SPI1、CD33和CLU)上的SNP基因型患AD的风险就会增加。在分层基因分析中使用COX模型，C反应蛋白水平较高(≥10与10 mg/L)与AD发病风险相关的危险比(HR)为1.94(95%CI：1.33-2.84，p <； 0.001)；CD33rs3865444-CC型为1.75(95%CI：1.20~2.55，p = 0.004)；C型为1.76(95%CI：1.25~2.48，p = 0.001)。相反，在这些基因的其他基因类型中没有观察到这些关联。最后，在321名阿尔茨海默病神经成像(ADNI)轻度认知障碍(MCI)患者中验证了两个SNPs。我们观察到，SPI1和CD33基因对MCI转化为AD的风险的影响因C反应蛋白水平升高而增强。此外，在ADNI队列中，当血中C-反应蛋白水平升高时，SPI1型与脑脊液AD生物标志物，包括t-Tau和p-Tau相关(p <； 0.01)。我们的研究结果表明，血C反应蛋白升高作为外周炎症生物标志物，是除载脂蛋白Eε4外，SPI1和CD33基因效应在AD风险中的重要调节因子。监测外周血中C反应蛋白水平可能有助于准确干预和预防AD的发生。
Apolipoprotein ε4 (APOE ε4) is the most significant genetic risk factor for late-onset Alzheimer’s disease (AD). Elevated blood C-reactive protein (CRP) further increases the risk of AD for people carrying the APOE ε4 allele. We hypothesized that CRP, as a key inflammatory element, could modulate the impact of other genetic variants on AD risk. We selected ten single nucleotide polymorphisms (SNPs) in reported AD risk loci encoding proteins related to inflammation. We then tested the interaction effects between these SNPs and blood CRP levels on AD incidence using the Cox proportional hazards model in UK Biobank (n = 279,176 white participants with 803 incident AD cases). The five top SNPs were tested for their interaction with different CRP cutoffs for AD incidence in the Framingham Heart Study (FHS) Generation 2 cohort (n = 3009, incident AD = 156). We found that for higher concentrations of serum CRP, the AD risk increased for SNP genotypes in 3 AD-associated genes (SPI1, CD33, and CLU). Using the Cox model in stratified genotype analysis, the hazard ratios (HRs) for the association between a higher CRP level (≥10 vs. <10 mg/L) and the risk of incident AD were 1.94 (95% CI: 1.33–2.84, p < 0.001) for the SPI1 rs1057233-AA genotype, 1.75 (95% CI: 1.20–2.55, p = 0.004) for the CD33 rs3865444-CC genotype, and 1.76 (95% CI: 1.25–2.48, p = 0.001) for the CLU rs9331896-C genotype. In contrast, these associations were not observed in the other genotypes of these genes. Finally, two SNPs were validated in 321 Alzheimer’s Disease Neuroimaging (ADNI) Mild Cognitive Impairment (MCI) patients. We observed that the SPI1 and CD33 genotype effects were enhanced by elevated CRP levels for the risk of MCI to AD conversion. Furthermore, the SPI1 genotype was associated with CSF AD biomarkers, including t-Tau and p-Tau, in the ADNI cohort when the blood CRP level was increased (p < 0.01). Our findings suggest that elevated blood CRP, as a peripheral inflammatory biomarker, is an important moderator of the genetic effects of SPI1 and CD33 in addition to APOE ε4 on AD risk. Monitoring peripheral CRP levels may be helpful for precise intervention and prevention of AD for these genotype carriers.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
DOI：
10.3233/jad-200747
发表时间：
2021
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Berger M;Cooter M;Roesler AS;Chung S;Park J;Modliszewski JL;VanDusen KW;Thompson JW;Moseley A;Devinney MJ;Smani S;Hall A;Cai V;Browndyke JN;Lutz MW;Corcoran DL;and Alzheimer’s Disease Neuroimaging Initiative
通讯作者：
and Alzheimer’s Disease Neuroimaging Initiative
影响因子：
14
作者：
通讯作者：
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影响因子：
5.1
作者：
Jiang, Teng;Yu, Jin-Tai;Tan, Lan
通讯作者：
Tan, Lan
影响因子：
5.6
作者：
Gerhardt, Stefan;Hassall, Giles;Abbott, W. Mark
通讯作者：
Abbott, W. Mark