UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
Neurosciences and Mental Health Institute, Cardiff University, Cardiff, CF244HQ, UK.
J Neuroinflammation. 2023 Jul 21;20(1):169. doi: 10.1186/s12974-023-02850-6.
Alzheimer's disease (AD) has been associated with immune dysregulation in biomarker and genome-wide association studies (GWAS). GWAS hits include the genes encoding complement regulators clusterin (CLU) and complement receptor 1 (CR1), recognised as key players in AD pathology, and complement proteins have been proposed as biomarkers.
To address whether changes in plasma complement protein levels in AD relate to AD-associated complement gene variants we first measured relevant plasma complement proteins (clusterin, C1q, C1s, CR1, factor H) in a large cohort comprising early onset AD (EOAD; n = 912), late onset AD (LOAD; n = 492) and control (n = 504) donors. Clusterin and C1q were significantly increased (p < 0.001) and sCR1 and factor H reduced (p < 0.01) in AD plasma versus controls. ROC analyses were performed to assess utility of the measured complement biomarkers, alone or in combination with amyloid beta, in predicting AD. C1q was the most predictive single complement biomarker (AUC 0.655 LOAD, 0.601 EOAD); combining C1q with other complement or neurodegeneration makers through stepAIC-informed models improved predictive values slightly. Effects of GWS SNPs (rs6656401, rs6691117 in CR1; rs11136000, rs9331888 in CLU; rs3919533 in C1S) on protein concentrations were assessed by comparing protein levels in carriers of the minor vs major allele. To identify new associations between SNPs and changes in plasma protein levels, we performed a GWAS combining genotyping data in the cohort with complement protein levels as endophenotype. SNPs in CR1 (rs6656401), C1S (rs3919533) and CFH (rs6664877) reached significance and influenced plasma levels of the corresponding protein, whereas SNPs in CLU did not influence clusterin levels.
Complement dysregulation is evident in AD and may contribute to pathology. AD-associated SNPs in CR1, C1S and CFH impact plasma levels of the encoded proteins, suggesting a mechanism for impact on disease risk.
阿尔茨海默病（AD）与生物标志物和全基因组关联研究（GWAS）中的免疫失调有关。GWAS 命中包括编码补体调节剂簇蛋白（CLU）和补体受体 1（CR1）的基因，这些基因被认为是 AD 病理的关键因素，并且补体蛋白已被提议作为生物标志物。
为了确定 AD 中血浆补体蛋白水平的变化是否与 AD 相关的补体基因变异有关，我们首先在包括早发性 AD（EOAD；n=912）、晚发性 AD（LOAD；n=492）和对照组（n=504）的大队列中测量了相关的血浆补体蛋白（簇蛋白、C1q、C1s、CR1、因子 H）。与对照组相比，AD 血浆中簇蛋白和 C1q 显著增加（p<0.001），sCR1 和因子 H 降低（p<0.01）。进行了 ROC 分析，以评估单独或与淀粉样β结合使用测量的补体生物标志物在预测 AD 中的效用。C1q 是最具预测性的单一补体生物标志物（AUC LOAD 为 0.655，EOAD 为 0.601）；通过通过 stepAIC 告知模型将 C1q 与其他补体或神经退行性标志物结合使用，可以略微提高预测值。通过比较次要等位基因与主要等位基因携带者的蛋白水平，评估了 GWAS 中 SNP（CR1 中的 rs6656401、rs6691117；CLU 中的 rs11136000、rs9331888；C1S 中的 rs3919533）对蛋白浓度的影响。为了确定 SNP 与血浆蛋白水平变化之间的新关联，我们进行了 GWAS，将队列中的基因分型数据与作为表型的补体蛋白水平相结合。CR1（rs6656401）、C1S（rs3919533）和 CFH（rs6664877）中的 SNP 达到了显著水平，并影响了相应蛋白的血浆水平，而 CLU 中的 SNP 并未影响簇蛋白水平。
AD 中补体失调明显，可能有助于发病机制。与 AD 相关的 CR1、C1S 和 CFH 中的 SNP 影响编码蛋白的血浆水平，表明对疾病风险有影响的机制。
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