Alzheimer’s disease-associated complement gene variants influence plasma complement protein levels

Veteleanu, Aurora, Stevenson-Hoare, Joshua, Keat, Samuel, Daskoulidou, Nikoleta, Zetterberg, Henrik, Heslegrave, Amanda, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, Zelek, Wioleta M., Carpanini, Sarah M. and Morgan, Bryan Paul 2023. Alzheimer’s disease-associated complement gene variants influence plasma complement protein levels. Journal of Neuroinflammation 20 (1) , 169. 10.1186/s12974-023-02850-6

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Abstract

Background: 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. Main body: 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. Conclusion: 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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	BioMed Central
ISSN:	1742-2094
Funders:	MRC
Date of First Compliant Deposit:	24 July 2023
Date of Acceptance:	8 July 2023
Last Modified:	07 Oct 2023 12:31
URI:	https://orca.cardiff.ac.uk/id/eprint/161207

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