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. 2025 Jul 27;31(1):267.
doi: 10.1186/s10020-025-01313-3.

Evaluating the usefulness of C5 and C5AR1 as genetic biomarkers of IgA-mediated vasculitis

Joao Carlos Batista-Liz  1 , Vanesa Calvo-Río  1   2 , María Sebastián Mora-Gil  1 , María Teresa Leonardo  3 , Ana Cristina Peñalba  3 , Luis Martín-Penagos  1   4 , Javier Narváez  5 , Belén Sevilla-Pérez  6 , José Luis Callejas-Rubio  7 , Ligia Gabrie  1   2 , Rafael Gálvez Sánchez  1   2 , Luis Caminal-Montero  8 , Paz Collado  9 , María José Rodríguez Valls  10 , Diego de Argila  11 , Patricia Quiroga-Colina  12 , Esther Francisca Vicente-Rabaneda  12 , Esteban Rubio  13 , Manuel León Luque  13 , Juan María Blanco-Madrigal  14 , Eva Galíndez-Agirregoikoa  14 , Ricardo Blanco #  1   2 , Verónica Pulito-Cueto #  15 , Raquel López-Mejías #  16
Affiliations

Evaluating the usefulness of C5 and C5AR1 as genetic biomarkers of IgA-mediated vasculitis

Joao Carlos Batista-Liz et al. Mol Med. .

Abstract

Background: IgA-mediated vasculitis (IgAV) is a complex inflammatory disease. Unravelling its genetic background would allow us to identify genetic biomarkers that may be used as additional tools in its daily management, helping to solve the clinical challenge that this vasculitis entails. C5 is a potent immune mediator that is proteolytically processed to generate C5a, a potent anaphylatoxin that exerts its function via C5aR1. C5 downstream variants (rs3761847 and rs10818488) have been recently related to IgAV pathogenesis. Additionally, C5a and C5aR1 dysregulation contributes to the development of inflammatory diseases, and, particularly, elevated C5a plasma levels have been observed in IgAV patients in the acute stage. Accordingly, we aimed to evaluate the influence of C5 and C5AR1 on the pathophysiology of IgAV.

Methods: Eight C5 (rs10760128, rs74971050, rs4310279, rs7868761, rs10818495, rs10156396, rs3815467, and rs16910280) and three C5AR1 (rs10853784, rs11673071, and rs11670789) tag variants were genotyped in 342 Caucasian IgAV patients and 723 ethnically matched healthy controls.

Results: No statistically significant differences were observed when C5 and C5AR1 frequencies were compared between IgAV patients and healthy controls. Likewise, similar C5 and C5AR1 frequencies were observed amongst IgAV patients stratified according to IgAV severity (presence/absence of nephritis). Furthermore, no C5 and C5AR1 differences were disclosed when IgAV patients were stratified according to demographic and clinical IgAV characteristics other than nephritis (age at disease onset, presence/absence of joint and gastrointestinal manifestations) and sex.

Conclusions: Our results suggest that C5 and C5AR1 are not related to IgAV pathogenesis and, therefore, these genes may not be useful as IgAV genetic biomarkers.

Keywords: C5; C5AR1; Biomarkers; Genetics; IgA Vasculitis.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate:: All the patients diagnosed with IgAV, and healthy controls gave written informed consent before their inclusion in our study. Likewise, methods were carried out following the ethical standards of the approved guidelines and regulations, according to the Declaration of Helsinki, and the study was also approved by the Clinical Research Ethics Committee of Cantabria, Spain (protocol code 15/2012). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Genomic context of C5 and C5AR1 polymorphisms. A Genomic context of the C5 variants evaluated in our study. B Genomic context of the C5AR1 polymorphisms assessed in our study
Fig. 2
Fig. 2
Linkage disequilibrium of C5 and C5AR1 polymorphisms in the European population. A Linkage disequilibrium of C5 variants measured by the r2 coefficient. Data were obtained by the 1000 Genomes Project and Haploview v.4.2 software, considering the r2 threshold set at 0.8 and minimum minor allele frequency at 0.10. The LD amongst the polymorphisms studied is shown on a scale from minimum (white) to maximum (black). B Linkage disequilibrium of C5AR1 polymorphisms measured by the r2 coefficient. Data were obtained by the 1000 Genomes Project and Haploview v.4.2 software, considering the r2 threshold set at 0.8 and minimum minor allele frequency at 0.10. The LD amongst the polymorphisms studied is shown on a scale from minimum (white) to maximum (black)
Fig. 3
Fig. 3
Linkage disequilibrium of C5 and C5AR1 polymorphisms in our patients with IgAV I. A Linkage disequilibrium of C5 variants measured by the r2 coefficient. Data were obtained by the Haploview v.4.2 software, considering the r2 threshold set at 0.8 and minimum minor allele frequency at 0.10. The LD amongst the polymorphisms studied is shown on a scale from minimum (white) to maximum (black). B Linkage disequilibrium of C5AR1 polymorphisms measured by the r2 coefficient. Data were obtained by the Haploview v.4.2 software, considering the r2 threshold set at 0.8 and minimum minor allele frequency at 0.10. The LD amongst the polymorphisms studied is shown on a scale from minimum (white) to maximum (black)
Fig. 4
Fig. 4
Linkage disequilibrium of C5 and C5AR1 polymorphisms in our cohort of healthy controls. A Linkage disequilibrium of C5 variants measured by the r2 coefficient. Data were obtained by the Haploview v.4.2 software, considering the r2 threshold set at 0.8 and minimum minor allele frequency at 0.10. The LD amongst the polymorphisms studied is shown on a scale from minimum(white) to maximum (black). B Linkage disequilibrium of C5AR1 polymorphisms measured by the r2 coefficient. Data were obtained by the Haploview v.4.2 software, considering the r2 threshold set at 0.8 and minimum minor allele frequency at 0.10. The LD amongst the polymorphisms studied is shown on a scale from minimum(white) to maximum (black)
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