AUTHOR=Pouw Richard B. , Gómez Delgado Irene , López Lera Alberto , Rodríguez de Córdoba Santiago , Wouters Diana , Kuijpers Taco W. , Sánchez-Corral Pilar 

TITLE=High Complement Factor H-Related (FHR)-3 Levels Are Associated With the Atypical Hemolytic-Uremic Syndrome-Risk Allele CFHR3*B

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00848

DOI=10.3389/fimmu.2018.00848

ISSN=1664-3224

ABSTRACT=<p>Dysregulation of the complement alternative pathway (AP) is a major pathogenic mechanism in atypical hemolytic-uremic syndrome (aHUS). Genetic or acquired defects in factor H (FH), the main AP regulator, are major aHUS drivers that associate with a poor prognosis. FH activity has been suggested to be downregulated by homologous FH-related (FHR) proteins, including FHR-3 and FHR-1. Hence, their relative levels in plasma could be disease-relevant. The genes coding for FH, FHR-3, and FHR-1 (<italic>CFH, CFHR3</italic>, and <italic>CFHR1</italic>, respectively) are polymorphic and located adjacent to each other on human chromosome 1q31.3. We have previously shown that haplotype <italic>CFH(H3)–CFHR3*B–CFHR1*B</italic> associates with aHUS and reduced FH levels. In this study, we used a specific enzyme-linked immunosorbent assay to quantify FHR-3 in plasma samples from controls and patients with aHUS genotyped for the three known <italic>CFHR3</italic> alleles (<italic>CFHR3*A, CFHR3*B</italic>, and <italic>CFHR3*Del</italic>). In the 218 patients carrying at least one copy of <italic>CFHR3</italic>, significant differences between <italic>CFHR3</italic> genotype groups were found, with <italic>CFHR3*A/Del</italic> patients having the lowest FHR-3 concentration (0.684–1.032 µg/mL), <italic>CFHR3*B/Del</italic> and <italic>CFHR3*A/A</italic> patients presenting intermediate levels (1.437–2.201 µg/mL), and <italic>CFHR3*A/B</italic> and <italic>CFHR3*B/B</italic> patients showing the highest concentration (2.330–4.056 µg/mL) (<italic>p</italic> &lt; 0.001). These data indicate that <italic>CFHR3*A</italic> is a low-expression allele, whereas <italic>CFHR3*B</italic>, associated with increased risk of aHUS, is a high-expression allele. Our study reveals that the aHUS-risk haplotype <italic>CFH(H3)–CFHR3*B–CFHR1*B</italic> generates twofold more FHR-3 than the non-risk <italic>CFH(H1)–CFHR3*A–CFHR1*A</italic> haplotype. In addition, FHR-3 levels were higher in patients with aHUS than in control individuals with the same <italic>CFHR3</italic> genotype. These data suggest that increased plasma levels of FHR-3, altering the balance between FH and FHR-3, likely impact the FH regulatory functions and contribute to the development of aHUS.</p>