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

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 (; CFH, CFHR3; , and; CFHR1; , respectively) are polymorphic and located adjacent to each other on human chromosome 1q31.3. We have previously shown that haplotype; CFH(H3)-CFHR3*B-CFHR1*B; 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; CFHR3; alleles (; CFHR3*A, CFHR3*B; , and; CFHR3*Del; ). In the 218 patients carrying at least one copy of; CFHR3; , significant differences between; CFHR3; genotype groups were found, with; CFHR3*A/Del; patients having the lowest FHR-3 concentration (0.684-1.032 µg/mL),; CFHR3*B/Del; and; CFHR3*A/A; patients presenting intermediate levels (1.437-2.201 µg/mL), and; CFHR3*A/B; and; CFHR3*B/B; patients showing the highest concentration (2.330-4.056 µg/mL) (; p; < 0.001). These data indicate that; CFHR3*A; is a low-expression allele, whereas; CFHR3*B; , associated with increased risk of aHUS, is a high-expression allele. Our study reveals that the aHUS-risk haplotype; CFH(H3)-CFHR3*B-CFHR1*B; generates twofold more FHR-3 than the non-risk; CFH(H1)-CFHR3*A-CFHR1*A; haplotype. In addition, FHR-3 levels were higher in patients with aHUS than in control individuals with the same; CFHR3; 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.