TY - JOUR
T1 - High complement factor H-related (FHR)-3 levels are associated with the atypical hemolytic-uremic syndrome-risk allele CFHR3*B
AU - Pouw, Richard B.
AU - Delgado, Irene G. mez
AU - Lera, Alberto L. pez
AU - de Córdoba, Santiago Rodríguez
AU - Wouters, Diana
AU - Kuijpers, Taco W.
AU - Sánchez-Corral, Pilar
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85046080395&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29740447
U2 - https://doi.org/10.3389/fimmu.2018.00848
DO - https://doi.org/10.3389/fimmu.2018.00848
M3 - Article
C2 - 29740447
SN - 1664-3224
VL - 9
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - APR
M1 - 848
ER -