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

Area of Science:

• Immunology
• Genetics
• Nephrology

Background:

• Dysregulation of the complement alternative pathway (AP) is central to atypical hemolytic-uremic syndrome (aHUS) pathogenesis.
• Factor H (FH) deficiency or dysfunction, often due to genetic defects, is a primary driver of aHUS.
• FH-related proteins (FHRs), such as FHR-3 and FHR-1, may downregulate FH activity, suggesting their plasma levels are disease-relevant.

Purpose of the Study:

• To quantify FHR-3 levels in aHUS patients and controls based on CFHR3 genotypes.
• To investigate the association between CFHR3 alleles, FHR-3 expression, and aHUS risk.
• To determine the impact of the aHUS-associated haplotype CFH(H3)-CFHR3*B-CFHR1*B on FHR-3 production.

Main Methods:

• Utilized a specific enzyme-linked immunosorbent assay (ELISA) to measure plasma FHR-3 concentrations.
• Genotyped 218 aHUS patients for three CFHR3 alleles: CFHR3*A, CFHR3*B, and CFHR3*Del.
• Compared FHR-3 levels across different CFHR3 genotypes and between aHUS patients and controls.

Main Results:

• Significant differences in FHR-3 levels were observed among CFHR3 genotype groups (p < 0.001).
• The CFHR3*A allele was associated with low FHR-3 expression, while CFHR3*B was linked to high expression.
• The aHUS-risk haplotype CFH(H3)-CFHR3*B-CFHR1*B produced twice as much FHR-3 as the non-risk haplotype CFH(H1)-CFHR3*A-CFHR1*A.

Conclusions:

• CFHR3*A is a low-expression allele, and CFHR3*B is a high-expression allele, influencing FHR-3 levels.
• Increased plasma FHR-3 levels, particularly from the CFHR3*B allele, likely impair FH regulatory function, contributing to aHUS.
• Elevated FHR-3 in aHUS patients suggests a role in disease pathogenesis by disrupting the FH/FHR balance.