Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Abstract

Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q32 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1Δ) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations. Group 1 included 1178 subjects with IgAN and available genome-wide association study data. Group 2 included 365 subjects with IgAN and available clinical follow-up data. In group 1, rs6677604 was associated with mesangial C3 deposition by genotype-phenotype correlation analysis. In group 2, we detected a linkage between the rs6677604-A allele and CFHR3-1Δ and found that the rs6677604-A allele was associated with higher serum levels of CFH and lower levels of the complement activation split product C3a. Furthermore, CFH levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition. Moreover, serum levels of the pathogenic galactose-deficient glycoform of IgA1 were also associated with the degree of mesangial C3 deposition in patients with IgAN. Our findings suggest that genetic variants in CFH, CFHR3, and CFHR1 affect complement activation and thereby, predispose patients to develop IgAN.

The role of the alternative pathway of complement activation in glomerular diseases

“…Nevertheless, Zhu et al proposed systemic complement activation after having found higher C3 kidney deposition in patients with low circulating C3 levels. Surprisingly, and on the contrary to previous reports, results of a recent study revealed no correlation between decreased serum C3 levels and renal progression [70]. Rambausek et al have shown a higher frequency of C3FF and lower of C3F/S alleles in IgAN patients compared to controls (10.4 vs. 3.4 and 19.4 vs. 35.8%, respectively).…”

“…In a study performed by Zhu et al, among five healthy individuals with rs6677604-AA genotype, four had homozygous CFHR3-1Δ, and one was heterozygous for CFHR1Δ. Conversely, both 41 patients and 28 healthy controls with rs6677604-GG genotype carried two copies of CFHR1 and CFHR3 genes, and 90% of rs6677604-AG heterozygotes (39 patients and 49 controls) were also heterozygous for CFHR3-1Δ [70]. It has been estimated that the deletion of one CFHR3-1 allele reduced the disease risk by 26%, while the absence of two alleles decreased the disease risk by 45% [72].…”

“…As an example, SNP rs6677604 located in an intronic region of CFH gene has no functional consequence. However, it tags a common copy number polymorphism CFHR3-1Δ, which confers protection for IgAN, has been shown to be a risk factor for SLE [65,[69][70][71][72]. Also, several rare mutations of the AP components have been described in GN patients.…”

“…In fact, autoantibodies to the C-terminal end of CFH are found in approximately 10% of aHUS patients, and the majority of them have a homozygous deletion of CHFR1 [37,108,109]. Furthermore, the prevalence of anti-CFH antibodies correlates with the occurrence of CFHR3-1Δ variant, known to be protective against IgAN and AMD, and a risk factor for SLE and aHUS [47,70,83]. The exact impact of the same mutation being protective in some diseases and predisposing to the other remains to be specified.…”

“…DAF decay accelerating factor. The diagram was based on Maillard et al [32], modified region of the CFH gene, which tagged CFHR3-1Δ and conferred protection against IgAN [70,71]. In a study performed by Zhu et al, among five healthy individuals with rs6677604-AA genotype, four had homozygous CFHR3-1Δ, and one was heterozygous for CFHR1Δ.…”