In:
Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 38, No. Supplement_1 ( 2023-06-14)
Abstract:
Excessive complement activation is particularly important in the pathogenesis of IgAN nephropathy (IgAN). The relationship of complement CFH gene genetics and IgAN phenotype has not been clearly established in IgAN. Method We performed a genetic analysis of 234 French IgAN patients by next generation sequencing and Sanger. CFH polymorphisms were combined into haplotypes using the Michigan imputation Server1. CFH rare variants (MAF & lt;0.1%) and haplotypes frequencies were compared to the 1k genome population of European ancestry. Recombinant full-length FH rare variants were produced and studied functionally in vitro. Results Genetic analysis revealed an enrichment in CFH non synonymous rare variants in IgAN patients (n = 234) compared to the reference population (n = 503) (5.1 versus 1.8%, p = 0.010). Interestingly, the identified variants preferentially located in FH functional domains. In vitro functional studies based on new functional Luminex® assays showed a decrease in C3b-binding, C3bBb decay-accelerating activity and/or FI-cofactor activity for 4 variants, classifying a newly identified variant as a pathogenic variant. CFH haplotypes distribution differed between the IgAN patients and controls (p & lt;0.001), with a higher prevalence of the H3 haplotype (rs80029 c.184G & gt;A, rs1061170 c.1204T & gt;C, rs7542235 chr1:196854483 A & gt;G, GTA) in IgAN patients (28.2 versus 21.1%, p = 0.0029), but this haplotype was not associated with renal survival. Conclusion In our series of French IgAN patients, CFH rare variants and haplotypes are associated with disease's susceptibility. Our results support the hypothesis of a complement dysregulation underlying the IgAN pathogenesis.
Type of Medium:
Online Resource
ISSN:
0931-0509
,
1460-2385
DOI:
10.1093/ndt/gfad063a_5419
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2023
detail.hit.zdb_id:
1465709-0
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