Association of Complement Genetics with Outcomes in IgA Nephropathy
Anna Duval1,2,3, Nicolas Maillard4,5, Martin Morin6
1Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Paris, France.
Summary
Complement gene variants impact IgA nephropathy (IgAN) risk and progression. Rare CFH variants are more common in IgAN patients, and specific MCP haplotypes predict end-stage kidney disease.
Area of Science:
- Genetics
- Nephrology
- Immunology
Background:
- Complement activation is implicated in IgA nephropathy (IgAN) pathogenesis.
- Genome-wide association studies link IgAN susceptibility to the CFH-CFHR gene region.
- The precise role of complement genetics in IgAN severity remains unclear.
Purpose of the Study:
- To investigate the association between genetic variations in complement genes and IgAN.
- To determine the relationship between complement genetics and IgAN disease severity.
- To explore the functional impact of identified genetic variants.
Main Methods:
- Next-generation sequencing of CFH, CFI, CFB, MCP, C3, and CFHR5 genes in 260 primary IgAN patients.
- Comparison of rare variant frequencies and haplotype data with the 1000 Genomes Project European population.
- In vitro functional assays of recombinant CFH variants to assess complement regulatory activity.
Main Results:
- A higher prevalence of rare non-synonymous CFH variants was observed in IgAN patients (5%) compared to controls (2%, p=0.03).
- Five identified CFH variants demonstrated impaired complement regulatory activity in vitro.
- The CFH-H2 haplotype was linked to reduced IgAN susceptibility (OR 0.52, p=0.03).
- Homozygous MCP ggaac haplotype was associated with end-stage kidney disease development 15 years post-diagnosis (HR 2.83, p=0.02).
Conclusions:
- Complement gene genetics play a dual role in IgA nephropathy, influencing both susceptibility and disease progression.
- These findings support the involvement of complement genetics in IgAN.
- Further validation in larger, independent cohorts is warranted to confirm these exploratory results.
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