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FDX1 has been implicated in IgA glomerulonephritis based on genetic association studies conducted in Han Chinese populations. Two independent case‑control investigations evaluated polymorphisms in FDX1 alongside other immune‐related genes. In one study, 200 IgA nephropathy patients and 310 controls were analyzed, revealing that the allele “A” of a single‑nucleotide polymorphism in FDX1 was modestly associated with increased disease risk (PMID:26431901). A second study involving 347 patients further examined a similar variant, although the association lost significance after adjustments for age and sex (PMID:26370181). This limited magnitude of association supports a cautious interpretation of FDX1’s role in disease susceptibility.
The overall clinical validity for the association between FDX1 and IgA glomerulonephritis is therefore categorized as Limited. The genetic data are derived from large-scale association analyses rather than clear familial segregation; no affected relatives have been reported with segregating variants. The modest effect sizes (e.g. odds ratios of 1.88 and 1.27) and the loss of significance upon covariate adjustment underscore the need for further replication and functional correlation in this complex trait (PMID:26431901; PMID:26370181).
From the genetic evidence perspective, the case‑control studies provide support for an association. Although the variant details are based on SNP markers rather than classic coding alterations, they inform on the potential impact of FDX1 in IgA nephropathy. In contrast to high‑penetrance Mendelian disorders, these common variants demonstrate only a modest risk. The genetic evidence is thus rated as Limited given the absence of familial segregation and the borderline statistical significance.
Functional studies of FDX1 have been extensive and provide important biological context. Multiple experimental assessments, including site‑directed mutagenesis studies, have examined the role of residues critical for electron transfer in the protein. For instance, mutations at threonine 54 have been investigated and the T54S change has been characterized as c.161A>G (p.Thr54Ser) in enzymatic assays, revealing alterations in redox properties (PMID:8530396; PMID:8755728). Although these studies do not directly model IgA glomerulonephritis, they provide functional evidence that FDX1 is biologically active in pathways plausibly related to disease pathogenesis.
Integrating both genetic and experimental findings, the available evidence indicates that FDX1 may contribute to the development of IgA glomerulonephritis via subtle effects on electron transfer and steroidogenesis. The modest genetic associations, combined with robust functional characterization, lend biological plausibility to the gene’s involvement in the disease, even if the overall clinical impact remains limited. It is important to note that the genetic association does not reach the level of definitive causality, and further research is needed to clarify the contribution of FDX1 variants to disease risk.
Key take‑home: Although current evidence linking FDX1 to IgA glomerulonephritis is modest, the integration of genetic association data with detailed functional studies supports its potential utility in refining diagnostic evaluations and developing prognostic strategies for this complex renal disorder.
Gene–Disease AssociationLimitedAssociation derived from two case‑control studies with modest odds ratios (200 subjects [PMID:26431901] and 347 subjects [PMID:26370181]), with one study losing significance after adjustment for age and sex. Genetic EvidenceLimitedSNP analysis in FDX1 indicates a modest association (allele ‘A’ of rs10488764) with IgA nephropathy, but the evidence is tempered by lack of segregation data and borderline statistical significance. Functional EvidenceModerateMultiple functional studies, including the characterization of a T54S variant (c.161A>G, p.Thr54Ser), elucidate FDX1’s role in electron transfer, supporting its biological plausibility in disease contexts even though the experiments are not disease‑specific. |