{"gene":"CFH","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2005,"finding":"Factor H (CFH) protein accumulates within drusen and is synthesized by the retinal pigmented epithelium, establishing a local role for CFH as the major inhibitor of the alternative complement pathway in the retina.","method":"Immunohistochemistry/immunolocalization combined with genetic association analysis in AMD cases and controls","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein localization by immunohistochemistry and synthesis confirmed in RPE cells, single lab but two orthogonal approaches (protein localization + genetic association)","pmids":["15870199"],"is_preprint":false},{"year":2009,"finding":"CFH functions as a complement inhibitor present both as a soluble plasma protein and cell surface-attached form; mutations in CFH differentially affect plasma-bound versus surface-bound CFH function, producing distinct phenotypic outcomes (membranoproliferative glomerulonephritis, atypical HUS, or AMD) depending on which function is impaired.","method":"Mutational analysis correlated with functional assays (C3b binding, complement regulation) and clinical phenotyping","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of multiple CFH mutations with defined biochemical consequences, single review synthesizing multiple studies","pmids":["19297022"],"is_preprint":false},{"year":2006,"finding":"CFH mutations in atypical HUS patients result in either reduced protein expression or impaired C3b binding capability, demonstrating that loss of CFH-mediated C3b inactivation drives complement dysregulation and disease.","method":"Genetic screening of 156 aHUS patients combined with functional assays for C3b binding and protein expression levels","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — large cohort genetic analysis combined with direct functional assays (C3b binding, protein expression), multiple orthogonal methods, independently replicated findings","pmids":["16621965"],"is_preprint":false},{"year":2011,"finding":"A rare CFH missense variant R1210C abrogates C-terminal ligand binding of CFH, demonstrating that loss of CFH's C-terminal surface-recognition function drives both atypical HUS and AMD risk.","method":"High-throughput sequencing to identify variant, genotyping in 2,423 AMD cases and 1,122 controls, prior biochemical characterization of C-terminal ligand binding abrogation","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — variant functionally characterized (C-terminal ligand binding abrogation), replicated across two disease contexts (aHUS and AMD), large case-control cohort","pmids":["22019782"],"is_preprint":false},{"year":2010,"finding":"Autoantibodies targeting CFH in atypical HUS patients block CFH surface recognition at the C-terminus, mimicking the functional effect of genetic CFH mutations and impairing complement regulation on host cell surfaces; this occurs almost exclusively in patients with CFHR1/CFHR3 deletion (DEAP-HUS).","method":"Immunological characterization of IgG autoantibodies to Factor H, correlation with CFHR1/CFHR3 deletion genotyping and complement functional assays","journal":"Pediatric nephrology (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — autoantibody characterization with defined epitope (C-terminus), genotype-phenotype correlation, single review consolidating multiple studies","pmids":["20157737"],"is_preprint":false},{"year":2009,"finding":"IgG autoantibodies to Factor H in aHUS patients impair complement regulation by binding CFH, representing an acquired mechanism of complement dysregulation that defines the DEAP-HUS subgroup with CFHR1/CFHR3 protein deficiency.","method":"Autoantibody detection, CFHR1/CFHR3 deletion genotyping, complement pathway functional assessment","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct autoantibody characterization linked to functional complement impairment, replicated across multiple patient cohorts","pmids":["19190803"],"is_preprint":false},{"year":2012,"finding":"miR-125b and miR-146a, upregulated by NF-κB activation in response to IL-1β and Aβ42 in human neuronal-glial cells, target CFH mRNA and cause significant decreases in CFH expression, establishing a post-transcriptional regulatory mechanism for CFH in neuroinflammation.","method":"miRNA overexpression in primary human neuronal-glial cell cultures, qPCR measurement of CFH expression, NF-κB pathway analysis","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional experiment in primary cells with quantified CFH mRNA reduction, two miRNAs tested, single lab","pmids":["22302353"],"is_preprint":false},{"year":2021,"finding":"Loss of endogenous CFH in human RPE cells leads to increased inflammatory mediators (IL-6, IL-8, GM-CSF) and altered complement protein levels (C3 and CFB upregulation, C5 downregulation), with NF-κB identified as the major pathway mediating these effects, establishing an autocrine role for RPE-derived CFH in maintaining inflammatory and complement homeostasis.","method":"CFH siRNA knockdown in hTERT-RPE1 cells, cytokine/complement protein quantification, NF-κB pathway inhibition","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular phenotype, multiple orthogonal readouts (cytokines and complement proteins), NF-κB pathway confirmed, single lab","pmids":["34445430"],"is_preprint":false},{"year":2015,"finding":"CFH is required to maintain stemness in liver cancer cells; knockdown of CFH abrogates tumorsphere formation and induces differentiation, while overexpression stimulates stemness factor expression and in vivo cell growth, mechanistically through CFH-dependent LSF-1 expression which drives stemness factor transcription.","method":"siRNA knockdown and overexpression in liver cancer cell lines, tumorsphere assay, in vivo xenograft, LSF-1 expression analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with defined phenotypic readouts and mechanistic pathway (LSF-1), single lab","pmids":["26723877"],"is_preprint":false},{"year":2016,"finding":"The CFH Y402H at-risk polymorphism is associated with higher C5a, IL-18, and TNF-α levels in Bruch's membrane/choroid; C5a promotes NF-κB activation and IL-18 upregulation in polarized RPE cells, establishing a mechanistic link between the Y402H variant, complement activation, and inflammasome pathway regulation in AMD pathology.","method":"Post-mortem donor eye genotyping with protein quantification, polarized ARPE19 cell stimulation with C5a/TNF-α, NF-κB reporter assay, gene expression analysis","journal":"The British journal of ophthalmology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human tissue analysis combined with functional cell experiments (NF-κB reporter, gene expression), multiple readouts, single lab","pmids":["26746578"],"is_preprint":false},{"year":2019,"finding":"Molecular docking and experimental alanine scanning confirmed that the human anti-CFH antibody Ab42 interacts with CFH polypeptide through hydrogen bonds involving CDR residues (Tyr315, Ser100, Gly33, Tyr53) contacting CFH residues Pro441, Ile442, Asp443, Asn444, Ile447, and Thr448, defining the structural epitope of this interaction.","method":"Molecular docking, molecular dynamics simulation, free energy calculation, experimental alanine scanning mutagenesis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — computational structure prediction validated by experimental alanine scanning, but single lab and limited experimental validation of predicted interactions","pmids":["31130605"],"is_preprint":false},{"year":2021,"finding":"Common AMD-associated CFH variants (e.g., FH p.Tyr402His/Y402H) strongly associate with elevated plasma FHR-1, FHR-2, FHR-3, and FHR-4A concentrations but not with FH (CFH protein) concentrations, suggesting that CFH genetic variants modulate AMD risk predominantly through effects on FHR protein levels rather than FH protein levels.","method":"ELISA quantification of FH and FHR proteins in 202 controls and 216 AMD patients, genotype-protein association analysis, immunolocalization of FHR-2 and FHR-5 in choroid and drusen","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein quantification linked to genotype in well-characterized cohort, tissue localization, but single study design","pmids":["34260947"],"is_preprint":false},{"year":2017,"finding":"A missense variant N1050Y in CFH is protective against AMD (OR=0.76), and the rare R1210C variant confers high AMD risk (OR=18.82), with both variants having known functional consequences on CFH ligand binding, confirming that coding variation in CFH directly modulates AMD susceptibility through altered protein function.","method":"Exome chip genotyping meta-analysis in 4,332 cases and 25,268 controls; functional annotation of variants","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale genetic study with functionally annotated variants, replicated associations, but mechanistic inference relies on prior biochemical data","pmids":["28011711"],"is_preprint":false},{"year":2023,"finding":"Structural variants involving CFH-CFHR rearrangements in aHUS patients include CFH::CFHR1 hybrid genes that produce dysfunctional CFH protein, and are associated with poor prognosis; eculizumab (anti-C5) treatment induced remission in affected acute episodes, confirming that CFH structural variants drive complement-mediated aHUS through loss of complement regulation.","method":"MLPA copy number variation analysis, long-read SMRT sequencing for breakpoint characterization in 258 primary aHUS and 92 secondary aHUS patients, clinical outcome analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comprehensive genomic characterization with clinical outcome correlation, large cohort, but mechanistic inference relies on known biology of CFH function","pmids":["36793547"],"is_preprint":false}],"current_model":"CFH encodes complement factor H (FH), a soluble and cell surface-bound regulator of the alternative complement pathway that functions primarily by binding C3b and acting as a cofactor for Factor I-mediated C3b inactivation; loss-of-function mutations, autoantibodies targeting its C-terminal surface-recognition domain, or structural rearrangements producing hybrid CFH-CFHR proteins all impair this regulatory activity, leading to uncontrolled complement activation that underlies atypical HUS, C3 glomerulopathy, and AMD; CFH is synthesized locally by the retinal pigmented epithelium where it modulates NF-κB-driven inflammatory and complement gene expression, and its expression is post-transcriptionally repressed by NF-κB-activated miR-125b and miR-146a in neuroinflammatory contexts."},"narrative":{"mechanistic_narrative":"CFH encodes complement factor H (FH), the major soluble and cell-surface regulator of the alternative complement pathway, acting through C3b binding to restrain complement activation on host surfaces [PMID:19297022, PMID:16621965]. Loss-of-function arises through multiple routes that converge on impaired regulation: missense mutations that reduce protein expression or abolish C3b binding, C-terminal variants such as R1210C that abrogate surface-recognition ligand binding, autoantibodies that block the C-terminal recognition function (notably in patients carrying CFHR1/CFHR3 deletions, defining DEAP-HUS), and CFH::CFHR1 hybrid genes generated by structural rearrangement [PMID:16621965, PMID:22019782, PMID:20157737, PMID:19190803, PMID:36793547]. These defects cause uncontrolled complement activation underlying atypical hemolytic uremic syndrome, membranoproliferative/C3 glomerulopathy, and age-related macular degeneration, with phenotype determined by whether plasma-bound or surface-bound FH function is impaired [PMID:19297022, PMID:16621965, PMID:22019782]; coding variation in CFH directly modulates AMD susceptibility, with R1210C strongly raising risk and N1050Y protective [PMID:28011711]. In the retina, FH is synthesized locally by the retinal pigmented epithelium, where it accumulates in drusen and acts as the principal local inhibitor of the alternative pathway [PMID:15870199]. RPE-derived FH also serves an autocrine homeostatic role: its loss elevates inflammatory mediators (IL-6, IL-8, GM-CSF) and remodels complement protein levels through NF-κB signaling [PMID:34445430], and the Y402H at-risk variant is linked to increased C5a, IL-18, and TNF-α and inflammasome-associated NF-κB activation in RPE [PMID:26746578]. CFH expression is post-transcriptionally repressed by NF-κB-induced miR-125b and miR-146a in neuroinflammatory contexts [PMID:22302353]. A distinct role in maintaining cancer stem-cell properties has been described in liver cancer cells, mediated through CFH-dependent LSF-1 expression [PMID:26723877].","teleology":[{"year":2005,"claim":"Established that CFH is not only a plasma protein but is synthesized locally in the eye and accumulates in disease deposits, defining a tissue-resident role for complement regulation in the retina.","evidence":"Immunolocalization of FH in drusen and RPE synthesis with parallel AMD genetic association","pmids":["15870199"],"confidence":"Medium","gaps":["Does not establish the molecular regulatory mechanism of local FH","Causal direction between drusen FH accumulation and AMD not resolved"]},{"year":2006,"claim":"Showed that aHUS-associated CFH mutations cause disease either by lowering protein levels or by abolishing C3b binding, directly linking loss of FH-mediated C3b inactivation to complement dysregulation.","evidence":"Genetic screening of 156 aHUS patients with C3b-binding and expression functional assays","pmids":["16621965"],"confidence":"High","gaps":["Does not separate surface-bound from fluid-phase regulatory defects","Does not address downstream tissue injury mechanism"]},{"year":2009,"claim":"Distinguished plasma-bound from surface-bound FH function, explaining how different CFH mutations produce distinct diseases (MPGN, aHUS, AMD), and identified acquired autoantibody-mediated FH inhibition as a parallel disease mechanism.","evidence":"Mutational/functional correlation review plus autoantibody detection with CFHR1/CFHR3 genotyping and complement assays","pmids":["19297022","19190803"],"confidence":"Medium","gaps":["Genotype-to-tissue-specificity link remains correlative","Mechanism by which CFHR1/CFHR3 deletion predisposes to autoantibodies not resolved"]},{"year":2010,"claim":"Localized the functional autoantibody epitope to the FH C-terminus, showing autoantibodies phenocopy genetic C-terminal mutations by blocking surface recognition, and defined the DEAP-HUS subgroup.","evidence":"Epitope characterization of anti-FH IgG with CFHR1/CFHR3 deletion correlation","pmids":["20157737"],"confidence":"Medium","gaps":["Does not establish why autoantibodies arise in CFHR-deficient patients","Single-review consolidation rather than primary structural mapping"]},{"year":2011,"claim":"Demonstrated that a single C-terminal variant (R1210C) abrogating ligand binding drives risk across two distinct diseases, unifying aHUS and AMD around loss of the surface-recognition function of FH.","evidence":"Sequencing and genotyping in 2,423 AMD cases and 1,122 controls with prior biochemical characterization","pmids":["22019782"],"confidence":"High","gaps":["Does not explain divergent organ targeting of the same variant","Mechanism of penetrance modulation unknown"]},{"year":2012,"claim":"Identified a post-transcriptional control layer for CFH, showing NF-κB-induced miR-125b and miR-146a repress CFH mRNA in inflammatory conditions.","evidence":"miRNA overexpression in primary human neuronal-glial cells with qPCR of CFH","pmids":["22302353"],"confidence":"Medium","gaps":["Direct miRNA-CFH 3'UTR binding not demonstrated here","Protein-level and functional consequences not quantified"]},{"year":2015,"claim":"Revealed a non-complement role for CFH in sustaining liver cancer stem-cell properties via LSF-1-driven stemness transcription, expanding FH function beyond complement regulation.","evidence":"siRNA knockdown/overexpression, tumorsphere assays, xenografts, and LSF-1 expression analysis in liver cancer lines","pmids":["26723877"],"confidence":"Medium","gaps":["Mechanism linking CFH to LSF-1 not defined","Independence from complement activity not established"]},{"year":2016,"claim":"Connected the Y402H risk variant to inflammasome and cytokine signaling, showing elevated C5a/IL-18/TNF-α in choroid and C5a-driven NF-κB activation in RPE.","evidence":"Genotyped donor-eye protein quantification with polarized ARPE19 stimulation and NF-κB reporter assays","pmids":["26746578"],"confidence":"Medium","gaps":["Causal chain from Y402H to elevated C5a not directly demonstrated","Single-lab cell-model findings"]},{"year":2017,"claim":"Quantified directionality of CFH coding variation in AMD, confirming N1050Y protection and R1210C high risk through altered protein function.","evidence":"Exome-chip meta-analysis in 4,332 cases and 25,268 controls with functional annotation","pmids":["28011711"],"confidence":"Medium","gaps":["Functional consequences inferred from prior biochemistry, not measured here","Tissue-level mechanism not addressed"]},{"year":2021,"claim":"Refined the AMD risk model by showing common CFH variants associate with elevated FHR protein levels rather than altered FH levels, implicating the FH/FHR balance.","evidence":"ELISA quantification of FH/FHR in 202 controls and 216 AMD patients with genotype association and choroid/drusen immunolocalization","pmids":["34260947"],"confidence":"Medium","gaps":["Does not establish the regulatory mechanism by which FHR proteins promote risk","Single study design"]},{"year":2021,"claim":"Defined an autocrine homeostatic function for RPE-derived FH, showing its loss raises inflammatory mediators and remodels complement protein expression via NF-κB.","evidence":"CFH siRNA knockdown in hTERT-RPE1 cells with cytokine/complement quantification and NF-κB inhibition","pmids":["34445430"],"confidence":"Medium","gaps":["Intracellular versus secreted FH contributions not separated","Single-lab cell-line model"]},{"year":2023,"claim":"Characterized CFH-CFHR structural rearrangements (including CFH::CFHR1 hybrids) as drivers of complement-mediated aHUS with poor prognosis, with anti-C5 (eculizumab) inducing remission.","evidence":"MLPA and long-read SMRT sequencing in 258 primary and 92 secondary aHUS patients with clinical outcome analysis","pmids":["36793547"],"confidence":"Medium","gaps":["Precise functional defect of hybrid protein inferred from known biology","Mechanism of breakpoint formation not resolved"]},{"year":null,"claim":"How the FH/FHR protein balance, local RPE FH synthesis, and the same C-terminal recognition defect together determine organ-specific disease (kidney versus retina) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of tissue-specific phenotype from shared molecular defects","Direct structural mechanism of FHR competition with FH not established","Functional link between non-complement (cancer stemness) and complement roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,13]}],"complexes":[],"partners":["C3","CFI","CFHR1","CFHR3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08603","full_name":"Complement factor H","aliases":["H factor 1"],"length_aa":1231,"mass_kda":139.1,"function":"Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation. Acts as a soluble inhibitor of complement, where its binding to self markers such as glycan structures prevents complement activation and amplification on cell surfaces (PubMed:21285368, PubMed:21317894, PubMed:25402769). Accelerates the decay of the complement alternative pathway (AP) C3 convertase C3bBb, thus preventing local formation of more C3b, the central player of the complement amplification loop (PubMed:19503104, PubMed:21317894, PubMed:26700768). As a cofactor of the serine protease factor I, CFH also regulates proteolytic degradation of already-deposited C3b (PubMed:18252712, PubMed:23332154, PubMed:28671664). In addition, mediates several cellular responses through interaction with specific receptors. For example, interacts with CR3/ITGAM receptor and thereby mediates the adhesion of human neutrophils to different pathogens. In turn, these pathogens are phagocytosed and destroyed (PubMed:20008295, PubMed:9558116) (Microbial infection) In the mosquito midgut, binds to the surface of parasite P.falciparum gametocytes and protects the parasite from alternative complement pathway-mediated elimination","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P08603/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFH","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"AKAP12","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CFH","total_profiled":1310},"omim":[{"mim_id":"616842","title":"DNase1 HYPERSENSITIVITY, CHROMOSOME 6, SITE 1; DHS6S1","url":"https://www.omim.org/entry/616842"},{"mim_id":"615489","title":"MACULAR DEGENERATION, AGE-RELATED, 14; ARMD14","url":"https://www.omim.org/entry/615489"},{"mim_id":"615439","title":"MACULAR DEGENERATION, AGE-RELATED, 13; ARMD13","url":"https://www.omim.org/entry/615439"},{"mim_id":"615008","title":"NEPHROTIC SYNDROME, TYPE 7; NPHS7","url":"https://www.omim.org/entry/615008"},{"mim_id":"614809","title":"C3 GLOMERULOPATHY 3; C3G3","url":"https://www.omim.org/entry/614809"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":1585.8}],"url":"https://www.proteinatlas.org/search/CFH"},"hgnc":{"alias_symbol":["HUS","FHL1","ARMS1","ARMD4"],"prev_symbol":["HF","HF1","HF2"]},"alphafold":{"accession":"P08603","domains":[{"cath_id":"2.10.70.10","chopping":"32-83","consensus_level":"high","plddt":81.7173,"start":32,"end":83},{"cath_id":"2.10.70.10","chopping":"95-144","consensus_level":"medium","plddt":84.6094,"start":95,"end":144},{"cath_id":"2.10.70.10","chopping":"146-208","consensus_level":"medium","plddt":78.439,"start":146,"end":208},{"cath_id":"2.10.70.10","chopping":"211-265","consensus_level":"high","plddt":81.7731,"start":211,"end":265},{"cath_id":"2.10.70.10","chopping":"269-323","consensus_level":"high","plddt":77.7084,"start":269,"end":323},{"cath_id":"2.10.70.10","chopping":"334-385","consensus_level":"medium","plddt":84.341,"start":334,"end":385},{"cath_id":"2.10.70.10","chopping":"448-511","consensus_level":"medium","plddt":78.5845,"start":448,"end":511},{"cath_id":"2.10.70.10","chopping":"512-567","consensus_level":"medium","plddt":76.2857,"start":512,"end":567},{"cath_id":"2.10.70.10","chopping":"689-802","consensus_level":"medium","plddt":77.093,"start":689,"end":802},{"cath_id":"2.10.70.10","chopping":"880-929","consensus_level":"medium","plddt":71.1844,"start":880,"end":929},{"cath_id":"2.10.70.10","chopping":"941-986","consensus_level":"medium","plddt":73.7207,"start":941,"end":986},{"cath_id":"2.10.70.10","chopping":"990-1046","consensus_level":"medium","plddt":75.0611,"start":990,"end":1046},{"cath_id":"2.10.70.10","chopping":"1058-1105","consensus_level":"medium","plddt":77.9788,"start":1058,"end":1105},{"cath_id":"2.10.70.10","chopping":"1119-1165","consensus_level":"medium","plddt":83.4168,"start":1119,"end":1165},{"cath_id":"2.10.70.10","chopping":"1168-1231","consensus_level":"high","plddt":83.0159,"start":1168,"end":1231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08603","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08603-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08603-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFH","jax_strain_url":"https://www.jax.org/strain/search?query=CFH"},"sequence":{"accession":"P08603","fasta_url":"https://rest.uniprot.org/uniprotkb/P08603.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08603/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08603"}},"corpus_meta":[{"pmid":"15870199","id":"PMC_15870199","title":"A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15870199","citation_count":1648,"is_preprint":false},{"pmid":"9774349","id":"PMC_9774349","title":"The OxyS regulatory RNA represses rpoS translation and binds the Hfq (HF-I) protein.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9774349","citation_count":590,"is_preprint":false},{"pmid":"16621965","id":"PMC_16621965","title":"Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16621965","citation_count":555,"is_preprint":false},{"pmid":"22986360","id":"PMC_22986360","title":"STEC-HUS, atypical HUS and TTP are all diseases of complement activation.","date":"2012","source":"Nature reviews. 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Heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/39111953","citation_count":16,"is_preprint":false},{"pmid":"27471351","id":"PMC_27471351","title":"Critical Questions about PARADIGM-HF and the Future.","date":"2016","source":"Acta Cardiologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/27471351","citation_count":16,"is_preprint":false},{"pmid":"38328481","id":"PMC_38328481","title":"SpCas9-HF1 enhances accuracy of cell cycle-dependent genome editing by increasing HDR efficiency, and by reducing off-target effects and indel rates.","date":"2024","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/38328481","citation_count":16,"is_preprint":false},{"pmid":"24453474","id":"PMC_24453474","title":"CFH haplotypes and ARMS2, C2, C3, and CFB alleles show association with susceptibility to age-related macular degeneration in Mexicans.","date":"2014","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/24453474","citation_count":16,"is_preprint":false},{"pmid":"32919915","id":"PMC_32919915","title":"Angiotensin-Neprilysin Inhibition in Black Americans: Data From the PIONEER-HF Trial.","date":"2020","source":"JACC. Heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/32919915","citation_count":16,"is_preprint":false},{"pmid":"34751777","id":"PMC_34751777","title":"LIPCAR Is Increased in Chronic Symptomatic HF Patients. A Sub-Study of the GISSI-HF Trial.","date":"2021","source":"Clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34751777","citation_count":16,"is_preprint":false},{"pmid":"31742829","id":"PMC_31742829","title":"Pathogenic functions and diagnostic utility of cytokines/chemokines in EHEC-HUS.","date":"2020","source":"Pediatrics international : official journal of the Japan Pediatric Society","url":"https://pubmed.ncbi.nlm.nih.gov/31742829","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55792,"output_tokens":3353,"usd":0.108836,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11079,"output_tokens":3865,"usd":0.07601,"stage2_stop_reason":"end_turn"},"total_usd":0.184846,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Factor H (CFH) protein accumulates within drusen and is synthesized by the retinal pigmented epithelium, establishing a local role for CFH as the major inhibitor of the alternative complement pathway in the retina.\",\n      \"method\": \"Immunohistochemistry/immunolocalization combined with genetic association analysis in AMD cases and controls\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein localization by immunohistochemistry and synthesis confirmed in RPE cells, single lab but two orthogonal approaches (protein localization + genetic association)\",\n      \"pmids\": [\"15870199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CFH functions as a complement inhibitor present both as a soluble plasma protein and cell surface-attached form; mutations in CFH differentially affect plasma-bound versus surface-bound CFH function, producing distinct phenotypic outcomes (membranoproliferative glomerulonephritis, atypical HUS, or AMD) depending on which function is impaired.\",\n      \"method\": \"Mutational analysis correlated with functional assays (C3b binding, complement regulation) and clinical phenotyping\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of multiple CFH mutations with defined biochemical consequences, single review synthesizing multiple studies\",\n      \"pmids\": [\"19297022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CFH mutations in atypical HUS patients result in either reduced protein expression or impaired C3b binding capability, demonstrating that loss of CFH-mediated C3b inactivation drives complement dysregulation and disease.\",\n      \"method\": \"Genetic screening of 156 aHUS patients combined with functional assays for C3b binding and protein expression levels\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large cohort genetic analysis combined with direct functional assays (C3b binding, protein expression), multiple orthogonal methods, independently replicated findings\",\n      \"pmids\": [\"16621965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A rare CFH missense variant R1210C abrogates C-terminal ligand binding of CFH, demonstrating that loss of CFH's C-terminal surface-recognition function drives both atypical HUS and AMD risk.\",\n      \"method\": \"High-throughput sequencing to identify variant, genotyping in 2,423 AMD cases and 1,122 controls, prior biochemical characterization of C-terminal ligand binding abrogation\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — variant functionally characterized (C-terminal ligand binding abrogation), replicated across two disease contexts (aHUS and AMD), large case-control cohort\",\n      \"pmids\": [\"22019782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Autoantibodies targeting CFH in atypical HUS patients block CFH surface recognition at the C-terminus, mimicking the functional effect of genetic CFH mutations and impairing complement regulation on host cell surfaces; this occurs almost exclusively in patients with CFHR1/CFHR3 deletion (DEAP-HUS).\",\n      \"method\": \"Immunological characterization of IgG autoantibodies to Factor H, correlation with CFHR1/CFHR3 deletion genotyping and complement functional assays\",\n      \"journal\": \"Pediatric nephrology (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — autoantibody characterization with defined epitope (C-terminus), genotype-phenotype correlation, single review consolidating multiple studies\",\n      \"pmids\": [\"20157737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IgG autoantibodies to Factor H in aHUS patients impair complement regulation by binding CFH, representing an acquired mechanism of complement dysregulation that defines the DEAP-HUS subgroup with CFHR1/CFHR3 protein deficiency.\",\n      \"method\": \"Autoantibody detection, CFHR1/CFHR3 deletion genotyping, complement pathway functional assessment\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct autoantibody characterization linked to functional complement impairment, replicated across multiple patient cohorts\",\n      \"pmids\": [\"19190803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-125b and miR-146a, upregulated by NF-κB activation in response to IL-1β and Aβ42 in human neuronal-glial cells, target CFH mRNA and cause significant decreases in CFH expression, establishing a post-transcriptional regulatory mechanism for CFH in neuroinflammation.\",\n      \"method\": \"miRNA overexpression in primary human neuronal-glial cell cultures, qPCR measurement of CFH expression, NF-κB pathway analysis\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional experiment in primary cells with quantified CFH mRNA reduction, two miRNAs tested, single lab\",\n      \"pmids\": [\"22302353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of endogenous CFH in human RPE cells leads to increased inflammatory mediators (IL-6, IL-8, GM-CSF) and altered complement protein levels (C3 and CFB upregulation, C5 downregulation), with NF-κB identified as the major pathway mediating these effects, establishing an autocrine role for RPE-derived CFH in maintaining inflammatory and complement homeostasis.\",\n      \"method\": \"CFH siRNA knockdown in hTERT-RPE1 cells, cytokine/complement protein quantification, NF-κB pathway inhibition\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular phenotype, multiple orthogonal readouts (cytokines and complement proteins), NF-κB pathway confirmed, single lab\",\n      \"pmids\": [\"34445430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CFH is required to maintain stemness in liver cancer cells; knockdown of CFH abrogates tumorsphere formation and induces differentiation, while overexpression stimulates stemness factor expression and in vivo cell growth, mechanistically through CFH-dependent LSF-1 expression which drives stemness factor transcription.\",\n      \"method\": \"siRNA knockdown and overexpression in liver cancer cell lines, tumorsphere assay, in vivo xenograft, LSF-1 expression analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with defined phenotypic readouts and mechanistic pathway (LSF-1), single lab\",\n      \"pmids\": [\"26723877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The CFH Y402H at-risk polymorphism is associated with higher C5a, IL-18, and TNF-α levels in Bruch's membrane/choroid; C5a promotes NF-κB activation and IL-18 upregulation in polarized RPE cells, establishing a mechanistic link between the Y402H variant, complement activation, and inflammasome pathway regulation in AMD pathology.\",\n      \"method\": \"Post-mortem donor eye genotyping with protein quantification, polarized ARPE19 cell stimulation with C5a/TNF-α, NF-κB reporter assay, gene expression analysis\",\n      \"journal\": \"The British journal of ophthalmology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human tissue analysis combined with functional cell experiments (NF-κB reporter, gene expression), multiple readouts, single lab\",\n      \"pmids\": [\"26746578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Molecular docking and experimental alanine scanning confirmed that the human anti-CFH antibody Ab42 interacts with CFH polypeptide through hydrogen bonds involving CDR residues (Tyr315, Ser100, Gly33, Tyr53) contacting CFH residues Pro441, Ile442, Asp443, Asn444, Ile447, and Thr448, defining the structural epitope of this interaction.\",\n      \"method\": \"Molecular docking, molecular dynamics simulation, free energy calculation, experimental alanine scanning mutagenesis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — computational structure prediction validated by experimental alanine scanning, but single lab and limited experimental validation of predicted interactions\",\n      \"pmids\": [\"31130605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Common AMD-associated CFH variants (e.g., FH p.Tyr402His/Y402H) strongly associate with elevated plasma FHR-1, FHR-2, FHR-3, and FHR-4A concentrations but not with FH (CFH protein) concentrations, suggesting that CFH genetic variants modulate AMD risk predominantly through effects on FHR protein levels rather than FH protein levels.\",\n      \"method\": \"ELISA quantification of FH and FHR proteins in 202 controls and 216 AMD patients, genotype-protein association analysis, immunolocalization of FHR-2 and FHR-5 in choroid and drusen\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein quantification linked to genotype in well-characterized cohort, tissue localization, but single study design\",\n      \"pmids\": [\"34260947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A missense variant N1050Y in CFH is protective against AMD (OR=0.76), and the rare R1210C variant confers high AMD risk (OR=18.82), with both variants having known functional consequences on CFH ligand binding, confirming that coding variation in CFH directly modulates AMD susceptibility through altered protein function.\",\n      \"method\": \"Exome chip genotyping meta-analysis in 4,332 cases and 25,268 controls; functional annotation of variants\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale genetic study with functionally annotated variants, replicated associations, but mechanistic inference relies on prior biochemical data\",\n      \"pmids\": [\"28011711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Structural variants involving CFH-CFHR rearrangements in aHUS patients include CFH::CFHR1 hybrid genes that produce dysfunctional CFH protein, and are associated with poor prognosis; eculizumab (anti-C5) treatment induced remission in affected acute episodes, confirming that CFH structural variants drive complement-mediated aHUS through loss of complement regulation.\",\n      \"method\": \"MLPA copy number variation analysis, long-read SMRT sequencing for breakpoint characterization in 258 primary aHUS and 92 secondary aHUS patients, clinical outcome analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive genomic characterization with clinical outcome correlation, large cohort, but mechanistic inference relies on known biology of CFH function\",\n      \"pmids\": [\"36793547\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFH encodes complement factor H (FH), a soluble and cell surface-bound regulator of the alternative complement pathway that functions primarily by binding C3b and acting as a cofactor for Factor I-mediated C3b inactivation; loss-of-function mutations, autoantibodies targeting its C-terminal surface-recognition domain, or structural rearrangements producing hybrid CFH-CFHR proteins all impair this regulatory activity, leading to uncontrolled complement activation that underlies atypical HUS, C3 glomerulopathy, and AMD; CFH is synthesized locally by the retinal pigmented epithelium where it modulates NF-κB-driven inflammatory and complement gene expression, and its expression is post-transcriptionally repressed by NF-κB-activated miR-125b and miR-146a in neuroinflammatory contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CFH encodes complement factor H (FH), the major soluble and cell-surface regulator of the alternative complement pathway, acting through C3b binding to restrain complement activation on host surfaces [#1, #2]. Loss-of-function arises through multiple routes that converge on impaired regulation: missense mutations that reduce protein expression or abolish C3b binding, C-terminal variants such as R1210C that abrogate surface-recognition ligand binding, autoantibodies that block the C-terminal recognition function (notably in patients carrying CFHR1/CFHR3 deletions, defining DEAP-HUS), and CFH::CFHR1 hybrid genes generated by structural rearrangement [#2, #3, #4, #5, #13]. These defects cause uncontrolled complement activation underlying atypical hemolytic uremic syndrome, membranoproliferative/C3 glomerulopathy, and age-related macular degeneration, with phenotype determined by whether plasma-bound or surface-bound FH function is impaired [#1, #2, #3]; coding variation in CFH directly modulates AMD susceptibility, with R1210C strongly raising risk and N1050Y protective [#12]. In the retina, FH is synthesized locally by the retinal pigmented epithelium, where it accumulates in drusen and acts as the principal local inhibitor of the alternative pathway [#0]. RPE-derived FH also serves an autocrine homeostatic role: its loss elevates inflammatory mediators (IL-6, IL-8, GM-CSF) and remodels complement protein levels through NF-\\u03baB signaling [#7], and the Y402H at-risk variant is linked to increased C5a, IL-18, and TNF-\\u03b1 and inflammasome-associated NF-\\u03baB activation in RPE [#9]. CFH expression is post-transcriptionally repressed by NF-\\u03baB-induced miR-125b and miR-146a in neuroinflammatory contexts [#6]. A distinct role in maintaining cancer stem-cell properties has been described in liver cancer cells, mediated through CFH-dependent LSF-1 expression [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that CFH is not only a plasma protein but is synthesized locally in the eye and accumulates in disease deposits, defining a tissue-resident role for complement regulation in the retina.\",\n      \"evidence\": \"Immunolocalization of FH in drusen and RPE synthesis with parallel AMD genetic association\",\n      \"pmids\": [\"15870199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish the molecular regulatory mechanism of local FH\", \"Causal direction between drusen FH accumulation and AMD not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that aHUS-associated CFH mutations cause disease either by lowering protein levels or by abolishing C3b binding, directly linking loss of FH-mediated C3b inactivation to complement dysregulation.\",\n      \"evidence\": \"Genetic screening of 156 aHUS patients with C3b-binding and expression functional assays\",\n      \"pmids\": [\"16621965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate surface-bound from fluid-phase regulatory defects\", \"Does not address downstream tissue injury mechanism\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Distinguished plasma-bound from surface-bound FH function, explaining how different CFH mutations produce distinct diseases (MPGN, aHUS, AMD), and identified acquired autoantibody-mediated FH inhibition as a parallel disease mechanism.\",\n      \"evidence\": \"Mutational/functional correlation review plus autoantibody detection with CFHR1/CFHR3 genotyping and complement assays\",\n      \"pmids\": [\"19297022\", \"19190803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype-to-tissue-specificity link remains correlative\", \"Mechanism by which CFHR1/CFHR3 deletion predisposes to autoantibodies not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Localized the functional autoantibody epitope to the FH C-terminus, showing autoantibodies phenocopy genetic C-terminal mutations by blocking surface recognition, and defined the DEAP-HUS subgroup.\",\n      \"evidence\": \"Epitope characterization of anti-FH IgG with CFHR1/CFHR3 deletion correlation\",\n      \"pmids\": [\"20157737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish why autoantibodies arise in CFHR-deficient patients\", \"Single-review consolidation rather than primary structural mapping\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that a single C-terminal variant (R1210C) abrogating ligand binding drives risk across two distinct diseases, unifying aHUS and AMD around loss of the surface-recognition function of FH.\",\n      \"evidence\": \"Sequencing and genotyping in 2,423 AMD cases and 1,122 controls with prior biochemical characterization\",\n      \"pmids\": [\"22019782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain divergent organ targeting of the same variant\", \"Mechanism of penetrance modulation unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a post-transcriptional control layer for CFH, showing NF-\\u03baB-induced miR-125b and miR-146a repress CFH mRNA in inflammatory conditions.\",\n      \"evidence\": \"miRNA overexpression in primary human neuronal-glial cells with qPCR of CFH\",\n      \"pmids\": [\"22302353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miRNA-CFH 3'UTR binding not demonstrated here\", \"Protein-level and functional consequences not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-complement role for CFH in sustaining liver cancer stem-cell properties via LSF-1-driven stemness transcription, expanding FH function beyond complement regulation.\",\n      \"evidence\": \"siRNA knockdown/overexpression, tumorsphere assays, xenografts, and LSF-1 expression analysis in liver cancer lines\",\n      \"pmids\": [\"26723877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CFH to LSF-1 not defined\", \"Independence from complement activity not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected the Y402H risk variant to inflammasome and cytokine signaling, showing elevated C5a/IL-18/TNF-\\u03b1 in choroid and C5a-driven NF-\\u03baB activation in RPE.\",\n      \"evidence\": \"Genotyped donor-eye protein quantification with polarized ARPE19 stimulation and NF-\\u03baB reporter assays\",\n      \"pmids\": [\"26746578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from Y402H to elevated C5a not directly demonstrated\", \"Single-lab cell-model findings\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Quantified directionality of CFH coding variation in AMD, confirming N1050Y protection and R1210C high risk through altered protein function.\",\n      \"evidence\": \"Exome-chip meta-analysis in 4,332 cases and 25,268 controls with functional annotation\",\n      \"pmids\": [\"28011711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences inferred from prior biochemistry, not measured here\", \"Tissue-level mechanism not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined the AMD risk model by showing common CFH variants associate with elevated FHR protein levels rather than altered FH levels, implicating the FH/FHR balance.\",\n      \"evidence\": \"ELISA quantification of FH/FHR in 202 controls and 216 AMD patients with genotype association and choroid/drusen immunolocalization\",\n      \"pmids\": [\"34260947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish the regulatory mechanism by which FHR proteins promote risk\", \"Single study design\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an autocrine homeostatic function for RPE-derived FH, showing its loss raises inflammatory mediators and remodels complement protein expression via NF-\\u03baB.\",\n      \"evidence\": \"CFH siRNA knockdown in hTERT-RPE1 cells with cytokine/complement quantification and NF-\\u03baB inhibition\",\n      \"pmids\": [\"34445430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular versus secreted FH contributions not separated\", \"Single-lab cell-line model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Characterized CFH-CFHR structural rearrangements (including CFH::CFHR1 hybrids) as drivers of complement-mediated aHUS with poor prognosis, with anti-C5 (eculizumab) inducing remission.\",\n      \"evidence\": \"MLPA and long-read SMRT sequencing in 258 primary and 92 secondary aHUS patients with clinical outcome analysis\",\n      \"pmids\": [\"36793547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise functional defect of hybrid protein inferred from known biology\", \"Mechanism of breakpoint formation not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the FH/FHR protein balance, local RPE FH synthesis, and the same C-terminal recognition defect together determine organ-specific disease (kidney versus retina) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of tissue-specific phenotype from shared molecular defects\", \"Direct structural mechanism of FHR competition with FH not established\", \"Functional link between non-complement (cancer stemness) and complement roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"C3\", \"CFI\", \"CFHR1\", \"CFHR3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}