{"gene":"HP","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1984,"finding":"The human Hp alpha2 allele is approximately twice the length of Hp alpha1 alleles and arose from a partial gene duplication, likely by unequal crossover in a heterozygous Hp alpha1F/Hp alpha1S individual. cDNA sequencing showed the Hp alpha2FS coding region is composed of alpha1F and alpha1S domains differing by four nucleotide replacements, establishing the evolutionary origin of the HP polymorphism.","method":"cDNA cloning and nucleotide sequence comparison of Hp alpha1S and Hp alpha2FS","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct cDNA sequencing establishing gene structure and duplication mechanism, single study","pmids":["6330675"],"is_preprint":false},{"year":2016,"finding":"Recurring exon deletions in the HP gene (reversions of an ancient hominin-specific duplication of two exons) affect haptoglobin protein structure and multimerization. By imputation from SNP haplotypes in 22,288 individuals, these HP exonic deletions associate with reduced LDL and total cholesterol levels, and a SNP affecting HP expression also drives this cholesterol association.","method":"Copy number variant analysis, SNP imputation from haplotypes, population genetic analysis, association study (n=22,288)","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale genetic association with functional structural inference, single study with multiple orthogonal analyses but no direct in vitro reconstitution of mechanism","pmids":["26901066"],"is_preprint":false},{"year":2007,"finding":"In individuals with diabetes mellitus and the Hp 2-2 genotype, expression of the hemoglobin scavenger receptor CD163 is significantly reduced on peripheral blood monocytes and in atherosclerotic plaques despite increased macrophage infiltration, resulting in impaired hemoglobin clearance capacity after intraplaque hemorrhage.","method":"Immunohistochemistry of plaques, FACS of peripheral blood monocytes, ELISA of soluble CD163 in plasma; comparison across Hp genotype and diabetes status","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal quantification methods (IHC, FACS, ELISA) in human samples, single lab, no direct in vitro mechanistic reconstitution","pmids":["17525367"],"is_preprint":false},{"year":2007,"finding":"A promoter SNP (A-61C) in the HP gene is associated with decreased HP protein levels (confirmed by in vitro studies referenced in the paper), and the -61C allele is in high haplotype association with the Hp2 allele, potentially explaining conflicting reports on Hp genotype and malaria susceptibility.","method":"Cohort genotyping, haplotype analysis, reference to in vitro promoter activity studies confirming reduced expression with -61C allele","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro confirmation of promoter effect is referenced but not performed in this paper; primary data are genetic association","pmids":["17426810"],"is_preprint":false},{"year":2013,"finding":"The HP gene harbors a polymorphic small intragenic duplication defining Hp1 and Hp2 alleles in human populations, with no evidence for recent natural selection by extended haplotype analysis. The paralogous HPR gene is also copy number variable (whole-gene duplication at polymorphic frequencies in west/central Africa), with the HPR duplication occurring on a single SNP haplotype.","method":"Fiber-FISH, paralog ratio test, array-CGH, extended haplotype homozygosity analysis across 52 populations","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal structural genomics methods (fiber-FISH, paralog ratio test, array-CGH) establishing copy number architecture, single study","pmids":["24005574"],"is_preprint":false},{"year":2004,"finding":"Haptoglobin mRNA is expressed locally within bovine mammary gland parenchymal tissue, tissue around cisternal milk ducts, and teat tissue, as demonstrated by RT-PCR and quantitative real-time RT-PCR of mammary biopsies. Local HP mRNA expression increased in the LPS-challenged quarter relative to controls, with milk Hp concentration rising 3 h after LPS challenge, earlier than blood Hp increase (9 h), supporting local mammary synthesis.","method":"RT-PCR and real-time RT-PCR of mammary biopsies; ELISA quantification of Hp in blood and milk after intracisternal LPS challenge","journal":"Journal of dairy science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization of HP mRNA by RT-PCR combined with functional ELISA readout in a controlled LPS challenge model, single lab","pmids":["15483161"],"is_preprint":false}],"current_model":"Haptoglobin (HP) is a plasma acute-phase glycoprotein whose protein structure and multimerization are determined by a polymorphic intragenic exon duplication (Hp1 vs. Hp2 alleles arising from ancient unequal crossover); it scavenges free hemoglobin and facilitates its clearance via the CD163 receptor on macrophages, with the Hp 2-2 genotype in diabetic individuals causing downregulation of CD163 and impaired hemoglobin clearance; recurring exon deletions in HP reduce protein levels and are associated with lower LDL and total cholesterol; and HP is expressed not only in the liver but also locally in extrahepatic tissues such as the mammary gland, where expression is upregulated during inflammation."},"narrative":{"mechanistic_narrative":"Haptoglobin (HP) is a plasma acute-phase glycoprotein whose structural diversity in human populations is governed by a polymorphic intragenic exon duplication that defines the Hp1 and Hp2 alleles [PMID:6330675, PMID:24005574]. The Hp alpha2 allele is approximately twice the length of Hp alpha1 and arose by unequal crossover in a heterozygous individual, generating a coding region built from fused alpha1F and alpha1S domains [PMID:6330675]; this duplication and its recurring exonic reversions alter haptoglobin protein structure and multimerization [PMID:26901066, PMID:24005574]. Functionally, HP scavenges free hemoglobin for clearance through the macrophage scavenger receptor CD163: in diabetic individuals carrying the Hp 2-2 genotype, CD163 expression is reduced on peripheral blood monocytes and in atherosclerotic plaques, impairing hemoglobin clearance after intraplaque hemorrhage [PMID:17525367]. Genetic variation in HP expression has systemic metabolic consequences, with recurring HP exonic deletions and an expression-altering SNP associating with reduced LDL and total cholesterol [PMID:26901066]. Beyond hepatic production, HP is synthesized locally in extrahepatic tissue such as the mammary gland, where its mRNA and secreted protein rise rapidly upon LPS challenge ahead of the blood response, indicating an in situ inflammatory function [PMID:15483161].","teleology":[{"year":1984,"claim":"Established the evolutionary and molecular origin of the human HP polymorphism, explaining why the Hp alpha2 protein is structurally distinct from Hp alpha1.","evidence":"cDNA cloning and nucleotide sequence comparison of Hp alpha1S and Hp alpha2FS alleles","pmids":["6330675"],"confidence":"Medium","gaps":["Does not establish functional consequences of the duplication for hemoglobin binding or clearance","Single study without independent confirmation of the crossover mechanism","No structural model of the resulting multimers"]},{"year":2004,"claim":"Showed HP is not exclusively hepatic but is synthesized locally in mammary tissue and induced by inflammation, reframing HP as a local acute-phase effector.","evidence":"RT-PCR and real-time RT-PCR of bovine mammary biopsies with ELISA of milk and blood Hp after intracisternal LPS challenge","pmids":["15483161"],"confidence":"Medium","gaps":["Demonstrated in bovine tissue; human extrahepatic expression not directly tested here","Does not identify the signaling pathway driving local induction","Functional role of locally produced Hp in milk not established"]},{"year":2007,"claim":"Linked the Hp 2-2 genotype to impaired hemoglobin clearance via reduced CD163, providing a mechanistic basis for genotype-dependent vascular risk in diabetes.","evidence":"IHC of atherosclerotic plaques, FACS of monocytes, and ELISA of soluble CD163 stratified by Hp genotype and diabetes status","pmids":["17525367"],"confidence":"Medium","gaps":["Correlative human-sample data without in vitro reconstitution of the Hp-CD163 clearance defect","Mechanism connecting Hp genotype to CD163 downregulation not resolved","Single lab"]},{"year":2007,"claim":"Identified a promoter SNP (A-61C) lowering HP expression in tight haplotype linkage with Hp2, offering a candidate explanation for inconsistent Hp-malaria associations.","evidence":"Cohort genotyping and haplotype analysis with reference to prior in vitro promoter activity data","pmids":["17426810"],"confidence":"Low","gaps":["In vitro promoter effect was referenced rather than performed in this study","Primary data are genetic association, not functional","Causal contribution to disease phenotype not directly demonstrated"]},{"year":2013,"claim":"Mapped the copy-number architecture of HP and its paralog HPR across populations, defining the structural variant landscape underlying Hp protein diversity.","evidence":"Fiber-FISH, paralog ratio test, array-CGH, and extended haplotype homozygosity across 52 populations","pmids":["24005574"],"confidence":"Medium","gaps":["No evidence of recent selection found, leaving the polymorphism's maintenance unexplained","Functional consequences of HPR copy number not characterized","Single study"]},{"year":2016,"claim":"Connected HP structural variation to systemic lipid metabolism, showing exonic deletions and an expression SNP associate with lower cholesterol.","evidence":"Copy number variant analysis with SNP imputation and association testing in 22,288 individuals","pmids":["26901066"],"confidence":"Medium","gaps":["Mechanism linking HP structure/expression to cholesterol not established in vitro","Causal direction inferred from imputed genetics rather than perturbation","Multimerization effect on lipid handling not directly measured"]},{"year":null,"claim":"The biochemical mechanism by which Hp genotype and expression level alter hemoglobin clearance, cholesterol levels, and inflammatory responses remains uncharacterized at the level of direct reconstitution.","evidence":"No direct in vitro mechanistic study present in the available corpus","pmids":[],"confidence":"Low","gaps":["No reconstituted Hp-hemoglobin-CD163 clearance assay in the timeline","No structural basis for multimer-dependent function","Causal pathway from HP variation to lipid metabolism unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5]}],"pathway":[],"complexes":[],"partners":["CD163"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P00738","full_name":"Haptoglobin","aliases":["Zonulin"],"length_aa":406,"mass_kda":45.2,"function":"As a result of hemolysis, hemoglobin is found to accumulate in the kidney and is secreted in the urine. Haptoglobin captures, and combines with free plasma hemoglobin to allow hepatic recycling of heme iron and to prevent kidney damage. Haptoglobin also acts as an antioxidant, has antibacterial activity, and plays a role in modulating many aspects of the acute phase response. Hemoglobin/haptoglobin complexes are rapidly cleared by the macrophage CD163 scavenger receptor expressed on the surface of liver Kupfer cells through an endocytic lysosomal degradation pathway The uncleaved form of allele alpha-2 (2-2), known as zonulin, plays a role in intestinal permeability, allowing intercellular tight junction disassembly, and controlling the equilibrium between tolerance and immunity to non-self antigens","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P00738/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":383,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HP","total_profiled":1310},"omim":[{"mim_id":"621395","title":"DEAD-BOX HELICASE 19A; DDX19A","url":"https://www.omim.org/entry/621395"},{"mim_id":"621315","title":"MINDY LYSINE-48 DEUBIQUITINASE 4; MINDY4","url":"https://www.omim.org/entry/621315"},{"mim_id":"621169","title":"MONILETHRIX 2; MNLIX2","url":"https://www.omim.org/entry/621169"},{"mim_id":"620793","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 29; LGMDR29","url":"https://www.omim.org/entry/620793"},{"mim_id":"620660","title":"CCZ1 HOMOLOG, VACUOLAR PROTEIN TRAFFICKING- AND BIOGENESIS-ASSOCIATED PROTEIN; CCZ1","url":"https://www.omim.org/entry/620660"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":55848.1}],"url":"https://www.proteinatlas.org/search/HP"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P00738","domains":[{"cath_id":"2.10.70.10","chopping":"102-147","consensus_level":"high","plddt":90.9954,"start":102,"end":147},{"cath_id":"2.40.10.10","chopping":"167-406","consensus_level":"medium","plddt":92.6927,"start":167,"end":406}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00738","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00738-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00738-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HP","jax_strain_url":"https://www.jax.org/strain/search?query=HP"},"sequence":{"accession":"P00738","fasta_url":"https://rest.uniprot.org/uniprotkb/P00738.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00738/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00738"}},"corpus_meta":[{"pmid":"1644277","id":"PMC_1644277","title":"The heterochromatin-associated protein HP-1 is an essential protein in Drosophila with dosage-dependent effects on position-effect variegation.","date":"1992","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1644277","citation_count":274,"is_preprint":false},{"pmid":"10790422","id":"PMC_10790422","title":"The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a protective antigen and a major virulence factor.","date":"2000","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10790422","citation_count":239,"is_preprint":false},{"pmid":"19339125","id":"PMC_19339125","title":"An attenuated live vaccine based on highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) protects piglets against HP-PRRS.","date":"2009","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19339125","citation_count":126,"is_preprint":false},{"pmid":"17525367","id":"PMC_17525367","title":"Downregulation of the 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sulfate (HP/HS) interacting protein (HIP) supports cell attachment and selective, high affinity binding of HP/HS.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9325317","citation_count":31,"is_preprint":false},{"pmid":"1620650","id":"PMC_1620650","title":"The levels and biologic action of the human neutrophil granule peptide HP-1 in lung tumors.","date":"1992","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/1620650","citation_count":31,"is_preprint":false},{"pmid":"12532440","id":"PMC_12532440","title":"Association of cyclooxygenase-2 expression with Hp-cagA infection in gastric cancer.","date":"2003","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/12532440","citation_count":30,"is_preprint":false},{"pmid":"8469233","id":"PMC_8469233","title":"The gene encoding the human corticostatin HP-4 precursor contains a recent 86-base duplication and is located on chromosome 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biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9545307","citation_count":28,"is_preprint":false},{"pmid":"33988885","id":"PMC_33988885","title":"The parasite cytokine mimic Hp-TGM potently replicates the regulatory effects of TGF-β on murine CD4+ T cells.","date":"2021","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33988885","citation_count":27,"is_preprint":false},{"pmid":"27203711","id":"PMC_27203711","title":"Hp: an inflammatory indicator in cardiovascular disease.","date":"2016","source":"Future cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/27203711","citation_count":26,"is_preprint":false},{"pmid":"31427001","id":"PMC_31427001","title":"HP-1 inhibits the progression of ccRCC and enhances sunitinib therapeutic effects by suppressing EMT.","date":"2019","source":"Carbohydrate 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L.","date":"2019","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/31398403","citation_count":25,"is_preprint":false},{"pmid":"30344716","id":"PMC_30344716","title":"Analysis of correlation between HP infection and activation of PI3K/Akt pathway in mucosal tissues of gastric cancer and precancerous lesions.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30344716","citation_count":25,"is_preprint":false},{"pmid":"31971306","id":"PMC_31971306","title":"Choline Chloride as a Nano-Crowder Protects HP-36 from Urea-Induced Denaturation: Insights from Solvent Dynamics and Protein-Solvent Interactions.","date":"2020","source":"Chemphyschem : a European journal of chemical physics and physical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31971306","citation_count":24,"is_preprint":false},{"pmid":"31717616","id":"PMC_31717616","title":"Ginsenoside Rg1 Suppresses Type 2 PRRSV Infection via NF-κB Signaling Pathway In Vitro, and Provides Partial Protection against HP-PRRSV in Piglet.","date":"2019","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/31717616","citation_count":23,"is_preprint":false},{"pmid":"4204438","id":"PMC_4204438","title":"Beta-D-phosphogalactoside galactohydrolase from Streptococcus cremoris HP: purification and enzyme properties.","date":"1974","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/4204438","citation_count":23,"is_preprint":false},{"pmid":"35844568","id":"PMC_35844568","title":"HP-NAP of Helicobacter pylori: The Power of the Immunomodulation.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35844568","citation_count":22,"is_preprint":false},{"pmid":"37670901","id":"PMC_37670901","title":"Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial.","date":"2023","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/37670901","citation_count":22,"is_preprint":false},{"pmid":"35798224","id":"PMC_35798224","title":"Hydroxypropyl-beta-cyclodextrin (HP-BCD) inhibits SARS-CoV-2 replication and virus-induced inflammatory cytokines.","date":"2022","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/35798224","citation_count":21,"is_preprint":false},{"pmid":"33836390","id":"PMC_33836390","title":"Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) induces IL-6 production through TAK-1/JNK/AP-1 and TAK-1/NF-κB signaling pathways.","date":"2021","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33836390","citation_count":21,"is_preprint":false},{"pmid":"33182033","id":"PMC_33182033","title":"Serum exosomes derived from Hp-positive gastritis patients inhibit MCP-1 and MIP-1α expression via NLRP12-Notch signaling pathway in intestinal epithelial cells and improve DSS-induced colitis in mice.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33182033","citation_count":21,"is_preprint":false},{"pmid":"24166638","id":"PMC_24166638","title":"RFLP mapping of the dwarfing (Ddw1) and hairy peduncle (Hp) genes on chromosome 5 of rye (Secale cereale L.).","date":"1996","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/24166638","citation_count":21,"is_preprint":false},{"pmid":"22843314","id":"PMC_22843314","title":"Evaluation of a DNA vaccine candidate co-expressing GP3 and GP5 of porcine reproductive and respiratory syndrome virus (PRRSV) with interferon α/γ in immediate and long-lasting protection against HP-PRRSV challenge.","date":"2012","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/22843314","citation_count":21,"is_preprint":false},{"pmid":"9278060","id":"PMC_9278060","title":"Local rules for protein folding on a triangular lattice and generalized hydrophobicity in the HP model.","date":"1997","source":"Journal of computational biology : a journal of computational molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9278060","citation_count":21,"is_preprint":false},{"pmid":"30700328","id":"PMC_30700328","title":"FLT PET/CT imaging of metastatic prostate cancer patients treated with pTVG-HP DNA vaccine and pembrolizumab.","date":"2019","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30700328","citation_count":20,"is_preprint":false},{"pmid":"34959278","id":"PMC_34959278","title":"Formulation of Genistein-HP β Cyclodextrin-Poloxamer 188 Ternary Inclusion Complex: Solubility to Cytotoxicity Assessment.","date":"2021","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/34959278","citation_count":20,"is_preprint":false},{"pmid":"24868096","id":"PMC_24868096","title":"Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF.","date":"2014","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/24868096","citation_count":20,"is_preprint":false},{"pmid":"35758054","id":"PMC_35758054","title":"Suppression of airway allergic eosinophilia by Hp-TGM, a helminth mimic of TGF-β.","date":"2022","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35758054","citation_count":19,"is_preprint":false},{"pmid":"1758971","id":"PMC_1758971","title":"The effect of HP-1 and related neutrophil granule peptides on DNA synthesis in HL60 cells.","date":"1991","source":"Regulatory peptides","url":"https://pubmed.ncbi.nlm.nih.gov/1758971","citation_count":19,"is_preprint":false},{"pmid":"32222356","id":"PMC_32222356","title":"Notch signaling contributes to the expression of inflammatory cytokines induced by highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) infection in porcine alveolar macrophages.","date":"2020","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32222356","citation_count":19,"is_preprint":false},{"pmid":"21147083","id":"PMC_21147083","title":"Haptoglobin (HP) polymorphisms and human longevity: a cross-sectional association study in a Central Italy population.","date":"2010","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21147083","citation_count":19,"is_preprint":false},{"pmid":"30386616","id":"PMC_30386616","title":"Peptide Hp(2-20) accelerates healing of TNBS-induced colitis in the rat.","date":"2018","source":"United European gastroenterology journal","url":"https://pubmed.ncbi.nlm.nih.gov/30386616","citation_count":18,"is_preprint":false},{"pmid":"32175596","id":"PMC_32175596","title":"Inclusion complexes of tea polyphenols with HP-β-cyclodextrin:Preparation, characterization, molecular docking, and antioxidant activity.","date":"2020","source":"Journal of food science","url":"https://pubmed.ncbi.nlm.nih.gov/32175596","citation_count":18,"is_preprint":false},{"pmid":"26143005","id":"PMC_26143005","title":"Distribution of highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) in different stages of gestation sows: HP-PRRSV distribution in gestation sows.","date":"2015","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/26143005","citation_count":18,"is_preprint":false},{"pmid":"17368441","id":"PMC_17368441","title":"VacA and HP-NAP, Ying and Yang of Helicobacter pylori-associated gastric inflammation.","date":"2007","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17368441","citation_count":17,"is_preprint":false},{"pmid":"31817887","id":"PMC_31817887","title":"Preparation and Characterisation of Polyphenol-HP-β-Cyclodextrin Inclusion Complex that Protects Lamb Tripe Protein against Oxidation.","date":"2019","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31817887","citation_count":17,"is_preprint":false},{"pmid":"25412589","id":"PMC_25412589","title":"Expression of recombinant and mosaic Cry1Ac receptors from Helicoverpa armigera and their influences on the cytotoxicity of activated Cry1Ac to Spodoptera litura Sl-HP cells.","date":"2014","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/25412589","citation_count":17,"is_preprint":false},{"pmid":"32184034","id":"PMC_32184034","title":"Oral supplementation of quercetin in PRRSV-1 modified-live virus vaccinated pigs in response to HP-PRRSV-2 challenge.","date":"2020","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/32184034","citation_count":17,"is_preprint":false},{"pmid":"36680205","id":"PMC_36680205","title":"Recombination and Mutation in a New HP-PRRSV Strain (SD2020) from China.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/36680205","citation_count":16,"is_preprint":false},{"pmid":"1714562","id":"PMC_1714562","title":"HP 0.35, a cephalosporin degradation product is a specific inhibitor of lentiviral RNAses H.","date":"1991","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1714562","citation_count":16,"is_preprint":false},{"pmid":"32891719","id":"PMC_32891719","title":"Silibinin-hydroxypropyl-β-cyclodextrin (SLB-HP-β-CD) complex prevents apoptosis in liver and kidney after hepatic ischemia-reperfusion injury.","date":"2020","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/32891719","citation_count":16,"is_preprint":false},{"pmid":"10657971","id":"PMC_10657971","title":"Human phenol sulfotransferases hP-PST and hM-PST activate propane 2-nitronate to a genotoxicant.","date":"2000","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/10657971","citation_count":15,"is_preprint":false},{"pmid":"39126939","id":"PMC_39126939","title":"Interaction of zein/HP-β-CD nanoparticles with digestive enzymes: Enhancing curcumin bioavailability.","date":"2024","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39126939","citation_count":15,"is_preprint":false},{"pmid":"32452419","id":"PMC_32452419","title":"Aspartic acid at residue 185 modulates the capacity of HP-PRRSV nsp4 to antagonize IFN-I expression.","date":"2020","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/32452419","citation_count":15,"is_preprint":false},{"pmid":"38625481","id":"PMC_38625481","title":"hP-MSCs attenuate severe acute pancreatitis in mice via inhibiting NLRP3 inflammasome-mediated acinar cell pyroptosis.","date":"2024","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/38625481","citation_count":14,"is_preprint":false},{"pmid":"22736819","id":"PMC_22736819","title":"Identification of a secreted fatty acid and retinol-binding protein (Hp-FAR-1) from Heligmosomoides polygyrus.","date":"2009","source":"Journal of nematology","url":"https://pubmed.ncbi.nlm.nih.gov/22736819","citation_count":14,"is_preprint":false},{"pmid":"6330675","id":"PMC_6330675","title":"Evolution of haptoglobin: comparison of complementary DNA encoding Hp alpha 1S and Hp alpha 2FS.","date":"1984","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/6330675","citation_count":14,"is_preprint":false},{"pmid":"11473599","id":"PMC_11473599","title":"Nucleotide sequence and characterization of the cell envelope proteinase plasmid in Lactococcus lactis subsp. cremoris HP.","date":"2001","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11473599","citation_count":14,"is_preprint":false},{"pmid":"35163566","id":"PMC_35163566","title":"Macrophage-Mediated Melanoma Reduction after HP-NAP Treatment in a Zebrafish Xenograft Model.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35163566","citation_count":13,"is_preprint":false},{"pmid":"30408641","id":"PMC_30408641","title":"Endometrial expression of the acute phase molecule SAA is more significant than HP in reflecting the severity of endometritis.","date":"2018","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/30408641","citation_count":13,"is_preprint":false},{"pmid":"30346715","id":"PMC_30346715","title":"Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer's Disease Model Cells.","date":"2018","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30346715","citation_count":12,"is_preprint":false},{"pmid":"36631812","id":"PMC_36631812","title":"Molecular imaging of HER2 expression in breast cancer patients using a novel peptide-based tracer 99mTc-HP-Ark2: a pilot study.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36631812","citation_count":12,"is_preprint":false},{"pmid":"31888183","id":"PMC_31888183","title":"Significance and Transformation of 3-Alkyl-2-Methoxypyrazines Through Grapes to Wine: Olfactory Properties, Metabolism, Biochemical Regulation, and the HP-MP Cycle.","date":"2019","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31888183","citation_count":12,"is_preprint":false},{"pmid":"33003399","id":"PMC_33003399","title":"Hp-s1 Ganglioside Suppresses Proinflammatory Responses by Inhibiting MyD88-Dependent NF-κB and JNK/p38 MAPK Pathways in Lipopolysaccharide-Stimulated Microglial Cells.","date":"2020","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/33003399","citation_count":12,"is_preprint":false},{"pmid":"29902601","id":"PMC_29902601","title":"Study of Correlation Between Hp α1 Expression of Haptoglobin 2-1 and Clinical Course in Aneurysmal Subarachnoid Hemorrhage.","date":"2018","source":"World neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/29902601","citation_count":12,"is_preprint":false},{"pmid":"18493720","id":"PMC_18493720","title":"Regulation of cell invasion and signalling pathways in the pituitary adenoma cell line, HP-75, by reversion-inducing cysteine-rich protein with kazal motifs (RECK).","date":"2008","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18493720","citation_count":12,"is_preprint":false},{"pmid":"39979934","id":"PMC_39979934","title":"Metabolic engineering of Komagataella phaffii for enhanced 3-hydroxypropionic acid (3-HP) production from methanol.","date":"2025","source":"Journal of biological engineering","url":"https://pubmed.ncbi.nlm.nih.gov/39979934","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52467,"output_tokens":2446,"usd":0.097046,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8467,"output_tokens":2323,"usd":0.050205,"stage2_stop_reason":"end_turn"},"total_usd":0.147251,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human HP gene (haptoglobin). The corpus contains many papers with \"HP\" abbreviations referring to different things (Helicobacter pylori, HP-PRRSV virus, HP-NAP protein, HP-β-cyclodextrin, Drosophila HP-1 heterochromatin protein, defensin peptides HP-1/HP-4, etc.). I need to focus only on papers about the canonical human haptoglobin (HP) gene/protein.\n\nRelevant papers about human haptoglobin (HP):\n- PMID:26901066 - Boettger et al. (2016) - HP exonic deletions, cholesterol levels, protein structure/multimerization\n- PMID:17525367 - Levy et al. (2007) - HP genotype, CD163 receptor, hemoglobin clearance\n- PMID:1572675 - Teige et al. (1992) - HP allele/subtype characterization\n- PMID:6330675 - Brune et al. (1984) - HP cDNA comparison, Hp alpha2 as partial gene duplication\n- PMID:24005574 - Hardwick et al. (2013) - HP/HPR copy number variation\n- PMID:15483161 - Hiss et al. (2004) - HP mRNA expression in mammary gland (bovine)\n- PMID:22230385 - Lecchi et al. (2011) - HP mRNA expression in bovine tissues\n- PMID:16897611 - Wan et al. (2006) - HP genotype/schizophrenia\n- PMID:17426810 - Cox et al. (2007) - HP promoter SNP, Hp expression levels\n- PMID:19474129 - McDermid et al. (2009) - HP genotypes and HIV mortality\n- PMID:1572675 - population genetics\n- PMID:29902601 - Kim et al. (2018) - Hp phenotypes and SAH outcomes\n- PMID:21147083 - Napolioni et al. (2010) - HP polymorphisms and longevity\n\nFor mechanistic discoveries specifically:\n\n1. PMID:26901066 - HP exon copy number variation affects protein structure/multimerization; deletions associate with reduced LDL/cholesterol\n2. PMID:6330675 - Hp alpha2 allele arose from partial gene duplication (unequal crossover); cDNA sequencing established structure\n3. PMID:17525367 - HP genotype (Hp 2-2) + diabetes → downregulation of CD163 hemoglobin scavenger receptor → impaired hemoglobin clearance\n4. PMID:24005574 - HP gene has polymorphic intragenic duplication (Hp1/Hp2 alleles); HPR is copy number variable\n5. PMID:17426810 - A-61C SNP in HP promoter associated with decreased Hp protein levels (confirmed in vitro)\n6. PMID:15483161 - HP mRNA expressed locally in mammary gland (RT-PCR, real-time PCR); local Hp expression demonstrated\n7. PMID:33836390 - not about HP gene\n8. PMID:30386616 - not about HP gene (Hp(2-20) is H. pylori peptide)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1984,\n      \"finding\": \"The human Hp alpha2 allele is approximately twice the length of Hp alpha1 alleles and arose from a partial gene duplication, likely by unequal crossover in a heterozygous Hp alpha1F/Hp alpha1S individual. cDNA sequencing showed the Hp alpha2FS coding region is composed of alpha1F and alpha1S domains differing by four nucleotide replacements, establishing the evolutionary origin of the HP polymorphism.\",\n      \"method\": \"cDNA cloning and nucleotide sequence comparison of Hp alpha1S and Hp alpha2FS\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct cDNA sequencing establishing gene structure and duplication mechanism, single study\",\n      \"pmids\": [\"6330675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Recurring exon deletions in the HP gene (reversions of an ancient hominin-specific duplication of two exons) affect haptoglobin protein structure and multimerization. By imputation from SNP haplotypes in 22,288 individuals, these HP exonic deletions associate with reduced LDL and total cholesterol levels, and a SNP affecting HP expression also drives this cholesterol association.\",\n      \"method\": \"Copy number variant analysis, SNP imputation from haplotypes, population genetic analysis, association study (n=22,288)\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale genetic association with functional structural inference, single study with multiple orthogonal analyses but no direct in vitro reconstitution of mechanism\",\n      \"pmids\": [\"26901066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In individuals with diabetes mellitus and the Hp 2-2 genotype, expression of the hemoglobin scavenger receptor CD163 is significantly reduced on peripheral blood monocytes and in atherosclerotic plaques despite increased macrophage infiltration, resulting in impaired hemoglobin clearance capacity after intraplaque hemorrhage.\",\n      \"method\": \"Immunohistochemistry of plaques, FACS of peripheral blood monocytes, ELISA of soluble CD163 in plasma; comparison across Hp genotype and diabetes status\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal quantification methods (IHC, FACS, ELISA) in human samples, single lab, no direct in vitro mechanistic reconstitution\",\n      \"pmids\": [\"17525367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A promoter SNP (A-61C) in the HP gene is associated with decreased HP protein levels (confirmed by in vitro studies referenced in the paper), and the -61C allele is in high haplotype association with the Hp2 allele, potentially explaining conflicting reports on Hp genotype and malaria susceptibility.\",\n      \"method\": \"Cohort genotyping, haplotype analysis, reference to in vitro promoter activity studies confirming reduced expression with -61C allele\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro confirmation of promoter effect is referenced but not performed in this paper; primary data are genetic association\",\n      \"pmids\": [\"17426810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The HP gene harbors a polymorphic small intragenic duplication defining Hp1 and Hp2 alleles in human populations, with no evidence for recent natural selection by extended haplotype analysis. The paralogous HPR gene is also copy number variable (whole-gene duplication at polymorphic frequencies in west/central Africa), with the HPR duplication occurring on a single SNP haplotype.\",\n      \"method\": \"Fiber-FISH, paralog ratio test, array-CGH, extended haplotype homozygosity analysis across 52 populations\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal structural genomics methods (fiber-FISH, paralog ratio test, array-CGH) establishing copy number architecture, single study\",\n      \"pmids\": [\"24005574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Haptoglobin mRNA is expressed locally within bovine mammary gland parenchymal tissue, tissue around cisternal milk ducts, and teat tissue, as demonstrated by RT-PCR and quantitative real-time RT-PCR of mammary biopsies. Local HP mRNA expression increased in the LPS-challenged quarter relative to controls, with milk Hp concentration rising 3 h after LPS challenge, earlier than blood Hp increase (9 h), supporting local mammary synthesis.\",\n      \"method\": \"RT-PCR and real-time RT-PCR of mammary biopsies; ELISA quantification of Hp in blood and milk after intracisternal LPS challenge\",\n      \"journal\": \"Journal of dairy science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization of HP mRNA by RT-PCR combined with functional ELISA readout in a controlled LPS challenge model, single lab\",\n      \"pmids\": [\"15483161\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Haptoglobin (HP) is a plasma acute-phase glycoprotein whose protein structure and multimerization are determined by a polymorphic intragenic exon duplication (Hp1 vs. Hp2 alleles arising from ancient unequal crossover); it scavenges free hemoglobin and facilitates its clearance via the CD163 receptor on macrophages, with the Hp 2-2 genotype in diabetic individuals causing downregulation of CD163 and impaired hemoglobin clearance; recurring exon deletions in HP reduce protein levels and are associated with lower LDL and total cholesterol; and HP is expressed not only in the liver but also locally in extrahepatic tissues such as the mammary gland, where expression is upregulated during inflammation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Haptoglobin (HP) is a plasma acute-phase glycoprotein whose structural diversity in human populations is governed by a polymorphic intragenic exon duplication that defines the Hp1 and Hp2 alleles [#0, #4]. The Hp alpha2 allele is approximately twice the length of Hp alpha1 and arose by unequal crossover in a heterozygous individual, generating a coding region built from fused alpha1F and alpha1S domains [#0]; this duplication and its recurring exonic reversions alter haptoglobin protein structure and multimerization [#1, #4]. Functionally, HP scavenges free hemoglobin for clearance through the macrophage scavenger receptor CD163: in diabetic individuals carrying the Hp 2-2 genotype, CD163 expression is reduced on peripheral blood monocytes and in atherosclerotic plaques, impairing hemoglobin clearance after intraplaque hemorrhage [#2]. Genetic variation in HP expression has systemic metabolic consequences, with recurring HP exonic deletions and an expression-altering SNP associating with reduced LDL and total cholesterol [#1]. Beyond hepatic production, HP is synthesized locally in extrahepatic tissue such as the mammary gland, where its mRNA and secreted protein rise rapidly upon LPS challenge ahead of the blood response, indicating an in situ inflammatory function [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Established the evolutionary and molecular origin of the human HP polymorphism, explaining why the Hp alpha2 protein is structurally distinct from Hp alpha1.\",\n      \"evidence\": \"cDNA cloning and nucleotide sequence comparison of Hp alpha1S and Hp alpha2FS alleles\",\n      \"pmids\": [\"6330675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not establish functional consequences of the duplication for hemoglobin binding or clearance\",\n        \"Single study without independent confirmation of the crossover mechanism\",\n        \"No structural model of the resulting multimers\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed HP is not exclusively hepatic but is synthesized locally in mammary tissue and induced by inflammation, reframing HP as a local acute-phase effector.\",\n      \"evidence\": \"RT-PCR and real-time RT-PCR of bovine mammary biopsies with ELISA of milk and blood Hp after intracisternal LPS challenge\",\n      \"pmids\": [\"15483161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Demonstrated in bovine tissue; human extrahepatic expression not directly tested here\",\n        \"Does not identify the signaling pathway driving local induction\",\n        \"Functional role of locally produced Hp in milk not established\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked the Hp 2-2 genotype to impaired hemoglobin clearance via reduced CD163, providing a mechanistic basis for genotype-dependent vascular risk in diabetes.\",\n      \"evidence\": \"IHC of atherosclerotic plaques, FACS of monocytes, and ELISA of soluble CD163 stratified by Hp genotype and diabetes status\",\n      \"pmids\": [\"17525367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Correlative human-sample data without in vitro reconstitution of the Hp-CD163 clearance defect\",\n        \"Mechanism connecting Hp genotype to CD163 downregulation not resolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified a promoter SNP (A-61C) lowering HP expression in tight haplotype linkage with Hp2, offering a candidate explanation for inconsistent Hp-malaria associations.\",\n      \"evidence\": \"Cohort genotyping and haplotype analysis with reference to prior in vitro promoter activity data\",\n      \"pmids\": [\"17426810\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"In vitro promoter effect was referenced rather than performed in this study\",\n        \"Primary data are genetic association, not functional\",\n        \"Causal contribution to disease phenotype not directly demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped the copy-number architecture of HP and its paralog HPR across populations, defining the structural variant landscape underlying Hp protein diversity.\",\n      \"evidence\": \"Fiber-FISH, paralog ratio test, array-CGH, and extended haplotype homozygosity across 52 populations\",\n      \"pmids\": [\"24005574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No evidence of recent selection found, leaving the polymorphism's maintenance unexplained\",\n        \"Functional consequences of HPR copy number not characterized\",\n        \"Single study\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected HP structural variation to systemic lipid metabolism, showing exonic deletions and an expression SNP associate with lower cholesterol.\",\n      \"evidence\": \"Copy number variant analysis with SNP imputation and association testing in 22,288 individuals\",\n      \"pmids\": [\"26901066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking HP structure/expression to cholesterol not established in vitro\",\n        \"Causal direction inferred from imputed genetics rather than perturbation\",\n        \"Multimerization effect on lipid handling not directly measured\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which Hp genotype and expression level alter hemoglobin clearance, cholesterol levels, and inflammatory responses remains uncharacterized at the level of direct reconstitution.\",\n      \"evidence\": \"No direct in vitro mechanistic study present in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstituted Hp-hemoglobin-CD163 clearance assay in the timeline\",\n        \"No structural basis for multimer-dependent function\",\n        \"Causal pathway from HP variation to lipid metabolism unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"CD163\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}