GEO combined with quantitative protein trait loci identify causative proteins in hypertrophic cardiomyopathy.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40348582", "kind": "science-record", "revision": 2, "content_hash": "sha256:b18b1cf2a6d624bbf8fc3209e543556a05900b433b69316bfeb737ef00528a13", "created_at": "2026-11-01T20:30:30Z", "updated_at": "2026-11-01T21:35:10Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "GEO combined with quantitative protein trait loci identify causative proteins in hypertrophic cardiomyopathy.", "doi": "10.1002/ehf2.15287", "pmid": "40348582", "authors": ["Bo Li", "Xu Zhao", "Yan Ding", "Yi Zhang"], "journal": "ESC heart failure", "year": 2025, "abstract": "AIMS: Hypertrophic cardiomyopathy (HCM) is a rare genetic heart disease characterized by a limited patient population and scarce research and treatment resources. This study aimed to identify HCM-associated proteins by integrating cardiac tissue data from the Gene Expression Omnibus (GEO) database with the latest protein quantitative trait locus (pQTL) dataset.\nMETHODS AND RESULTS: We analysed data from the GEO database. The GSE36961 dataset included 106 HCM samples and 39 healthy controls. The GSE180313 dataset included 13 HCM samples and 7 healthy controls. pQTL data were obtained from the plasma of 54 000 UK Biobank participants, covering 1463 proteins. HCM genome-wide association study (GWAS) data were sourced from the FinnGen study, which included 1125 HCM cases and 411 056 controls. We analysed the GEO dataset of cardiac tissue from HCM patients to identify differentially expressed genes (DEGs). These DEGs were compared with pQTL data to identify protein phenotypes suitable for Mendelian randomization (MR) analysis. A two-sample MR analysis was performed to assess the causal association between these protein phenotypes and HCM. The robustness of the study results was further assessed through sensitivity analysis of heterogeneity and horizontal pleiotropy tests. Two proteins were identified as causally associated with HCM risk: carbonic anhydrase 3 (CA3) [inverse variance weighted (IVW): odds ratio (OR) = 1.292, 95% confidence interval (CI) = 1.021-1.636, P = 0.033] and serpin family E member 1 (SERPINE1) [IVW: OR = 1.313, 95% CI = 1.063-1.621, P = 0.011]. Both proteins were associated with increased HCM risk, with no significant heterogeneity (P > 0.05) or evidence of horizontal pleiotropy (P > 0.05).\nCONCLUSIONS: CA3 and SERPINE1 proteins may exert causal effects on HCM and may serve as characteristic markers and therapeutic targets for this condition.", "claims": [{"id": "claim-data-access", "statement": "The publicly available datasets were analysed in this study. These data can be found at the following websites: https://www.ncbi.nlm.nih.gov/geo/; https://r10.risteys.finngen.fi/. Further inquiries can be directed to the corresponding author.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40348582", "locator": "sections[23] \"Data availability statement\" paragraph 2", "quote": "The publicly available datasets were analysed in this study. These data can be found at the following websites: https://www.ncbi.nlm.nih.gov/geo/; https://r10.risteys.finngen.fi/. Further inquiries can be directed to the corresponding author."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Higher plasma levels of CA3 and SERPINE1 were causally associated with increased HCM risk, with each standard deviation increase associated with a 29.2% and 31.3% increase in risk, respectively.", "kind": "quantitative", "target": {"value": 1.313, "unit": "odds ratio", "tolerance": null, "source": "Two proteins were identified as causally associated with HCM risk: carbonic anhydrase 3 (CA3) [inverse variance weighted (IVW): odds ratio (OR) = 1.292, 95% confidence interval (CI) = 1.021–1.636, P = 0.033] and serpin family E member 1 (SERPINE1) [IVW: OR = 1.313, 95% CI = 1.063–1.621, P = 0.011]."}, "evidence": [{"asset": "source:pmid:40348582", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "Two proteins were identified as causally associated with HCM risk: carbonic anhydrase 3 (CA3) [inverse variance weighted (IVW): odds ratio (OR) = 1.292, 95% confidence interval (CI) = 1.021–1.636, P = 0.033] and serpin family E member 1 (SERPINE1) [IVW: OR = 1.313, 95% CI = 1.063–1.621, P = 0.011]."}, {"asset": "source:pmid:40348582", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "Both proteins were associated with increased HCM risk, with no significant heterogeneity (P > 0.05) or evidence of horizontal pleiotropy (P > 0.05)."}, {"asset": "source:pmid:40348582", "locator": "sections[15] \"Discussion\" paragraph 3", "quote": "Results showed a positive causal effect of plasma CA3 and SERPINE1 levels on HCM risk. Each standard deviation increase in plasma CA3 levels was associated with a 29.2% increase in HCM risk, while each standard deviation increase in SERPINE1 levels was associated with a 31.3% increase in HCM risk."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Higher plasma levels of CA3 and SERPINE1 were causally associated with increased HCM risk, with each standard deviation increase associated with a 29.2% and 31.3% increase in risk, respectively.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:40348582"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE180313"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE180313"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:40348582", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1002/ehf2.15287", "sha256": "sha256:5f3339a2e2406c4001ec94a6af70030bdc3751ecc9c2e147e131ad70884a8dce", "bytes": 33251, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1002/ehf2.15287", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12287861", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE180313", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE180313", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE180313", "version": null, "note": "The publicly available datasets were analysed in this study. These data can be found at the following websites: https://www.ncbi.nlm.nih.gov/geo/; https://r10.risteys.finngen.fi/. Further inquiries can be directed to the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The publicly available datasets were analysed in this study. These data can be found at the following websites: https://www.ncbi.nlm.nih.gov/geo/; https://r10.risteys.finngen.fi/. Further inquiries can be directed to the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM5460729", "GSM5460730", "GSM5460731", "GSM5460732", "GSM5460733", "GSM5460734", "GSM5460735", "GSM5460736", "GSM5460737", "GSM5460738", "GSM5460739", "GSM5460740", "GSM5460741", "GSM5460742", "GSM5460743", "GSM5460744", "GSM5460745", "GSM5460746", "GSM5460747", "GSM5460748"], "sample_count": 20, "group_sizes": null, "group_sizes_basis": null, "platform": "24676", "taxon": "Homo sapiens", "title": "Altered Cardiac Energetics and Mitochondrial Dysfunction  in Hypertrophic Cardiomyopathy", "resolution_checked_at": "2026-11-01T20:16:08Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE36961", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE36961", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE36961", "version": null, "note": "The publicly available datasets were analysed in this study. These data can be found at the following websites: https://www.ncbi.nlm.nih.gov/geo/; https://r10.risteys.finngen.fi/. Further inquiries can be directed to the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The publicly available datasets were analysed in this study. These data can be found at the following websites: https://www.ncbi.nlm.nih.gov/geo/; https://r10.risteys.finngen.fi/. Further inquiries can be directed to the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM907203", "GSM907204", "GSM907205", "GSM907206", "GSM907207", "GSM907208", "GSM907209", "GSM907210", "GSM907211", "GSM907212", "GSM907213", "GSM907214", "GSM907215", "GSM907216", "GSM907217", "GSM907218", "GSM907219", "GSM907220", "GSM907221", "GSM907222", "GSM907223", "GSM907224", "GSM907225", "GSM907226", "GSM907227", "GSM907228", "GSM907229", "GSM907230", "GSM907231", "GSM907232", "GSM907233", "GSM907234", "GSM907235", "GSM907236", "GSM907237", "GSM907238", "GSM907239", "GSM907240", "GSM907241", "GSM907242", "GSM907243", "GSM907244", "GSM907245", "GSM907246", "GSM907247", "GSM907248", "GSM907249", "GSM907250", "GSM907251", "GSM907252", "GSM907253", "GSM907254", "GSM907255", "GSM907256", "GSM907257", "GSM907258", "GSM907259", "GSM907260", "GSM907261", "GSM907262", "GSM907263", "GSM907264", "GSM907265", "GSM907266", "GSM907267", "GSM907268", "GSM907269", "GSM907270", "GSM907271", "GSM907272", "GSM907273", "GSM907274", "GSM907275", "GSM907276", "GSM907277", "GSM907278", "GSM907279", "GSM907280", "GSM907281", "GSM907282", "GSM907283", "GSM907284", "GSM907285", "GSM907286", "GSM907287", "GSM907288", "GSM907289", "GSM907290", "GSM907291", "GSM907292", "GSM907293", "GSM907294", "GSM907295", "GSM907296", "GSM907297", "GSM907298", "GSM907299", "GSM907300", "GSM907301", "GSM907302", "GSM907303", "GSM907304", "GSM907305", "GSM907306", "GSM907307", "GSM907308", "GSM907309", "GSM907310", "GSM907311", "GSM907312", "GSM907313", "GSM907314", "GSM907315", "GSM907316", "GSM907317", "GSM907318", "GSM907319", "GSM907320", "GSM907321", "GSM907322", "GSM907323", "GSM907324", "GSM907325", "GSM907326", "GSM907327", "GSM907328", "GSM907329", "GSM907330", "GSM907331", "GSM907332", "GSM907333", "GSM907334", "GSM907335", "GSM907336", "GSM907337", "GSM907338", "GSM907339", "GSM907340", "GSM907341", "GSM907342", "GSM907343", "GSM907344", "GSM907345", "GSM907346", "GSM907347"], "sample_count": 145, "group_sizes": null, "group_sizes_basis": null, "platform": "15389", "taxon": "Homo sapiens", "title": "Transcriptome Profiling of Surgical Myectomy Tissue from Patients with Hypertrophic Cardiomyopathy", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE180313 not downloaded", "asset:data:geo:GSE180313 licence not read", "asset:data:geo:GSE36961 not downloaded", "asset:data:geo:GSE36961 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "genetic_association", "specific": "gwas", "label": "Genetic association (GWAS / linkage / MR)", "dsl_operations": ["gwas_locus_scan"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["genotype_phenotype_table"], "evidence": {"score": 0.7, "band": "medium", "quote": "genome-wide association study"}}, {"id": "method-2", "family": "genetic_association", "specific": "mendelian_randomisation", "label": "Genetic association (GWAS / linkage / MR)", "dsl_operations": ["mr_estimate"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["genotype_phenotype_table"], "evidence": {"score": 0.7, "band": "medium", "quote": "Mendelian randomization"}}], "targets": [{"id": "target-published-estimate", "claim_id": "claim-target-result", "operation": "gwas_locus_scan", "expected_value": 1.313, "unit": "odds ratio", "tolerance": null, "state": "complete", "note": "The published estimate as the reader quoted it from the paper. No tolerance is published because the paper states none."}], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["gwas_locus_scan"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: gwas."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE36961", "GSE180313"], "resolved_accessions": ["GSE36961", "GSE180313"], "statements": ["The publicly available datasets were analysed in this study. These data can be found at the following websites: https://www.ncbi.nlm.nih.gov/geo/; https://r10.risteys.finngen.fi/. Further inquiries can be directed to the corresponding author."], "basis": "The paper names GSE36961, GSE180313 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["gwas_locus_scan"], "assets": ["source:pmid:40348582", "data:geo:GSE180313"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE180313"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:52:18Z", "independence": "single_reader"}, "evidence_check": {"method": null, "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 10432, "completion_tokens": 1721, "cached_tokens": 128}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:40348582", "type": "paper", "label": "pmid:40348582"}, {"id": "source:pmid:40348582", "type": "manuscript", "label": "PMID 40348582 full text"}, {"id": "data:geo:GSE180313", "type": "dataset", "label": "GEO GSE180313"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:40348582", "type": "paper", "label": "pmid:40348582"}, {"id": "source:pmid:40348582", "type": "manuscript", "label": "PMID 40348582 full text"}, {"id": "data:geo:GSE180313", "type": "dataset", "label": "GEO GSE180313"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-40348582", "type": "extraction", "used": ["source:pmid:40348582"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE180313", "type": "accession_resolution", "used": ["data:geo:GSE180313"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:40348582", "parent_hash": "sha256:79aca2ac76fd64abc479ab6b6ef95cce2ee8d8704f7a3bfffb10b46b24f48285", "fork_of": null, "generation": 1}, "gaps": ["asset:data:geo:GSE180313 licence not read", "asset:data:geo:GSE180313 not downloaded", "asset:data:geo:GSE36961 licence not read", "asset:data:geo:GSE36961 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "analysis", "definition_id": "genetic_association", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["gwas_locus_scan"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.7, "evidence": ["genome-wide association study"], "order_basis": "analysis_only", "id": "assay:1"}]}