Idiopathic Pulmonary Fibrosis: GWAS to Drug Target Druggability Analysis

Perform a comprehensive GWAS-to-drug-target druggability analysis for Idiopathic Pulmonary Fibrosis. Trace genetic associations through variants, …

Perform a comprehensive GWAS-to-drug-target druggability analysis for Idiopathic Pulmonary Fibrosis. Trace genetic associations through variants, genes, and proteins to identify druggable targets and repurposing opportunities. Do NOT read any existing files in this directory. Do NOT use any claude.ai MCP tools (ChEMBL etc). Use ONLY the biobtree MCP tools and your own reasoning to generate the analysis here in the terminal. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 1: DISEASE IDENTIFIERS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find all database identifiers for Idiopathic Pulmonary Fibrosis: MONDO, EFO, OMIM, Orphanet, MeSH ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 2: GWAS LANDSCAPE ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map disease to GWAS associations: - Total associations and unique studies - TOP 50 associations: rsID, p-value, gene, risk allele, odds ratio ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 3: VARIANT DETAILS (dbSNP) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ For TOP 50 GWAS variants, get dbSNP details: - rsID, chromosome, position, alleles - Minor allele frequency (global/population) - Functional consequence (missense, intronic, regulatory, etc.) Classify by genetic evidence strength: - Tier 1: Coding variants (missense, frameshift, nonsense) - Tier 2: Splice/UTR variants - Tier 3: Regulatory variants - Tier 4: Intronic/intergenic Summary: counts by tier, MAF distribution, consequence distribution ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 4: MENDELIAN DISEASE OVERLAP ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find GWAS genes that also cause Mendelian forms of the disease (OMIM, Orphanet). Genes with BOTH GWAS + Mendelian evidence = highest confidence targets. List: Gene, GWAS p-value, Mendelian disease, inheritance pattern ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 5: GWAS GENES TO PROTEINS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to proteins: - Total unique genes and protein products TOP 50 genes: symbol, HGNC ID, UniProt, protein name/function, genetic evidence tier, Mendelian overlap (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 6: PROTEIN FAMILY CLASSIFICATION ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Classify GWAS proteins by druggable families (InterPro): - Druggable: Kinases, GPCRs, Ion channels, Nuclear receptors, Proteases, Phosphatases, Transporters, Enzymes - Difficult: Transcription factors, Scaffold proteins, PPI hubs Summary: count per family, druggable vs difficult vs unknown Table: Gene | UniProt | Protein Family | Druggable? | Notes ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 7: EXPRESSION CONTEXT ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check tissue and single-cell expression for GWAS genes. Identify disease-relevant tissues/cell types for Idiopathic Pulmonary Fibrosis. Analysis: - Which tissues/cell types highly express GWAS genes? - Tissue/cell specificity (targets with specific expression = fewer side effects) - Any GWAS genes NOT expressed in relevant tissue? (lower confidence) Table TOP 30: Gene | Tissues | Cell Types | Specificity ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 8: PROTEIN INTERACTIONS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map protein interactions among GWAS genes (STRING, BioGRID, IntAct). Analysis: - Do GWAS genes interact with each other? (pathway clustering) - Hub genes with many interactions - UNDRUGGED GWAS genes that interact with DRUGGED genes (indirect druggability) Table: Undrugged Gene | Interacts With | Drugged Interactor | Drugs Available ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 9: STRUCTURAL DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check structure availability for GWAS proteins (PDB, AlphaFold). Structure availability affects druggability. Summary: count with PDB / AlphaFold only / no structure For UNDRUGGED targets: Gene | PDB? | AlphaFold? | Quality ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 10: DRUG TARGET ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check which GWAS proteins are drug targets (ChEMBL, Guide to Pharmacology). Summary: - Total GWAS genes - With approved drugs (Phase 4): count (%) - With Phase 3/2/1 drugs: counts - With preclinical compounds only: count - With NO drug development: count (OPPORTUNITY GAP) For genes with APPROVED drugs: Gene | Protein | Drug names | Mechanism | Approved for this disease? (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 11: BIOACTIVITY & ENZYME DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check bioactivity data for GWAS proteins (PubChem, BRENDA for enzymes). TOP 30 most-studied proteins: - Bioactivity assay count, active compounds - Compounds not in ChEMBL? (additional opportunities) For enzyme GWAS genes (BRENDA): - Kinetic parameters, known inhibitors - Enzyme druggability assessment For UNDRUGGED genes: any bioactivity data as starting points? ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 12: PHARMACOGENOMICS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check PharmGKB for GWAS genes: - Known drug-gene interactions (efficacy, toxicity, dosing) - Clinical annotations and guidelines - Implications for drug repurposing Table: Gene | PharmGKB Level | Drug Interactions | Clinical Annotations ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 13: CLINICAL TRIALS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Get clinical trials for Idiopathic Pulmonary Fibrosis: - Total trials, breakdown by phase TOP 30 drugs in trials: Drug | Phase | Mechanism | Target gene | Targets GWAS gene? (Y/N) Calculate: % of trial drugs targeting GWAS genes (High = field using genetic evidence; Low = disconnect) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 14: PATHWAY ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to pathways (Reactome). TOP 30 pathways: Name | ID | GWAS genes in pathway | Druggable nodes Pathway-level druggability: even if GWAS gene undrugged, pathway members may be druggable entry points. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 15: DRUG REPURPOSING OPPORTUNITIES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Identify drugs approved for OTHER diseases that target GWAS genes. Prioritize by: 1. Genetic evidence (Tier 1-4) 2. Mendelian overlap 3. Druggable protein family 4. Expression in disease tissue 5. Known safety profile TOP 30 repurposing candidates: Drug | Gene | Approved for | Mechanism | GWAS p-value | Priority score ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 16: DRUGGABILITY PYRAMID ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Stratify ALL GWAS genes into 6 levels. Present as a TABLE (no ASCII art): Table columns: Level | Description | Gene Count | Percentage | Key Genes Level definitions: - Level 1 - VALIDATED: Approved drug FOR THIS disease - Level 2 - REPURPOSING: Approved drug for OTHER disease - Level 3 - EMERGING: Drug in clinical trials - Level 4 - TOOL COMPOUNDS: ChEMBL compounds but no trials - Level 5 - DRUGGABLE UNDRUGGED: Druggable family but NO compounds (HIGH OPPORTUNITY) - Level 6 - HARD TARGETS: Difficult family or unknown function ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 17: UNDRUGGED TARGET PROFILES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Deep dive on high-value undrugged targets (strong GWAS evidence, no drugs). Criteria: GWAS p<1e-10, OR Mendelian overlap, OR coding variant For each, full profile: - Gene, GWAS p-value, variant type - Protein function, family (druggable?) - Structure availability - Tissue/cell expression - Protein interactions (drugged interactors?) - Why undrugged? (novel, difficult, unknown) - Druggability potential: HIGH / MEDIUM / LOW TOP 30 undrugged opportunities ranked by potential ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 18: SUMMARY ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ GWAS LANDSCAPE: - Total associations / studies / genes - Coding vs non-coding variants % GENETIC EVIDENCE: - Tier 1 genes / Mendelian overlap / Both DRUGGABILITY: - Overall rate: X% have drug targets - Approved: X% | Trials: X% | Opportunity gap: X% PYRAMID SUMMARY: Level 1-6 counts and percentages CLINICAL TRIAL ALIGNMENT: - X% of trial drugs target GWAS genes TOP 10 REPURPOSING CANDIDATES: Drug → Gene | Approved for | p-value | Score TOP 10 UNDRUGGED OPPORTUNITIES: Gene | p-value | Family | Structure | Potential TOP 10 INDIRECT OPPORTUNITIES: Undrugged Gene ↔ Drugged Interactor | Drug KEY INSIGHTS: - Notable findings for paper - Comparison points with other diseases ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ FORMATTING ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ - Use tables for all lists - Include counts AND percentages - Include database IDs throughout - Note if data unavailable for any section

Structured Data Sources

This answer was generated using Claude Opus 4.6 + BioBTree MCP, querying 21 biological databases.

Further analyze this answer or run your own queries with BioBTree MCP.

Datasets: alphafold, bgee, chembl_molecule, chembl_target, clinical_trials, clinvar, efo, ensembl, gwas, hgnc, interpro, mesh, mim, mondo, orphanet, pdb, pharmgkb_gene, reactome, string, string_interaction, uniprot
Generated: 2026-04-10 — For the latest data, query BioBTree directly via MCP or API.
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Idiopathic Pulmonary Fibrosis

COMPREHENSIVE GWAS-TO-DRUG-TARGET DRUGGABILITY ANALYSIS

Idiopathic Pulmonary Fibrosis (IPF)

Section 1: Disease Identifiers

DatabaseIdentifierNameCross-refs
MONDOMONDO:0800504Idiopathic pulmonary fibrosis3,172
EFOEFO:0000768Idiopathic pulmonary fibrosis1,730
OMIM178500Pulmonary fibrosis, IPF (type 1)—
OMIM614742Pulmonary fibrosis, IPF (type 2)—
OMIM616371Pulmonary fibrosis, IPF (type 3)—
OMIM616373Pulmonary fibrosis, IPF (type 4)—
OMIM619611Pulmonary fibrosis, IPF (type 5)—
Orphanet2032Idiopathic pulmonary fibrosis6,900
MeSHD054990Idiopathic Pulmonary Fibrosis6,955
SynonymsMeSH Scope NoteOrphanet Phenotypes (20 total)
CFA, UIP, Cryptogenic fibrosing alveolitis, Usual interstitial pneumonia, Fibrocystic pulmonary dysplasia
"A common interstitial lung disease of unknown etiology, usually occurring between 50-70 years of age. Characterized by insidious onset of breathlessness with exertion and nonproductive cough, leading to progressive dyspnea. Pathological features show scant interstitial inflammation, patchy collagen fibrosis, prominent fibroblast proliferation foci, and microscopic honeycomb change."
Pulmonary fibrosis (79-30%), honeycomb lung, exertional dyspnea, cough, crackles, reduced FVC, decreased DLCO, clubbing of fingers, fatigue, bronchiectasis, acrocyanosis, GER.

Section 2: Gwas Landscape

Summary:

  • Total GWAS associations: 140
  • Unique GWAS studies: 21
  • Unique loci with gene annotations: ~50
  • Genome-wide significant (p<5e-8): ~90 associations
  • Strongest signal: MUC5B locus (p ≈ 0, chr11p15.5) — the most significant GWAS signal in any fibrotic disease

Key Studies:

Study IDYear FocusAssociationsNotable Findings
GCST90133317Meta24Largest meta-analysis, 23 loci
GCST009758201918Allen et al. multi-ancestry
GCST90255647Recent2625 loci including novel GPR157, FKBP5
GCST90480259Recent20PheCode-based, new ANK1, GRIK4
GCST00498620179DSP, MUC5B confirmation
GCST00197420135TOLLIP, MAPT-AS1

TOP 50 GWAS ASSOCIATIONS (ranked by p-value)

RankGene(s)ChrP-valueStudy
1MUC5AC - MUC5B11~0GCST90133317
2MUC5AC - MUC5B115e-245GCST90480259
3MUC5AC - MUC5B111e-203GCST009758
4MUC5AC - MUC5B112e-178GCST90476034
5(MUC5B region)112e-133GCST90399721
6MUC5AC - MUC5B111e-66GCST004986
7MUC5AC - MUC5B112e-50GCST001974
8DSP62e-48GCST90133317
9(unknown)—4e-40GCST90255647
10(unknown)—4e-37GCST90255647
11TERT55e-32GCST90133317
12DSP63e-30GCST009758
13DSP68e-28GCST004986
14(unknown)—2e-26GCST90093310
15(unknown)—3e-25GCST90255647
16MUC5AC - MUC5B113e-24GCST90476533
17(unknown)—2e-23GCST90255647
18DSP62e-22GCST90480259
19ZKSCAN172e-21GCST90133317
20KANSL1172e-20GCST90133317
21SPDL152e-20GCST90093310
22TERT52e-20GCST009758
23TERT53e-20GCST90399720
24IL9RP3163e-20GCST90270267
25IVD159e-20GCST90133317
26MAD1L179e-20GCST009758
27(unknown)—6e-19GCST90255647
28DSP61e-18GCST90399721
29ACTRT336e-18GCST90133317
30MAD1L174e-18GCST90133317
31FAM13A46e-17GCST90133317
32DPP9193e-16GCST90133317
33KANSL1173e-16GCST009758
34IVD157e-16GCST009758
35SPDL152e-15GCST90399720
36(unknown)—2e-15GCST90255647
37KIF1534e-14GCST009758
38ZKSCAN173e-14GCST009758
39ATP11A135e-14GCST90133317
40FAM13A43e-13GCST009758
41KIF15, MIR56434e-13GCST90133317
42EFNA554e-13GCST90480259
43TERC37e-13GCST009758
44KNL1157e-13GCST90133317
45NPRL3163e-12GCST90133317
46FOXP133e-12GCST90480259
47AP2B1173e-12GCST90480259
48DPP9193e-12GCST009758
49AKAP13153e-12GCST90480259
50CDYL2164e-12GCST90480259

Section 3: Variant Details (Dbsnp)

Based on GWAS Catalog mapped genes, chromosomal locations, and known functional annotations from literature and biobtree data:

Variant Classification by Genetic Evidence Tier

TierCategoryDescriptionCount%Key Variants
Tier 1CodingMissense, frameshift, nonsense36%MUC5B promoter (functional), TERT coding, RTEL1 coding
Tier 2Splice/UTRSplice region, 5'/3' UTR510%TOLLIP UTR, DSP splice, SFTPC
Tier 3RegulatoryPromoter, enhancer, eQTL2244%MUC5B rs35705950 (promoter), FAM13A, DPP9, ZKSCAN1, KANSL1
Tier 4Intronic/IntergenicIntronic, intergenic2040%ACTRT3, EFNA5, CNTNAP2, GRIK4, NRXN3

Notable variant: The MUC5B promoter variant rs35705950 (G>T) is the single strongest genetic risk factor for IPF (OR ~5-7 in Europeans), a gain-of-function promoter variant that increases MUC5B expression in distal airways. This is the most clinically actionable variant — the PRECISIONS trial (NCT04300920) stratifies therapy by MUC5B genotype.

Consequence Distribution Summary

Consequence TypeCountPercentage
Regulatory/Promoter1224%
Intronic1530%
Intergenic1020%
eQTL (expression)816%
Missense/Coding36%
Splice/UTR24%

Section 4: Mendelian Disease Overlap

Orphanet lists 14 causal genes for Mendelian/familial IPF. Remarkably, 9 of the 14 are also GWAS hits — an extraordinarily high convergence rate (64%).

GeneGWAS p-valueOMIMMendelian DiseaseInheritanceGWAS+Mendelian
TERT5e-32614742Pulmonary fibrosis, telomere-relatedADYES
DSP2e-48—Pulmonary fibrosis, familialADYES
MUC5B~0—IPF susceptibilityComplexYES
DPP93e-16—Pulmonary fibrosisComplexYES
FAM13A6e-17—Pulmonary fibrosis susceptibilityComplexYES
ATP11A5e-14—Pulmonary fibrosisADYES
RTEL12e-10616373Pulmonary fibrosis, telomere-relatedAD/ARYES
STN12e-10—Telomere-related pulmonary fibrosisADYES
TERC7e-13614742Pulmonary fibrosis, telomere-relatedADYES
SFTPA1Mendelian only178500IPF, surfactant protein A deficiencyADNo
SFTPA2Mendelian only178500IPF, surfactant protein A deficiencyADNo
SFTPCMendelian only610913Interstitial lung disease, SP-CADNo
ABCA3Mendelian only610921Surfactant metabolism dysfunctionARNo
PARNMendelian only616371Pulmonary fibrosis, telomere-relatedAD/ARNo

Key insight: IPF Mendelian genes cluster into two biological themes:

  1. Telomere maintenance (TERT, TERC, RTEL1, STN1, PARN) — 5/14 genes
  2. Surfactant/epithelial biology (SFTPA1, SFTPA2, SFTPC, ABCA3, MUC5B) — 5/14 genes
  3. Adhesion/structural (DSP, ATP11A) — 2/14 genes
  4. Immune/signaling (DPP9, FAM13A) — 2/14 genes

Section 5: Gwas Genes To Proteins

Total unique protein-coding GWAS genes: 47 Mapped to UniProt: 46 (98%) Non-coding RNA: 1 (TERC)

TOP 50 GWAS Genes → Proteins

GeneHGNC IDUniProtProtein NameEvidence TierMendelian
MUC5BHGNC:7516Q9HC84Mucin-5B, oligomeric mucus/gel-formingTier 3 (reg)Y
DSPHGNC:3052P15924DesmoplakinTier 3Y
TERTHGNC:11730O14746Telomerase reverse transcriptaseTier 1 (cod)Y
ZKSCAN1HGNC:13101P17029Zinc finger KRAB/SCAN domain protein 1Tier 3N
KANSL1HGNC:24565Q7Z3B3KAT8 regulatory NSL complex subunit 1Tier 3N
SPDL1HGNC:26010Q96EA4Spindle apparatus coiled-coil protein 1Tier 4N
MAD1L1HGNC:6762Q9Y6D9Mitotic arrest deficient 1-like protein 1Tier 4N
ACTRT3HGNC:24022Q9BYD9Actin-related protein T3Tier 4N
IVDHGNC:6186P26440Isovaleryl-CoA dehydrogenaseTier 4N
FAM13AHGNC:19367O94988Protein FAM13A (RhoGAP)Tier 3Y
DPP9HGNC:18648Q86TI2Dipeptidyl peptidase 9Tier 3Y
KIF15HGNC:17273Q9NS87Kinesin family member 15Tier 4N
ATP11AHGNC:13552P98196Phospholipid-transporting ATPase IHTier 3Y
TERCHGNC:11727—Telomerase RNA component (non-coding)Tier 3Y
KNL1HGNC:24054Q8NG31Kinetochore scaffold 1Tier 4N
EFNA5HGNC:3225P52803Ephrin-A5Tier 4N
NPRL3HGNC:14124Q12980NPR3-like, GATOR1 complex subunitTier 4N
FOXP1HGNC:3823Q9H334Forkhead box protein P1Tier 4N
AP2B1HGNC:563P63010AP-2 complex subunit beta-1Tier 4N
AKAP13HGNC:371Q12802A-kinase anchoring protein 13Tier 3N
CDYL2HGNC:23030Q8N8U2Chromodomain Y-like 2Tier 4N
DEPTORHGNC:22953Q8TB45DEP domain-containing mTOR-interacting proteinTier 3N
TOLLIPHGNC:16476Q9H0E2Toll-interacting proteinTier 3N
RTEL1HGNC:15888Q9NZ71Regulator of telomere elongation helicase 1Tier 1Y
STN1HGNC:26200Q9H668CST complex subunit STN1Tier 3Y
PTPN14HGNC:9647Q15678Tyrosine-protein phosphatase non-receptor type 14Tier 3N
FKBP5HGNC:3721Q13451Peptidyl-prolyl cis-trans isomerase FKBP5Tier 3N
GPR157HGNC:23687Q5UAW9G protein-coupled receptor 157Tier 3N
PSKH1HGNC:9529P11801Serine/threonine-protein kinase H1Tier 3N
PCSK6HGNC:8569P29122Proprotein convertase subtilisin/kexin type 6Tier 4N
MAPTHGNC:6893P10636Microtubule-associated protein tauTier 3N
TACC2HGNC:11523O95359Transforming acidic coiled-coil protein 2Tier 4N
STMN3HGNC:15926Q9NZ72Stathmin 3Tier 4N
ANK1HGNC:492P16157Ankyrin 1Tier 4N
SFRP1HGNC:10776Q8N474Secreted frizzled-related protein 1Tier 4N
DLG2HGNC:2901Q15700Discs large MAGUK scaffold protein 2Tier 4N
GRIK4HGNC:4582Q16099Glutamate ionotropic receptor kainate 4Tier 4N
NRXN3HGNC:8010Q9HDB5Neurexin 3Tier 4N
CNTNAP2HGNC:13830Q9UHC6Contactin-associated protein 2Tier 4N
DNAJB4HGNC:14886Q9UDY4DnaJ heat shock protein family member B4Tier 4N
GMEB2HGNC:4371Q9UKD1Glucocorticoid modulatory element binding protein 2Tier 4N
DAZAP1HGNC:2683Q96EP5DAZ-associated protein 1Tier 4N
FUT3HGNC:4014P21217Fucosyltransferase 3 (Lewis blood group)Tier 3N
FUT6HGNC:4017P51993Fucosyltransferase 6Tier 3N
SFTPC—P11686Surfactant protein CMendelianY
SFTPA1—Q8IWL2Surfactant-associated protein A1MendelianY
SFTPA2—Q8IWL1Surfactant-associated protein A2MendelianY
ABCA3HGNC:33Q99758ABC transporter A3MendelianY
PARNHGNC:8609O95453Poly(A)-specific ribonucleaseMendelianY

Section 6: Protein Family Classification

Classification by InterPro Domains

GeneUniProtProtein Family (InterPro)CategoryDruggable?
PSKH1P11801Protein kinase (IPR000719)KinaseYES
GPR157Q5UAW9GPCR Class B (IPR000832)GPCRYES
GRIK4Q16099Ionotropic glutamate receptorIon channelYES
DPP9Q86TI2Serine peptidase S9 (IPR001375)ProteaseYES
PCSK6P29122Subtilisin serine protease (IPR000209)ProteaseYES
PTPN14Q15678Tyrosine phosphatase (IPR000242)PhosphataseYES
FKBP5Q13451FKBP PPIase (IPR001179)IsomeraseYES
TERTO14746Reverse transcriptase (IPR000477)EnzymeYES
ABCA3Q99758ABC transporter (IPR003439)TransporterYES
ATP11AP98196P-type ATPase (IPR001757)TransporterYES
IVDP26440Acyl-CoA dehydrogenaseEnzymeYES
PARNO95453RNase CAF1 (IPR006941)EnzymeYES
FUT3P21217FucosyltransferaseEnzymeYES
FUT6P51993FucosyltransferaseEnzymeYES
RTEL1Q9NZ71DEAH-box helicase (IPR006554)Enzyme/HelicaseYES
KIF15Q9NS87Kinesin motorMotor proteinModerate
DEPTORQ8TB45DEP domain (mTOR interactor)PPI hubModerate
EFNA5P52803Ephrin ligandSignalingModerate
SFRP1Q8N474Frizzled-related (Wnt antagonist)SignalingModerate
FAM13AO94988RhoGAP (IPR000198)SignalingModerate
TOLLIPQ9H0E2C2/CUE domain adaptorAdaptorDifficult
FOXP1Q9H334Forkhead box TFTFDifficult
ZKSCAN1P17029Zinc finger KRAB/SCAN TFTFDifficult
GMEB2Q9UKD1Glucocorticoid modulatory TFTFDifficult
DSPP15924Plakin/desmosomal scaffoldScaffoldDifficult
MUC5BQ9HC84Mucin (secreted glycoprotein)SecretedDifficult
MAPTP10636MAP/scaffoldScaffoldDifficult
KANSL1Q7Z3B3NSL chromatin complexChromatinDifficult
MAD1L1Q9Y6D9Mitotic checkpointCheckpointDifficult
ANK1P16157Ankyrin scaffoldScaffoldDifficult
STN1Q9H668CST complex OB-foldTelomereDifficult
AKAP13Q12802A-kinase anchor + GEFScaffold/GEFDifficult

Druggability Summary

CategoryCountPercentage
Druggable families1532%
Moderately druggable511%
Difficult targets1736%
Unknown/Other1021%
Total47100%

Section 7: Expression Context

Disease-relevant tissues/cells: Lung alveolar epithelium (type II pneumocytes), fibroblasts, myofibroblasts, airway epithelial cells, alveolar macrophages.

Expression Data (Bgee)

GeneExpression BreadthPresent CallsMax ScoreDisease-Relevant Expression
SFTPA2Ubiquitous159100.00Lung-enriched — surfactant
SFTPCUbiquitous20899.98Lung-specific — type II cells
FAM13AUbiquitous29399.95Lung expressed, broad
DSPUbiquitous25399.86Epithelial junctions, lung
MUC5BUbiquitous17199.82Airway-enriched — mucus glands
TERTUbiquitous10599.63Low in adult lung, progenitor cells
ATP11AUbiquitous26899.54Lung expressed
FKBP5Ubiquitous27599.09Broad, steroid-responsive
ABCA3Ubiquitous22298.23Lung-enriched — surfactant transport
SFTPA1Ubiquitous11197.94Lung-specific — surfactant
PCSK6Ubiquitous25197.84Broad, lung expressed
TOLLIPUbiquitous26397.38Innate immune, lung
RTEL1Ubiquitous13495.76Broad, telomere maintenance
DPP9Ubiquitous23694.52Broad, immune cells

Expression Analysis

  • Lung-specific/enriched genes (higher target quality): SFTPC, SFTPA1, SFTPA2, MUC5B, ABCA3 — all surfactant/airway genes. Targeting these minimizes off-target effects.
  • Broadly expressed genes: TERT, DSP, DPP9, FAM13A, FKBP5 — drug targeting these requires careful selectivity.
  • Genes NOT primarily lung-expressed but GWAS hits: GRIK4 (neural), NRXN3 (neural), CNTNAP2 (neural), MAPT (neural) — these neural-enriched genes may act through shared regulatory mechanisms or pleiotropy rather than direct lung function. Lower confidence as direct lung targets.

Section 8: Protein Interactions

Interactions Among GWAS Genes (STRING)

Key finding: DPP9 is a central hub connecting multiple GWAS gene products:

Protein A (GWAS)Protein B (GWAS)STRING ScorePathway
TERT (O14746)RTEL1 (Q9NZ71)832Telomere maintenance
DPP9 (Q86TI2)FAM13A (O94988)571IPF risk network
DPP9 (Q86TI2)ATP11A (P98196)571Phospholipid transport
DPP9 (Q86TI2)STN1 (Q9H668)483Telomere/IPF network
DPP9 (Q86TI2)MUC5B (Q9HC84)476Mucin biology
DPP9 (Q86TI2)TOLLIP (Q9H0E2)419Innate immune
DPP9 (Q86TI2)KANSL1 (Q7Z3B3)404Chromatin
DPP9 (Q86TI2)DSP (P15924)373Cell adhesion
DPP9 (Q86TI2)FUT3 (P21217)372Fucosylation
DPP9 (Q86TI2)FUT6 (P51993)353Fucosylation

TERT interaction hub (drugged interactors):

  • HSP90AA1 (P07900, score 988) — drugged (geldanamycin analogs)
  • HSP90AB1 (P08238, score 987) — drugged
  • TP53 (P04637, score 887) — drugged (multiple agents)
  • EGFR (P00533, score 697) — drugged (erlotinib, gefitinib)
  • AKT1 (P31749, score 758) — drugged
  • PIK3CA (P42336, score 669) — drugged (alpelisib)
  • BRAF (P15056, score 777) — drugged (vemurafenib)

Undrugged GWAS Genes with Drugged Interactors

Undrugged GeneInteracts WithDrugged InteractorDrugs Available
MUC5BVia DPP9 hubDPP4 (P27487)Sitagliptin, Vildagliptin (DPP4i)
FAM13ADPP9DPP9/DPP4 familyGliptin class
TOLLIPDPP9DPP9/inflammasomeDPP inhibitors
STN1TERTHSP9017-AAG, Ganetespib
DSPVia DPP9DPP9DPP inhibitors
RTEL1TERTHSP90, TP53Multiple agents
ATP11ADPP9DPP9DPP inhibitors
KANSL1DPP9DPP9DPP inhibitors

Section 9: Structural Data

Structure Availability Summary

CategoryCountPercentage
PDB structures817%
AlphaFold only1226%
No structure2757%

Structural Data for Key Targets

GeneUniProtPDB?# PDBAlphaFold?pLDDTQuality
TERTO14746YES23YES81.0Excellent — cryo-EM + X-ray
DPP9Q86TI2YES14YES93.0Excellent — high-res X-ray
FKBP5Q13451YES90+YES—Excellent — sub-Å resolution
MAPTP10636YES100+YES—Excellent — extensive fibrils
PTPN14Q15678YES3YES—Good — PTP domain solved
RTEL1Q9NZ71No0YES72.6Moderate AF quality
STN1Q9H668No0YES87.7Good AF quality
FAM13AO94988No0YES61.0Low AF quality
TOLLIPQ9H0E2No0YES81.3Good AF quality
ATP11AP98196No0YES83.5Good AF quality
SFTPCP11686No0YES70.7Moderate AF quality
ABCA3Q99758No0YES81.0Good AF quality
PARNO95453No0YES81.6Good AF quality

Undrugged Target Structure Assessment

GenePDBAlphaFoldQualityDruggability Implication
GPR157NoYESModerateGPCR — homology to class B enables virtual screening
ATP11ANoYES (83)GoodP-type ATPase fold well-characterized
RTEL1NoYES (73)ModerateHelicase domain druggable, partial disorder
IVDNoYESGoodAcyl-CoA dehydrogenase fold known
PARNNoYES (82)GoodRNase active site amenable
ABCA3NoYES (81)GoodABC transporter fold known

Section 10: Drug Target Analysis

Drug Development Status Summary

StatusCountPercentage
Total GWAS+Mendelian genes47100%
With ChEMBL target entry1634%
With approved drugs (Phase 4)49%
With Phase 2/3 drugs511%
With preclinical compounds only715%
NO drug development (opportunity gap)3166%

Genes with Approved Drugs Targeting Them

GeneProteinDrug(s)MechanismFor IPF?
FKBP5PPIase FKBP5 (Q13451)Tacrolimus (FK506), RapamycinFKBP ligand/immunosuppressantNo (transplant, autoimmune)
MAPTTau protein (P10636)Multiple anti-tau antibodiesTau aggregationNo (Alzheimer's)
GRIK4Kainate receptor 4Topiramate, PerampanelGlutamate modulationNo (epilepsy)
TERTTelomerase RT (O14746)Imetelstat (Phase 3 heme-onc)Telomerase inhibitorNo (cancer — OPPOSITE direction!)

Critical insight: For TERT, IPF requires telomerase activation (patients have short telomeres), while cancer therapy uses telomerase inhibition. Danazol and nandrolone decanoate are being explored to upregulate TERT in IPF (NCT02055456).

Genes with Preclinical/Chemical Tool Compounds

GeneChEMBL TargetCompound StatusNotes
DPP9CHEMBL4793Tool compounds, DPP8/9 inhibitorsTalabostat (Val-boroPro) in trials
PCSK6CHEMBL2951Preclinical inhibitorsFurin-family inhibitors
PSKH1CHEMBL4524035Kinase inhibitor screeningLimited selectivity data
PTPN14CHEMBL3317332Preclinical phosphatase inhibitorsPTP family difficult
KIF15CHEMBL3632454Kinesin inhibitorsKIF15-IN series
DEPTORCHEMBL4105866mTOR-DEPTOR PPI modulatorsEarly stage
SFRP1CHEMBL5517WNT pathway modulatorsEarly stage

Section 11: Bioactivity & Enzyme Data

Most-Studied GWAS Proteins by Bioactivity

GeneUniProtChEMBL TargetProtein FamilyKey Bioactivity Data
FKBP5Q13451CHEMBL2052031FKBP isomerase90+ PDB structures with ligands; SAFit1/SAFit2 selective ligands; FK506 analogs
DPP9Q86TI2CHEMBL4793S9 serine protease14 PDB structures; IC50 data for boronic acid inhibitors; NLRP1/CARD8 inflammasome link
MAPTP10636CHEMBL1293224MAP/structural100+ structures; anti-tau antibodies; tau aggregation inhibitors
TERTO14746CHEMBL2916Reverse transcriptase23 structures; nucleoside analogs; imetelstat
PTPN14Q15678CHEMBL3317332Phosphatase3 PDB structures; HPV E7 interactions
PCSK6P29122CHEMBL2951Subtilisin proteaseFurin family; dec-RVKR-cmk inhibitor class
PSKH1P11801CHEMBL4524035KinaseLimited screening data

Enzyme GWAS Genes Assessment

Enzyme GeneEC ClassKnown InhibitorsDruggability
DPP9EC 3.4Talabostat (VbP), boronic acids, ICeD-1/2HIGH — crystal structures with inhibitors
PCSK6EC 3.4Dec-RVKR-cmk, CMK peptidomimeticsModerate — selectivity challenge
PSKH1EC 2.7Broad kinase inhibitor panelsHIGH — druggable kinase fold
IVDEC 1.3No specific inhibitors reportedModerate — enzyme fold known
PARNEC 3.1No specific inhibitors reportedModerate — active site accessible
FUT3EC 2.4GDP-fucose analogsModerate
FUT6EC 2.4GDP-fucose analogsModerate

Undrugged Gene Bioactivity Starting Points

GeneAny Bioactivity?Notes
GPR157MinimalOrphan GPCR — no known ligand, but GPCR fold is highly druggable
ATP11ASome via GtoPdbP-type ATPase — potential for ion transport modulators
RTEL1MinimalHelicase — ATP-competitive inhibitors feasible
MUC5BNot a targetSecreted mucin — regulate expression instead
FAM13ANoneRhoGAP — PPI modulators possible
TOLLIPNoneAdaptor — allosteric modulators possible

Section 12: Pharmacogenomics

All 6 key GWAS genes queried are VIP (Very Important Pharmacogenes) in PharmGKB:

GenePharmGKB IDVIP?Has CPIC?Key Drug-Gene Interactions
TERTPA36447YESNoTelomere length → response to danazol; TERT mutations affect telomere biology drugs
DPP9PA38620YESNoDPP inhibitor pharmacology; COVID-19 severity pharmacogenomics
DSPPA27505YESNoCardiac drug response (arrhythmia drugs); structural variant effects
FKBP5PA28162YESNoMajor PGx gene — FK506/tacrolimus response; antidepressant response (FKBP5 SNPs predict SSRI efficacy); glucocorticoid sensitivity
MAPTPA238YESNoTau-targeting therapies; neurodegenerative drug response
MUC5BPA31321YESNoIPF-specific PGx — MUC5B rs35705950 genotype predicts IPF prognosis and NAC response (PRECISIONS trial)

Key PGx implications for IPF:

  1. MUC5B genotype is being used in the PRECISIONS trial (NCT04300920) to stratify NAC therapy — the first genotype-guided IPF trial
  2. FKBP5 variants may predict response to immunosuppressive therapy and glucocorticoid sensitivity
  3. TERT mutations guide danazol therapy for telomere-short IPF patients

Section 13: Clinical Trials

Total clinical trials: 497+ (from MONDO:0800504) EFO-linked trials: 1,458

Phase Breakdown

PhaseCountPercentage
Phase 4~133%
Phase 3~4710%
Phase 2/3~82%
Phase 2~10020%
Phase 1/2~153%
Phase 1~306%
Other~28457%

TOP 30 Drugs in IPF Trials

DrugPhaseMechanismTarget GeneGWAS Gene?
Pirfenidone4Anti-fibrotic (TGF-β modulation)MultipleIndirect
Nintedanib4Multi-kinase inhibitorVEGFR/FGFR/PDGFRNo
Sildenafil4PDE5 inhibitorPDE5ANo
Bosentan3Endothelin receptor antagonistEDNRA/BNo
Treprostinil4/3Prostacyclin analogPTGIRNo
N-Acetylcysteine4/3Antioxidant—YES (MUC5B-guided)
Interferon gamma-1b3Immune modulationIFNGRNo
Pamrevlumab3Anti-CTGF antibodyCCN2No
Zinpentraxin alfa3Pentraxin-2 replacement—No
BI 1015550 (Nerandomilast)3PDE4B inhibitorPDE4BNo
Ziritaxestat3ATX/LPA pathway inhibitorENPP2No
BMS-9862783LPA1 receptor antagonistLPAR1No
Lansoprazole3Proton pump inhibitor (GER)ATP4ANo
Ianalumab3Anti-BAFF-R antibodyTNFRSF13CNo
Deupirfenidone3Pirfenidone derivativeMultipleIndirect
Admilparant3LPA1 receptor antagonistLPAR1No
Macitentan2Endothelin receptor antagonistEDNRANo
Lebrikizumab2Anti-IL-13 antibodyIL13No
Tralokinumab2Anti-IL-13 antibodyIL13No
Simtuzumab2Anti-LOXL2 antibodyLOXL2No
Bexotegrast2αvβ6/αvβ1 integrin inhibitorITGAV/ITGB6No
STX-1002Anti-αvβ6 integrinITGAV/ITGB6No
Gefapixant2P2X3 receptor antagonistP2RX3No
Vismodegib2Hedgehog inhibitorSMONo
Dasatinib2Multi-kinase inhibitorABL/SRCNo
Imatinib2BCR-ABL/PDGFR inhibitorABL1/PDGFRANo
Omipalisib2PI3K/mTOR inhibitorPIK3CA/MTORIndirect (DEPTOR)
Belumosudil2ROCK2 inhibitorROCK2No
Tanzisertib (CC-930)2JNK inhibitorMAPK8No
Olitigaltin (TD139)2Galectin-3 inhibitorLGALS3No

GWAS-Trial Alignment

Drugs targeting GWAS genes directly: ~3/30 (10%)

  • N-Acetylcysteine (MUC5B-guided trial)
  • Omipalisib indirectly (mTOR → DEPTOR)
  • Danazol/Nandrolone (TERT upregulation)

This is remarkably LOW. Only ~10% of IPF trial drugs directly target GWAS genes, suggesting a major disconnect between genetic evidence and drug development in this disease. This represents a significant opportunity gap.

Section 14: Pathway Analysis

GWAS Genes Mapped to Reactome Pathways

Pathway NameReactome IDGWAS GenesDruggable Nodes
Telomere Extension By TelomeraseR-HSA-171319TERT, RTEL1TERT (telomerase inhibitors)
O-linked glycosylation of mucinsR-HSA-913709MUC5BGlycosyltransferases (FUT3, FUT6)
Keratinization / Cornified envelopeR-HSA-6805567DSP—
Neutrophil degranulationR-HSA-6798695DSP, ATP11AMultiple kinases
Apoptotic cleavage of adhesion proteinsR-HSA-351906DSPCaspases (drugged)
Ion transport by P-type ATPasesR-HSA-936837ATP11AATPase modulators
HSP90 chaperone cycle for SHRR-HSA-3371497FKBP5HSP90 (ganetespib), FKBP5 (SAFit)
ESR-mediated signalingR-HSA-8939211FKBP5ESR1 (tamoxifen), HSP90
Signaling by NODALR-HSA-1181150PCSK6TGF-β superfamily (existing drugs)
NGF processingR-HSA-167060PCSK6Neurotrophins
β-catenin:TCF transactivating complexR-HSA-201722TERTWNT pathway (vantictumab)
Cytosolic iron-sulfur cluster assemblyR-HSA-2564830RTEL1—
Resolution of D-loop Structures (SDSA)R-HSA-5693554RTEL1DNA repair pathway
Assembly of LPL/LIPC lipase complexesR-HSA-8963889PCSK6PCSK6 processing
Dectin-2 familyR-HSA-5621480MUC5BInnate immune receptors

Pathway-Level Druggability Opportunities

  1. Telomere maintenance pathway (TERT, TERC, RTEL1, STN1, PARN) → Telomerase modulators, danazol, HSP90 inhibitors
  2. TGF-β / NODAL signaling (PCSK6 processes NODAL/TGF-β ligands) → TGF-β pathway drugs (pirfenidone, fresolimumab)
  3. WNT signaling (SFRP1, TERT, β-catenin) → WNT inhibitors in oncology
  4. Innate immune / IL-1 signaling (TOLLIP, DPP9/NLRP1 inflammasome) → Inflammasome inhibitors
  5. Mucin biology / glycosylation (MUC5B, FUT3, FUT6) → Glycosylation modulators

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates

RankDrugGene TargetApproved ForMechanismGWAS p-valuePriority Score
1DanazolTERTEndometriosisTelomerase activator (via androgen pathway)5e-3298
2SitagliptinDPP4→DPP9Type 2 diabetesDPP4 inhibitor (some DPP9 cross-react)3e-1692
3TacrolimusFKBP5Transplant rejectionFKBP ligand/calcineurin inhibitor3e-888
4Rapamycin/SirolimusFKBP5/mTORTransplantmTOR inhibitor via FKBP12→mTOR (DEPTOR link)3e-886
5TopiramateGRIK4EpilepsyKainate/AMPA receptor antagonist4e-1178
6PerampanelGRIK4EpilepsyAMPA/kainate antagonist4e-1176
7GanetespibHSP90→TERTCancer (trials)HSP90 inhibitor5e-32 (indirect)74
8NandroloneTERTAnemiaAndrogen/telomerase activator5e-3272
9VildagliptinDPP4→DPP9Type 2 diabetesDPP4 inhibitor3e-1670
10SaxagliptinDPP4→DPP9Type 2 diabetesDPP4 inhibitor3e-1668
11EverolimusmTOR/FKBP5Cancer, transplantmTOR inhibitor3e-866
12OmipalisibPI3K→mTOR/DEPTORCancerPI3K/mTOR dual inhibitor6e-11 (DEPTOR)64
13Dec-RVKR-cmkPCSK6Tool compoundFurin/PCSK6 inhibitor9e-960
14AlpelisibPIK3CA→TERTCancerPI3K inhibitor5e-32 (indirect)58
15Talabostat (VbP)DPP8/9Cancer (trials)DPP8/9 inhibitor3e-1656
16ErenumabEFNA5 pathwayMigraineEphrin pathway modulation4e-1350
17VenetoclaxBCL2→apoptosisCLLBCL2 inhibitor(pathway)48
18N-AcetylcysteineMUC5B (expression)MucolyticAntioxidant/mucolytic~046
19OmeprazoleGER/MUC5BGERDProton pump inhibitor~0 (indirect)44
20LosartanTGF-β pathwayHypertensionARB / anti-fibrotic(pathway)42
21DasatinibSRC/ABL→fibrosisCMLMulti-kinase inhibitor(pathway)40
22ImatinibPDGFR→fibrosisCMLPDGFR/ABL inhibitor(pathway)38
23ThalidomideAnti-fibroticMyelomaTNF/angiogenesis modulator(pathway)36
24Zileuton5-LOX→inflammationAsthma5-LOX inhibitor(pathway)34
25RituximabCD20→B cellsLymphomaAnti-CD20(immune)32
26AtezolizumabPD-L1→immuneCancerPD-L1 antibody(immune)30
27BelumosudilROCK2→fibrosisGVHDROCK2 inhibitor(fibrosis)28
28ArtesunateAnti-fibroticMalariaTGF-β/NF-κB modulation(pathway)26
29ParoxetineSSRI→FKBP5DepressionSerotonin reuptake3e-8 (indirect)24
30MinocyclineMMP→fibrosisInfectionMMP inhibitor/anti-inflammatory(fibrosis)22

Section 16: Druggability Pyramid

LevelDescriptionGene CountPercentageKey Genes
1VALIDATED: Approved drug FOR IPF24%(Nintedanib/Pirfenidone — not directly GWAS gene targets; NAC in MUC5B-guided trial)
2REPURPOSING: Approved drug for OTHER disease49%FKBP5 (tacrolimus), MAPT (anti-tau), GRIK4 (topiramate), TERT (danazol)
3EMERGING: Drug in clinical trials36%DPP9 (talabostat), DEPTOR (mTOR inhibitors), PCSK6 (furin inhibitors)
4TOOL COMPOUNDS: ChEMBL compounds, no trials715%PSKH1, PTPN14, KIF15, SFRP1, FUT3, FUT6, AP2B1
5DRUGGABLE UNDRUGGED: Druggable family, NO compounds715%GPR157 (GPCR!), ATP11A (ATPase), RTEL1 (helicase), IVD (enzyme), PARN (RNase), ABCA3 (ABC transporter), FAM13A (RhoGAP)
6HARD TARGETS: Difficult family or unknown TOTAL24 4751% 100%MUC5B, DSP, TOLLIP, STN1, KANSL1, MAD1L1, ZKSCAN1, FOXP1, SPDL1, ACTRT3, ANK1, CNTNAP2, NRXN3, DLG2, CDYL2, STMN3, TACC2, KNL1, GMEB2, DNAJB4, DAZAP1, NPRL3, SFTPC, SFTPA1/2

Section 17: Undrugged Target Profiles

TOP Undrugged Opportunities (Level 5 — Druggable family, no drugs)

  1. GPR157 — G Protein-Coupled Receptor 157
AttributeDetail
GWAS p-value3e-9
Variant typeRegulatory (eQTL)
Protein functionOrphan GPCR, class B secretin-like
FamilyGPCR — most druggable protein family
StructureAlphaFold available; GPCR fold well-characterized
ExpressionLung expressed
InteractionsLimited interactome data
Why undrugged?Orphan receptor — no known endogenous ligand
Druggability: HIGHGPCRs are targets of ~34% of approved drugs
  1. DPP9 — Dipeptidyl Peptidase 9
AttributeDetail
GWAS p-value3e-16
Mendelian overlapYES
Variant typeRegulatory
Protein functionSerine protease; NLRP1/CARD8 inflammasome regulator
FamilySerine protease — highly druggable
Structure14 PDB structures at 1.8-3.0 Å — excellent
ExpressionUbiquitous (lung, immune cells)
InteractionsHub gene — interacts with FAM13A, ATP11A, STN1, MUC5B, TOLLIP, DSP
Why undrugged?DPP4 inhibitors (gliptins) have limited DPP9 selectivity; DPP9 inhibition activates inflammasome — safety concern
Druggability: HIGHTalabostat in trials; selective modulators needed
  1. ATP11A — Phospholipid-Transporting ATPase IH
AttributeDetail
GWAS p-value5e-14
Mendelian overlapYES
Variant typeRegulatory
Protein functionP-type ATPase phospholipid flippase; maintains membrane asymmetry
FamilyP-type ATPase — druggable (cardiac glycosides target Na/K ATPase)
StructureAlphaFold (pLDDT 83.5); P-type ATPase fold well-characterized
ExpressionUbiquitous, lung expressed
InteractionsDPP9 (score 571)
Why undrugged?Limited understanding of specific biological role in IPF; selectivity challenge
Druggability: HIGHP-type ATPase fold amenable; needs specific modulators
  1. RTEL1 — Regulator of Telomere Elongation Helicase 1
AttributeDetail
GWAS p-value2e-10
Mendelian overlapYES (OMIM:616373)
Variant typeCoding (Tier 1)
Protein functionATP-dependent DNA helicase; telomere maintenance; anti-recombinase
FamilyDEAH-box helicase — enzyme, druggable
StructureAlphaFold (pLDDT 72.6); helicase domain well-characterized
ExpressionUbiquitous
InteractionsTERT (score 832)
Why undrugged?IPF needs activation, not inhibition; no activators known
Druggability: MEDIUMActivators harder than inhibitors
  1. IVD — Isovaleryl-CoA Dehydrogenase
AttributeDetail
GWAS p-value9e-20
Variant typeIntronic (may be eQTL for nearby gene)
Protein functionMitochondrial enzyme; leucine catabolism
FamilyAcyl-CoA dehydrogenase — enzyme
StructureAlphaFold available; enzyme fold known
ExpressionUbiquitous
Why undrugged?Metabolic enzyme; unclear IPF mechanism; may be a proxy for nearby gene
Druggability: MEDIUMEnzyme druggable, but unclear if correct causal gene
  1. PARN — Poly(A)-Specific Ribonuclease
AttributeDetail
GWAS p-valueMendelian only
Mendelian overlapYES (OMIM:616371)
Protein functionDeadenylase; telomere RNA processing; ribosome biogenesis
FamilyRNase/exonuclease — enzyme
StructureAlphaFold (pLDDT 81.6)
ExpressionUbiquitous
Why undrugged?IPF needs activation; loss-of-function mutations cause disease
Druggability: LOWNeed activator or gene therapy
  1. ABCA3 — ATP Binding Cassette Subfamily A Member 3
AttributeDetail
GWAS p-valueMendelian only
Mendelian overlapYES
Protein functionSurfactant lipid transport in type II pneumocytes
FamilyABC transporter — druggable
StructureAlphaFold (pLDDT 81.0)
ExpressionLung-enriched (surfactant biology)
Why undrugged?Loss-of-function; need potentiators like CFTR modulators
Druggability: MEDIUMPrecedent: ivacaftor (CFTR potentiator) approach
  1. PSKH1 — Protein Serine Kinase H1
AttributeDetail
GWAS p-value4e-9
Variant typeRegulatory
Protein functionSerine/threonine kinase
FamilyProtein kinase — most druggable enzyme family
StructureNo PDB; AlphaFold; kinase fold standard
ExpressionUbiquitous
Why undrugged?Poorly characterized kinase; limited biological understanding
Druggability: HIGHStandard kinase fold; ready for screening
  1. PTPN14 — Protein Tyrosine Phosphatase Non-Receptor Type 14
AttributeDetail
GWAS p-value3e-9
Protein functionTyrosine phosphatase; Hippo pathway regulator; YAP modulator
FamilyTyrosine phosphatase — druggable
Structure3 PDB structures (1.65 Å)
ExpressionUbiquitous
Why undrugged?PTP family historically difficult; new approaches emerging
Druggability: MEDIUMActive site solved; allosteric approaches possible
  1. PCSK6 — Proprotein Convertase Subtilisin/Kexin Type 6
AttributeDetail
GWAS p-value9e-9
Protein functionSerine protease; processes NODAL, TGF-β ligands, lipases
FamilySubtilisin protease — druggable
StructureNo PDB for human PCSK6; homologs solved
PathwaysNODAL signaling, NGF processing, cornified envelope
Druggability: HIGHProtease with defined active site; furin-family precedent

Undrugged Opportunity Ranking

RankGenep-valueFamilyStructureMendelianPotential
1DPP93e-16ProteaseExcellentYESHIGH
2GPR1573e-9GPCRAF goodNoHIGH
3ATP11A5e-14P-type ATPaseAF goodYESHIGH
4PSKH14e-9KinaseAFNoHIGH
5PCSK69e-9ProteaseHomologyNoHIGH
6RTEL12e-10HelicaseAF moderateYESMEDIUM
7PTPN143e-9PhosphatasePDBNoMEDIUM
8ABCA3MendelianABC transporterAF goodYESMEDIUM
9IVD9e-20EnzymeAFNoMEDIUM
10FAM13A6e-17RhoGAPAF lowYESMEDIUM

Section 18: Summary

GWAS LANDSCAPE

MetricValue
Total associations140
Unique studies21
Unique protein-coding genes47
Coding variants (Tier 1)6%
Regulatory variants (Tier 3)44%
Intronic/intergenic (Tier 4)40%

GENETIC EVIDENCE

MetricValue
Tier 1 (coding) genes3
Mendelian overlap genes14 (Orphanet), 9 also in GWAS
Genes with BOTH GWAS + Mendelian evidence9 (19%) — exceptionally high

DRUGGABILITY

MetricValue
Overall druggable rate (druggable family)32%
With approved drugs9%
In clinical trials6%
Tool compounds only15%
Druggable but undrugged (OPPORTUNITY)15%
Hard/difficult targets51%

PYRAMID SUMMARY

LevelCount%
L1 Validated24%
L2 Repurposing49%
L3 Emerging36%
L4 Tool compounds715%
L5 Druggable undrugged715%
L6 Hard targets2451%

CLINICAL TRIAL ALIGNMENT

Only ~10% of IPF trial drugs target GWAS genes directly. This is among the lowest genetic-therapeutic concordance rates, indicating a massive opportunity for genetically-informed drug development.

TOP 10 REPURPOSING CANDIDATES

Drug → GeneApproved Forp-valueScore
Danazol → TERTEndometriosis5e-3298
Sitagliptin → DPP4/DPP9T2D3e-1692
Tacrolimus → FKBP5Transplant3e-888
Sirolimus → FKBP/mTOR/DEPTORTransplant3e-886
Topiramate → GRIK4Epilepsy4e-1178
Perampanel → GRIK4Epilepsy4e-1176
Ganetespib → HSP90/TERTCancer5e-3274
Nandrolone → TERTAnemia5e-3272
Vildagliptin → DPP4/DPP9T2D3e-1670
Everolimus → mTOR/DEPTORCancer6e-1166

TOP 10 UNDRUGGED OPPORTUNITIES

Genep-valueFamilyStructurePotential
DPP93e-16Protease14 PDBHIGH
GPR1573e-9GPCRAlphaFoldHIGH
ATP11A5e-14P-type ATPaseAlphaFoldHIGH
PSKH14e-9KinaseAlphaFoldHIGH
PCSK69e-9ProteaseHomologyHIGH
RTEL12e-10HelicaseAlphaFoldMEDIUM
PTPN143e-9Phosphatase3 PDBMEDIUM
ABCA3MendelianABC transporterAlphaFoldMEDIUM
IVD9e-20EnzymeAlphaFoldMEDIUM
FAM13A6e-17RhoGAPAlphaFoldMEDIUM

TOP 10 INDIRECT OPPORTUNITIES (Undrugged → Drugged Interactor)

Undrugged Gene↔Drugged InteractorDrug(s)
MUC5B↔ DPP9DPP4Gliptins (sitagliptin)
FAM13A↔ DPP9DPP4/DPP8/9Talabostat, gliptins
TOLLIP↔ DPP9NLRP1 inflammasomeDPP9 modulators
STN1↔ TERTHSP90Ganetespib, 17-AAG
RTEL1↔ TERTHSP90, TP53Ganetespib, APR-246
DSP↔ DPP9DPP9/DPP4Gliptins
ATP11A↔ DPP9DPP9/DPP4Gliptins
KANSL1↔ DPP9DPP9Talabostat
DEPTOR↔ mTORmTORRapamycin, everolimus
SFRP1↔ WNTWNT pathwayVantictumab, ipafricept

KEY INSIGHTS

  1. MUC5B dominance: The MUC5B promoter variant rs35705950 is the single most powerful common-variant risk factor for any fibrotic disease (OR ~5-7). It accounts for the majority of IPF heritability and is the basis of the first genotype-guided IPF trial (PRECISIONS).

  2. Telomere biology convergence: 5 of 14 Mendelian IPF genes (TERT, TERC, RTEL1, STN1, PARN) are telomere maintenance genes, and TERT/TERC/RTEL1/STN1 are also GWAS hits. This makes telomere biology the strongest genetically-validated pathway in IPF. Yet telomerase activators are barely in clinical development.

  3. DPP9 as a central hub: DPP9 interacts with multiple other IPF GWAS genes (FAM13A, ATP11A, MUC5B, DSP, TOLLIP, STN1) and regulates the NLRP1/CARD8 inflammasome. This positions DPP9 as potentially the most therapeutically important GWAS target — a serine protease with excellent structural data and tool compounds already available.

  4. GPR157 — hidden gem: This orphan GPCR is a novel GWAS hit (p=3e-9) in the most druggable protein family. Deorphanizing GPR157 and developing modulators could open a new therapeutic avenue for IPF.

  5. Massive trial-genetics disconnect: Only ~10% of IPF clinical trial drugs target GWAS genes. The field is dominated by empirically-identified mechanisms (TGF-β, endothelin, LPA) rather than genetically-validated ones. This contrasts sharply with diseases like cardiovascular disease where genetic evidence guides most development.

  6. Comparison with other fibrotic diseases: IPF has exceptionally strong Mendelian-GWAS convergence (64%) compared to most complex diseases (typically <20%). This suggests IPF genetic architecture is more oligogenic than other common diseases, with large-effect variants in a concentrated set of pathways. This is favorable for drug development.

  7. Actionable pharmacogenomics: MUC5B genotyping is already being used clinically (PRECISIONS trial). FKBP5 variants could guide immunosuppressive therapy. TERT mutation status guides danazol consideration. IPF may be among the first fibrotic diseases with genotype-guided therapy.

Analysis generated using biobtree MCP tools (biobtree_search, biobtree_map, biobtree_entry) querying GWAS Catalog, MONDO, EFO, MeSH, Orphanet, OMIM, HGNC, UniProt, ChEMBL, STRING, InterPro, Reactome, Bgee, AlphaFold, PDB, PharmGKB, and ClinicalTrials.gov data. Date: 2026-04-10.