◎ Sugi Atlas

Atlas / Disease / Rheumatic heart disease

Rheumatic heart disease

disease
On this page

Also known as disease, rheumatic heartheart disease, rheumaticRHDrheumatic carditis

Summary

Rheumatic heart disease (MONDO:0006955) is a disease with 29 cohort genes (35 GWAS associations across 15 studies) and 46 clinical trials. Top therapeutic interventions include rivaroxaban, glutamine, and penicillin g benzathine.

At a glance

  • Cohort genes: 29
  • GWAS associations: 35
  • ClinVar variants: 2
  • Clinical trials: 46

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical namerheumatic heart disease
Mondo IDMONDO:0006955
EFOEFO:1001161
MeSHD012214
DOIDDOID:0050827
ICD-11291726710
NCITC34882
SNOMED CT23685000
UMLSC0035439
MedGen20565
MedDRA10062110
Is cancer (heuristic)no

Also known as: disease, rheumatic heart · heart disease, rheumatic · RHD · rheumatic carditis

Data availability: 2 ClinVar variants · 35 GWAS associations (15 studies).

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › rheumatic heart disease

Related subtypes (33): endocardium disorder, pericardium disorder, cardiac tuberculosis, heart conduction disease, hypertensive heart disease, heart valve disorder, cardiomyopathy, coronary artery disorder, heart failure, congenital heart disease, heart aneurysm, cardiac rhythm disease, white forelock with malformations, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, PHACE syndrome, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, cardiac anomalies-heterotaxy syndrome, polyvalvular heart disease syndrome, Thomas syndrome, 22q11.2 deletion syndrome, myocardial rupture, heart neoplasm, aortopulmonary window, cor biloculare, inflammation of heart layer, myocardial disorder, carcinoid heart disease, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, coronary microvascular disorder, cardiac ventricle disorder, cardiogenetic disease, cardiogenic shock

Subtypes (4): rheumatic congestive heart failure, rheumatic myocarditis, acute rheumatic heart disease, rheumatic pericarditis

Genetics & variants

GWAS landscape

35 GWAS associations across 15 studies. Top hits map to 10 distinct genes (as reported by GWAS).

Top associations by p-value

rsIDp-valueGeneRisk alleleOdds ratio
chr6:1605760861e-11T0.17
rs2010264763e-10PBX2?1.81
chr9:221159608e-10G0.09
rs2021178054e-09IGHV4-61; IGHV4-61; IGHV4-61; IGHV4-61; IGHV3-62 - IGHVII-62-1; IGHV4-61C1.43
rs118464094e-09IGHV3-62 - IGHVII-62-1?
chr13:890087699e-09A1.48
rs1490682731e-08RPL23AP68 - CYCSP30?
chrX:1530434761e-08A1.3
chr4:1107427772e-08T0.13
chr9:739739363e-08C2.39
rs12194064e-08SORL1 - RNU6-256PC1.65
chr8:429034544e-08G2.67
chr8:480711714e-08G2.67
chr17:119920535e-08C3.19
chr19:55783265e-08C2.92
chr22:333278975e-08A2.67
rs287242382e-07HLA-DQB1?1.75
rs111254262e-07NRXN1-DT - GGCTP3?0.41
rs23863253e-07IGKV1D-33 - IGKV1D-32?0.8
rs732954304e-07HNRNPA1P4 - DPPA3P9?0.8
rs102434364e-07STAG3L4 - MTATP6P21?1.49
rs133931207e-07MMADHC-DT?1.32
rs107558889e-07NRG1?0.71
rs37533959e-07CFH?0.81
rs17950301e-06LINC02775?0.78
rs107743431e-06NINJ2?1.28
rs115978591e-06CTNNA3?0.58
rs94050843e-06HLA-B?1.36
rs116007513e-06CCKBR - CAVIN3?1.55
rs352095623e-06PARVA - TEAD1?1.73

Top studies (by case count)

StudyLead authorYearCasesControlsTitle
GCST90473509UK Biobank Whole-Genome Sequencing Consortium202510,742447,698Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90667776UK Biobank Whole-Genome Sequencing Consortium202510,742447,698Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90477833Verma A20245,583433,012Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90436054Zhou W20184,895402,421Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST012115Machipisa T20211,6871,492Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals: Findings From the RHDGen Study.
GCST012117Machipisa T20211,6871,492Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals: Findings From the RHDGen Study.
GCST90477832Verma A20241,230117,496Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480796Verma A20241,230117,496Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST004366Parks T20177671,462Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania.
GCST010509Auckland K20205100The Human Leukocyte Antigen Locus and Rheumatic Heart Disease Susceptibility in South Asians and Europeans.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

TierVariants
Tier 1: coding0
Tier 2: splice/UTR1
Tier 3: regulatory0
Tier 4: intronic/intergenic32

MAF distribution

BucketVariants
common (>=0.05)21
low_freq (0.01-0.05)0
rare (<0.01)0
unknown12

Functional consequences

ConsequenceCount
intron_variant14
unknown11
intergenic_variant6
3_prime_UTR_variant1
missense_variant; missense_variant; missense_variant; missense_variant; intergenic_variant; missense_variant1

Top variants

rsIDChrPosAllelesMAFConsequenceGenep-valueTier
chr6:1605760861e-11Tier 4: intronic/intergenic
rs201026476632185564TAAAA>T,TAA,TAAA,TAAAAA,TAAAAAA0.053_prime_UTR_variantPBX23e-10Tier 2: splice/UTR
chr9:221159608e-10Tier 4: intronic/intergenic
rs20211780514;14;14;14;14;14106639291G>A,C,T0.05missense_variant; missense_variant; missense_variant; missense_variant; intergenic_variant; missense_variantIGHV4-61; IGHV4-61; IGHV4-61; IGHV4-61; IGHV3-62 - IGHVII-62-1; IGHV4-614e-09Tier 4: intronic/intergenic
rs1184640914106645692T>G0.05intergenic_variantIGHV3-62 - IGHVII-62-14e-09Tier 4: intronic/intergenic
chr13:890087699e-09Tier 4: intronic/intergenic
rs1490682731287461714C>Tintergenic_variantRPL23AP68 - CYCSP301e-08Tier 4: intronic/intergenic
chrX:1530434761e-08Tier 4: intronic/intergenic
chr4:1107427772e-08Tier 4: intronic/intergenic
chr9:739739363e-08Tier 4: intronic/intergenic
rs121940611121873661G>A,C,T0.05intron_variantSORL1 - RNU6-256P4e-08Tier 4: intronic/intergenic
chr8:429034544e-08Tier 4: intronic/intergenic
chr8:480711714e-08Tier 4: intronic/intergenic
chr17:119920535e-08Tier 4: intronic/intergenic
chr19:55783265e-08Tier 4: intronic/intergenic
chr22:333278975e-08Tier 4: intronic/intergenic
rs28724238632661289T>C,G0.05intron_variantHLA-DQB12e-07Tier 4: intronic/intergenic
rs11125426252417028C>T0.05intergenic_variantNRXN1-DT - GGCTP32e-07Tier 4: intronic/intergenic
rs2386325289917651C>G,T0.05intergenic_variantIGKV1D-33 - IGKV1D-323e-07Tier 4: intronic/intergenic
rs73295430882468501G>A0.05intron_variantHNRNPA1P4 - DPPA3P94e-07Tier 4: intronic/intergenic
rs10243436767576526G>T0.05intergenic_variantSTAG3L4 - MTATP6P214e-07Tier 4: intronic/intergenic
rs133931202149929552A>G0.05intron_variantMMADHC-DT7e-07Tier 4: intronic/intergenic
rs10755888832390501C>G0.05intron_variantNRG19e-07Tier 4: intronic/intergenic
rs37533951196717522A>G,T0.05intron_variantCFH9e-07Tier 4: intronic/intergenic
rs17950301214124300A>G,T0.05intron_variantLINC027751e-06Tier 4: intronic/intergenic
rs1077434312589713A>C0.05intron_variantNINJ21e-06Tier 4: intronic/intergenic
rs115978591066571620A>G0.05intron_variantCTNNA31e-06Tier 4: intronic/intergenic
rs9405084631358474C>T0.05intron_variantHLA-B3e-06Tier 4: intronic/intergenic
rs11600751116280973G>A,C0.05intron_variantCCKBR - CAVIN33e-06Tier 4: intronic/intergenic
rs352095621112626224C>A,G,T0.05intron_variantPARVA - TEAD13e-06Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 risk factor, 1 uncertain significance

ClinVarVariant (HGVS)GeneClassificationReview
992481NM_003665.4(FCN3):c.658+250C>AFCN3risk factorno assertion criteria provided
992482NM_003665.4(FCN3):c.393+178T>AFCN3Uncertain significanceno assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 24 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
SORL1Orphanet:1020Early-onset autosomal dominant Alzheimer disease
TEAD1Orphanet:86813Helicoid peripapillary chorioretinal degeneration
CTNNA3Orphanet:293888Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
CTNNA3Orphanet:293899Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
CTNNA3Orphanet:293910Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
FCN3Orphanet:331190Immunodeficiency due to ficolin3 deficiency
CFHOrphanet:200421Immunodeficiency with factor H anomaly
CFHOrphanet:244242HELLP syndrome
CFHOrphanet:244275De novo thrombotic microangiopathy after kidney transplantation
CFHOrphanet:329903Immunoglobulin-mediated membranoproliferative glomerulonephritis
CFHOrphanet:544472Atypical hemolytic uremic syndrome with complement gene abnormality
CFHOrphanet:75376Familial drusen
CFHOrphanet:93571Dense deposit disease
HLA-BOrphanet:117Behçet disease
HLA-BOrphanet:275798Pulmonary arterial hypertension associated with connective tissue disease
HLA-BOrphanet:29207Reactive arthritis
HLA-BOrphanet:3287Takayasu arteritis
HLA-BOrphanet:36426Stevens-Johnson syndrome
HLA-BOrphanet:397Giant cell arteritis
HLA-DQB1Orphanet:2073Narcolepsy type 1
HLA-DQB1Orphanet:477738Pediatric multiple sclerosis
HLA-DQB1Orphanet:703Bullous pemphigoid
HLA-DQB1Orphanet:83465Narcolepsy type 2
HLA-DQB1Orphanet:930Idiopathic achalasia

Cohort genes → proteins

29 cohort genes, 20 distinct canonical proteins.

Evidence partition

SubsetGenes
gwas_only28
multi_evidence1

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
SORL1HGNC:11185ENSG00000137642Q92673Sortilin-related receptorgwas
TEAD1HGNC:11714ENSG00000187079P28347Transcriptional enhancer factor TEF-1gwas
TINCRHGNC:14607ENSG00000223573A0A2R8Y7D0Ubiquitin domain-containing protein TINCRgwas
PARVAHGNC:14652ENSG00000197702Q9NVD7Alpha-parvingwas
SNX16HGNC:14980ENSG00000104497P57768Sorting nexin-16gwas
CCKBRHGNC:1571ENSG00000110148P32239Gastrin/cholecystokinin type B receptorgwas
CHODLHGNC:17807ENSG00000154645Q9H9P2Chondrolectingwas
SMYD2HGNC:20982ENSG00000143499Q9NRG4N-lysine methyltransferase SMYD2gwas
CTNNA3HGNC:2511ENSG00000183230Q9UI47Catenin alpha-3gwas
MIR125B1HGNC:31506ENSG00000207971microRNA 125b-1gwas
BLIDHGNC:33495ENSG00000259571Q8IZY5BH3-like motif-containing cell death inducergwas
FCN3HGNC:3625ENSG00000142748O75636Ficolin-3clinvar
MIR100HGHGNC:39522ENSG00000255248mir-100-let-7a-2-mir-125b-1 cluster host genegwas
MIR4431HGNC:41738ENSG00000264975microRNA 4431gwas
MIR4436AHGNC:41762ENSG00000265510microRNA 4436agwas
RNU6-256PHGNC:47219ENSG00000252556RNA, U6 small nuclear 256, pseudogenegwas
CFHHGNC:4883ENSG00000000971P08603Complement factor Hgwas
HLA-BHGNC:4932ENSG00000234745P01889HLA class I histocompatibility antigen, B alpha chaingwas
HLA-DQB1HGNC:4944ENSG00000179344P01920HLA class II histocompatibility antigen, DQ beta 1 chaingwas
LINC01372HGNC:50623long intergenic non-protein coding RNA 1372gwas
LINC01817HGNC:52622ENSG00000231420long intergenic non-protein coding RNA 1817gwas
LINC01931HGNC:52743ENSG00000162947long intergenic non-protein coding RNA 1931gwas
IGHV4-61HGNC:5655ENSG00000211970A0A0C4DH41Immunoglobulin heavy variable 4-61gwas
IGKV1D-33HGNC:5753ENSG00000239975P01593Immunoglobulin kappa variable 1D-33gwas
NINJ2HGNC:7825ENSG00000171840Q9NZG7Ninjurin-2gwas
NRG1HGNC:7997ENSG00000157168Q02297Pro-neuregulin-1, membrane-bound isoformgwas
PBX2P1HGNC:8635ENSG00000244171PBX homeobox 2 pseudogene 1gwas
CAVIN3HGNC:9400ENSG00000170955Q969G5Caveolae-associated protein 3gwas
PROX1HGNC:9459ENSG00000117707Q92786Prospero homeobox protein 1gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
SORL1Sortilin-related receptorSorting receptor that directs several proteins to their correct location within the cell.
TEAD1Transcriptional enhancer factor TEF-1Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis.
TINCRUbiquitin domain-containing protein TINCRPromotes epithelial differentiation by enhancing the sumoylation and activation of CDC42.
PARVAAlpha-parvinPlays a role in sarcomere organization and in smooth muscle cell contraction.
SNX16Sorting nexin-16May be involved in several stages of intracellular trafficking.
CCKBRGastrin/cholecystokinin type B receptorReceptor for the peptide hormones gastrin and cholecystokinin (CCK).
CHODLChondrolectinMay play a role in the development of the nervous system such as in neurite outgrowth and elongation.
SMYD2N-lysine methyltransferase SMYD2Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1.
CTNNA3Catenin alpha-3May be involved in formation of stretch-resistant cell-cell adhesion complexes.
BLIDBH3-like motif-containing cell death inducerFunctions as a proapoptotic molecule through the caspase-dependent mitochondrial pathway of cell death.
FCN3Ficolin-3Calcium-dependent lectin, which acts as a pattern recognition receptor that initiates the lectin pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens t…
CFHComplement factor HGlycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation.
HLA-BHLA class I histocompatibility antigen, B alpha chainAntigen-presenting major histocompatibility complex class I (MHCI) molecule.
HLA-DQB1HLA class II histocompatibility antigen, DQ beta 1 chainBinds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
IGHV4-61Immunoglobulin heavy variable 4-61V region of the variable domain of immunoglobulin heavy chains that participates in the antigen recognition.
IGKV1D-33Immunoglobulin kappa variable 1D-33V region of the variable domain of immunoglobulin light chains that participates in the antigen recognition.
NINJ2Ninjurin-2Its role in unclear.
NRG1Pro-neuregulin-1, membrane-bound isoformDirect ligand for ERBB3 and ERBB4 tyrosine kinase receptors.
CAVIN3Caveolae-associated protein 3Regulates the traffic and/or budding of caveolae.
PROX1Prospero homeobox protein 1Transcription factor involved in developmental processes such as cell fate determination, gene transcriptional regulation and progenitor cell regulation in a number of organs.

Protein-family classification

Druggable: 8 · Difficult: 2 · Unknown: 19 · Druggable fraction: 0.28

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

FamilyGenesFoldFDR
Antibody/Immunoglobulin66.0×0.002
Complement19.2×0.257
Other/Unknown191.2×0.323
GPCR10.8×0.882
Transcription factor20.6×0.882

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
SORL1Antibody/ImmunoglobulinyesLDLR_classB_rpt, LDrepeatLR_classA_rpt, FN3_dom
TEAD1Other/UnknownnoTEA/ATTS_dom, TEF_metazoa, TEA/ATTS_sf
TINCROther/UnknownnoUbiquitin-like_dom, Ubiquitin-like_domsf
PARVAOther/UnknownnoCH_dom, Parvin, CH_dom_sf
SNX16Other/UnknownnoPX_dom, PX_dom_sf, SNX16_PX
CCKBRGPCRyesGPCR_Rhodpsn, Gastrin_rcpt, Cholcskin_rcpt
CHODLOther/UnknownnoC-type_lectin-like, C-type_lectin-like/link_sf, CTDL_fold
SMYD2Transcription factornoSET_dom, Znf_MYND, TPR-like_helical_dom_sf
CTNNA3Other/UnknownnoAlpha_catenin, Vinculin/catenin, Alpha-catenin/vinculin-like_sf
MIR125B1Other/Unknownno
BLIDOther/Unknownno
FCN3Other/UnknownnoFibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_C_1, Fibrinogen_CS
MIR100HGOther/Unknownno
MIR4431Other/Unknownno
MIR4436AOther/Unknownno
RNU6-256POther/Unknownno
CFHComplementyesSushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
HLA-BAntibody/ImmunoglobulinyesMHC_I_a_a1/a2, Ig/MHC_CS, Ig_C1-set
HLA-DQB1Antibody/ImmunoglobulinyesMHC_II_b_N, Ig/MHC_CS, Ig_C1-set
LINC01372Other/Unknownno
LINC01817Other/Unknownno
LINC01931Other/Unknownno
IGHV4-61Antibody/ImmunoglobulinyesIg-like_dom, Ig_V-set, Ig-like_fold
IGKV1D-33Antibody/ImmunoglobulinyesIg_sub, Ig-like_dom, Ig_V-set
NINJ2Other/UnknownnoNinjurin
NRG1Antibody/ImmunoglobulinyesEGF, Neuregulin_C, Ig_sub2
PBX2P1Other/Unknownno
CAVIN3Other/UnknownnoCavin_fam
PROX1Transcription factornoHomeodomain-like_sf, Homeo_prospero_dom, Homeo_prospero_dom_sf

Expression context

Cohort genes with no expression data: 1.

19 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)2
broad (>20)26
unknown1

Top tissues across cohort

TissueCohort genes
calcaneal tendon5
male germ line stem cell (sensu Vertebrata) in testis4
frontal pole2
stromal cell of endometrium2
sperm2
prefrontal cortex2
right testis2
heart right ventricle2
corpus callosum2
cartilage tissue2
right lung2
upper lobe of left lung2
ganglionic eminence2
ventricular zone2
right coronary artery2
blood2
granulocyte2
spleen2
liver2
sural nerve2

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
SORL1293ubiquitousmarkerfrontal pole, paraflocculus, middle frontal gyrus
TEAD1263ubiquitousmarkerskeletal muscle tissue of rectus abdominis, biceps brachii, skeletal muscle tissue of biceps brachii
TINCR180broadmarkerupper arm skin, skin of leg, skin of abdomen
PARVA281ubiquitousmarkersmooth muscle tissue, stromal cell of endometrium, colonic epithelium
SNX16257ubiquitousyessperm, male germ cell, secondary oocyte
CCKBR148broadmarkerBrodmann (1909) area 10, frontal pole, prefrontal cortex
CHODL185broadmarkercalcaneal tendon, right testis, left testis
SMYD2285ubiquitousmarkerleft ventricle myocardium, heart right ventricle, apex of heart
CTNNA3211broadmarkercorpus callosum, heart right ventricle, medial globus pallidus
MIR125B176yesadrenal tissue, kidney, calcaneal tendon
BLID39yescartilage tissue, calcaneal tendon, corpus callosum
FCN3172tissue_specificmarkerright lung, upper lobe of left lung, upper lobe of lung
MIR100HG245ubiquitousmarkerventricular zone, ganglionic eminence, cartilage tissue
MIR443112yesheart, stomach, heart left ventricle
MIR4436A62yesright uterine tube, monocyte, right testis
RNU6-256P32yescalcaneal tendon, endometrium, thoracic mammary gland
CFH267ubiquitousmarkerurethra, calcaneal tendon, right coronary artery
HLA-B134ubiquitousmarkerblood, spleen, granulocyte
HLA-DQB1268broadmarkerright lung, spleen, upper lobe of left lung
LINC01372
LINC0181758yesmale germ line stem cell (sensu Vertebrata) in testis, liver, prefrontal cortex
LINC0193179yesprimordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, sperm
IGHV4-61118markerduodenum, rectum, vermiform appendix
IGKV1D-33113markerbone marrow cell, male germ line stem cell (sensu Vertebrata) in testis, tonsil
NINJ2219broadmarkerblood, C1 segment of cervical spinal cord, male germ line stem cell (sensu Vertebrata) in testis
NRG1209ubiquitousmarkerventricular zone, ganglionic eminence, oocyte
PBX2P112ubiquitousyesstromal cell of endometrium, sural nerve, granulocyte
CAVIN3258ubiquitousmarkerright coronary artery, ascending aorta, thoracic aorta
PROX1225broadmarkersural nerve, liver, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

SymbolInteractor count
HLA-B3,209
TEAD12,544
SORL12,524
CTNNA32,306
SMYD21,990
CFH1,844
PROX11,688
CCKBR1,528
PARVA1,196
CAVIN31,056

Intra-cohort edges

ABSources
BLIDSORL1string_interaction
CHODLNINJ2biogrid_interaction, intact

Structural data

PDB: 16 · AlphaFold-only: 4 · No structure: 9

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
HLA-BP01889237
CFHP0860351
SMYD2Q9NRG425
PARVAQ9NVD718
TEAD1P2834714
NRG1Q0229711
HLA-DQB1P0192010
SORL1Q926737
IGKV1D-33P015936
CCKBRP322395
FCN3O756363
SNX16P577682
IGHV4-61A0A0C4DH412
TINCRA0A2R8Y7D01
NINJ2Q9NZG71
PROX1Q927861

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
CTNNA3Q9UI4781.65
CHODLQ9H9P276.83
CAVIN3Q969G572.11
BLIDQ8IZY550.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 93. Enrichment computed across 29 evidence-associated genes (11 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Initial triggering of complement2109.3×0.013FCN3, IGKV1D-33
Regulation of Complement cascade242.4×0.045CFH, IGKV1D-33
Localization of the PINCH-ILK-PARVIN complex to focal adhesions1259.6×0.059PARVA
Ficolins bind to repetitive carbohydrate structures on the target cell surface1207.6×0.059FCN3
CD22 mediated BCR regulation1207.6×0.059IGKV1D-33
GRB7 events in ERBB2 signaling1173.0×0.059NRG1
Creation of C4 and C2 activators1173.0×0.059IGKV1D-33
Classical antibody-mediated complement activation1173.0×0.059IGKV1D-33
Regulation of cytoskeletal remodeling and cell spreading by IPP complex components1129.8×0.059PARVA
RUNX3 regulates YAP1-mediated transcription1129.8×0.059TEAD1
Lectin pathway of complement activation1115.3×0.059FCN3
Endosomal/Vacuolar pathway194.4×0.059HLA-B
PI3K events in ERBB4 signaling194.4×0.059NRG1
FCGR activation179.9×0.059IGKV1D-33
Scavenging of heme from plasma179.9×0.059IGKV1D-33
Gastrin-CREB signalling pathway via PKC and MAPK179.9×0.059CCKBR
Downregulation of ERBB2:ERBB3 signaling174.2×0.059NRG1
ERBB2 Activates PTK6 Signaling174.2×0.059NRG1
YAP1- and WWTR1 (TAZ)-stimulated gene expression169.2×0.059TEAD1
SHC1 events in ERBB4 signaling164.9×0.059NRG1
ERBB2 Regulates Cell Motility164.9×0.059NRG1
PI3K events in ERBB2 signaling161.1×0.059NRG1
Cell-extracellular matrix interactions161.1×0.059PARVA
Complement cascade157.7×0.059IGKV1D-33
GRB2 events in ERBB2 signaling157.7×0.059NRG1
Interferon gamma signaling222.8×0.059HLA-B, HLA-DQB1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell215.8×0.059HLA-B, IGKV1D-33
Role of LAT2/NTAL/LAB on calcium mobilization154.6×0.059IGKV1D-33
Binding and Uptake of Ligands by Scavenger Receptors149.4×0.059IGKV1D-33
Regulation of TP53 Activity through Methylation149.4×0.059SMYD2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
hepatocyte cell migration1842.6×0.022PROX1
otic placode formation1842.6×0.022PROX1
branching involved in pancreas morphogenesis1842.6×0.022PROX1
negative regulation of fermentation1842.6×0.022CAVIN3
positive regulation of cell cycle checkpoint1842.6×0.022PROX1
negative regulation of RNA biosynthetic process1842.6×0.022FCN3
obsolete positive regulation of early endosome to recycling endosome transport1842.6×0.022SORL1
negative regulation of neurofibrillary tangle assembly1842.6×0.022SORL1
positive regulation of forebrain neuron differentiation1842.6×0.022PROX1
protein targeting to lysosome262.4×0.022SORL1, SNX16
complement activation262.4×0.022FCN3, CFH
regulation of complement activation, alternative pathway1421.3×0.026CFH
ERBB3 signaling pathway1421.3×0.026NRG1
lens placode formation involved in camera-type eye formation1421.3×0.026PROX1
gland development1421.3×0.026CCKBR
smooth muscle cell chemotaxis1421.3×0.026PARVA
positive regulation of peptidyl-tyrosine autophosphorylation1421.3×0.026NRG1
positive regulation of glial cell-derived neurotrophic factor production1421.3×0.026SORL1
adaptive immune response312.6×0.026HLA-B, HLA-DQB1, IGKV1D-33
olfactory placode formation1280.9×0.026PROX1
cholecystokinin signaling pathway1280.9×0.026CCKBR
ventricular cardiac myofibril assembly1280.9×0.026PROX1
lymphatic endothelial cell fate commitment1280.9×0.026PROX1
actin-mediated cell contraction1280.9×0.026PARVA
negative regulation of bile acid biosynthetic process1280.9×0.026PROX1
regulation of dendritic cell differentiation1280.9×0.026HLA-B
regulation of T cell anergy1210.7×0.026HLA-B
regulation of interleukin-12 production1210.7×0.026HLA-B
insulin receptor recycling1210.7×0.026SORL1
endocardium formation1210.7×0.026PROX1

Therapeutics

Drugs indicated for this disease

0 approved, 3 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

DrugDevelopment status
AspirinPhase 3 (in late-stage trials)
RivaroxabanPhase 3 (in late-stage trials)
WarfarinPhase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Penicillin G, Penicillin V, Rituximab.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 27

Druggability breadth: 6 of 29 evidence-associated genes (21%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
CCKBRSINCALIDE

Top cohort targets by molecule count

SymbolMoleculesMax phase
CCKBR334
TEAD112
SORL100
TINCR00
PARVA00
SNX1600
CHODL00
SMYD200
CTNNA300
MIR125B100

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
SINCALIDE4CCKBR
CHLORDIAZEPOXIDE4CCKBR
CANDESARTAN CILEXETIL4CCKBR
CLOTRIMAZOLE4CCKBR
RIMONABANT4CCKBR
INDOCYANINE GREEN ACID FORM4CCKBR
FIDAXOMICIN4CCKBR
PENTAGASTRIN4CCKBR
FLUNITRAZEPAM4CCKBR
NITAZOXANIDE4CCKBR
ILOPERIDONE4CCKBR
DESOGESTREL4CCKBR
AZLOCILLIN4CCKBR
RIFAXIMIN4CCKBR
ISRADIPINE4CCKBR
FLUTRIMAZOLE4CCKBR
EFAVIRENZ4CCKBR
ENCORAFENIB4CCKBR
FLUOXETINE4CCKBR
LANSOPRAZOLE4CCKBR
APOMORPHINE4CCKBR
TAMOXIFEN4CCKBR
DOCETAXEL ANHYDROUS4CCKBR
LEFLUNOMIDE4CCKBR
NILVADIPINE3CCKBR
PIRLINDOLE2TEAD1
DEVAZEPIDE2CCKBR
CE-3265972CCKBR
LORGLUMIDE2CCKBR
SPIROGLUMIDE2CCKBR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

SymbolAssaysType breakdown
CCKBR374Binding:322, Functional:51, Toxicity:1
SMYD2148Binding:148
TEAD185Binding:82, Functional:3
CFH1Binding:1
HLA-B1Binding:1
PROX11Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
CCKBR374
SMYD2148

Pharmacogenomics

Cohort genes with a PharmGKB record: 22; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

SymbolCPIC guidelines
HLA-B1

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

CompoundMax phaseCohort target (bioactivity)
SINCALIDE4CCKBR
CHLORDIAZEPOXIDE4CCKBR
CANDESARTAN CILEXETIL4CCKBR
CLOTRIMAZOLE4CCKBR
RIMONABANT4CCKBR
INDOCYANINE GREEN ACID FORM4CCKBR
FIDAXOMICIN4CCKBR
PENTAGASTRIN4CCKBR
FLUNITRAZEPAM4CCKBR
NITAZOXANIDE4CCKBR
ILOPERIDONE4CCKBR
DESOGESTREL4CCKBR
AZLOCILLIN4CCKBR
RIFAXIMIN4CCKBR
ISRADIPINE4CCKBR
FLUTRIMAZOLE4CCKBR
EFAVIRENZ4CCKBR
ENCORAFENIB4CCKBR
FLUOXETINE4CCKBR
LANSOPRAZOLE4CCKBR
APOMORPHINE4CCKBR
TAMOXIFEN4CCKBR
DOCETAXEL ANHYDROUS4CCKBR
LEFLUNOMIDE4CCKBR
NILVADIPINE3CCKBR
PIRLINDOLE2TEAD1
DEVAZEPIDE2CCKBR
CE-3265972CCKBR
LORGLUMIDE2CCKBR
SPIROGLUMIDE2CCKBR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1CCKBR
BPhased (≥1) drug, not yet approved1TEAD1
CDruggable family + PDB, no drug7SORL1, CFH, HLA-B, HLA-DQB1, IGHV4-61, IGKV1D-33, NRG1
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug20TINCR, PARVA, SNX16, CHODL, SMYD2, CTNNA3, MIR125B1, BLID, FCN3, MIR100HG (+10 more)

Undrugged target profiles

27 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

SymbolChEMBL assaysDrugged partners (top 3)
SMYD2148—
SORL10—
TINCR0—
PARVA0—
SNX160—
CHODL0—
CTNNA30—
MIR125B10—
BLID0—
FCN30—
MIR100HG0—
MIR44310—
MIR4436A0—
RNU6-256P0—
CFH1—
HLA-B1—
HLA-DQB10—
LINC013720—
LINC018170—
LINC019310—
IGHV4-610—
IGKV1D-330—
NINJ20—
NRG10—
PBX2P10—
CAVIN30—
PROX11—

Clinical trials & evidence

Clinical trials

Clinical trials: 46.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified34
PHASE36
PHASE23
PHASE2/PHASE31
PHASE1/PHASE21
PHASE11

Top trials by phase / activity

NCTPhaseStatusTitle
NCT07146048PHASE3NOT_YET_RECRUITINGA Non-Inferiority Trial of Stopping Penicillin in Early Rheumatic Heart Disease: GOAL-Stop
NCT02832531PHASE3WITHDRAWNINVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Superiority
NCT02832544PHASE3COMPLETEDINVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Non-Inferiority
NCT02881398PHASE2/PHASE3COMPLETEDMobile Health in Structural Heart Disease
NCT03926156PHASE3TERMINATEDRIvoraxaban in Mitral Stenosis
NCT03991910PHASE3UNKNOWNThe Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients
NCT05618223PHASE3UNKNOWNDapagliflozin Effect on Rheumatic Mitral Stenosis
NCT05693545PHASE2ACTIVE_NOT_RECRUITINGGOALIE: Intramuscular vs. Enteral Penicillin Prophylaxis to Prevent Progression of Latent RHD Trial
NCT07078357PHASE1/PHASE2NOT_YET_RECRUITINGClinical Trial Phase I/IIa to Evaluate the Safety and Immunogenicity of StreptInCor
NCT01794884PHASE2COMPLETEDValidity Study of Glutamine to Improve Cardiac Function in Cardiac Surgery
NCT03346525PHASE2UNKNOWNDetermining the Impact of Penicillin in Latent RHD: The GOAL Trial
NCT00482573PHASE1COMPLETEDDental Anesthesia in Pregnant Women With Rheumatic Heart Disease
NCT04556188Not specifiedRECRUITINGThe Clinical Influence of Developing a Sustainable Cardiac Surgery Service to Reduce the Burden of Rheumatic Heart Disease in Sub-Saharan Africa
NCT04575857Not specifiedACTIVE_NOT_RECRUITINGRole of Statins In Slowing Rheumatic Heart Disease (RHD) Progression
NCT04936815Not specifiedACTIVE_NOT_RECRUITINGEchocardiographic Screening of Pregnant Women During Antenatal Care
NCT05250154Not specifiedACTIVE_NOT_RECRUITINGRheumatic Heart Disease Research and Screening in Nepal: A Feasibility Study
NCT05504928Not specifiedRECRUITINGEffectiveness of a School-centered Prevention Program on Prevalence of Latent Rheumatic Heart Disease
NCT05783375Not specifiedRECRUITINGAccelerating Delivery of rheUmatic Heart Disease Preventive iNterventions in Northern Uganda
NCT05991219Not specifiedRECRUITINGScreening and Secondary Prevention Rheumatic Heart Disease Study
NCT06952374Not specifiedRECRUITINGTreating Severe Mitral Valve Annular or Valvular Calcification Using Shockwave Balloon SMARTWAVE
NCT07065474Not specifiedNOT_YET_RECRUITINGEffectiveness of Edutainment-Based Interventions in Increasing Knowledge of Rheumatic Fever and Rheumatic Heart Disease Among School-Going Children in Nepal: Study Protocol for Colors to Save Hearts Quasi-Experimental Pretest-Posttest Study
NCT07068633Not specifiedNOT_YET_RECRUITINGKorea VHD Echo Study: Surveillance of Aortic, Mitral & Tricuspid Patients - Insights From Real-world Practice
NCT07146282Not specifiedNOT_YET_RECRUITINGVitamin K Antagonist in Rheumatic Heart Disease Patients With Mechanical Heart Valves: Our Current Status
NCT07599956Not specifiedNOT_YET_RECRUITINGArtificial Intelligence to Scale Early Rheumatic Heart Disease Detection
NCT07606131Not specifiedNOT_YET_RECRUITINGTesting a Registry-Based Strategy (ACT+) to Reduce Loss to Follow-Up in Rheumatic Heart Disease Screening in Uganda
NCT00264524Not specifiedCOMPLETEDDNA Typing of HLA-DR/DQ Alleles in Taiwan Chinese With Rheumatic Heart Disease
NCT00779662Not specifiedUNKNOWNThe Prevalence of Rheumatic Heart Disease in School Children in Fiji
NCT01178710Not specifiedCOMPLETEDEffect of Simvastatin on Cardiac Function
NCT01550068Not specifiedCOMPLETEDRheumatic Heart Disease School Project
NCT02118818Not specifiedCOMPLETEDRhEumatiC Heart diseAse Genetics
NCT02124109Not specifiedCOMPLETEDThe Genetic Basis of Acquired Heart Disease in Africa
NCT02188862Not specifiedCOMPLETEDGenetic Susceptibility to Rheumatic Heart Disease in the Pacific Region
NCT02353663Not specifiedCOMPLETEDRheumatic Heart Disease in Peru: Prevalence and Cardiovascular Outcomes Among Schoolchildren
NCT02474108Not specifiedCOMPLETEDSurgical Prevention of Atrial Fibrillation in Patients With Rheumatic Mitral Valve Lesion and Left Atrium Enlargement
NCT02661763Not specifiedCOMPLETEDRheumatic Heart Disease Study in Lusaka
NCT03156972Not specifiedUNKNOWNSpeckle Tracking for Timing of Surgical Operation in Severe Mitral Regurge
NCT03549052Not specifiedUNKNOWNRight Ventricular Echo Assessment in Mitral Valve Replacement
NCT05211024Not specifiedCOMPLETEDA Long-term Follow up Study for Patients Who Participated in the GOAL Trial (GOAL-Post)
NCT05276999Not specifiedCOMPLETEDRheumatic Heart Disease Community Streptococcal Treatment Program RESET
NCT05487469Not specifiedUNKNOWNThymosin α1 Use in Rheumatic Heart Disease Patients Undergoing Cardiac Surgery on Cardiopulmonary Bypass

Drugs tested across these trials (top 30)

MoleculeMax phaseTrials referencing
RIVAROXABAN43
GLUTAMINE41
PENICILLIN G BENZATHINE41
PENICILLIN V41
THYMALFASIN31
CHEMBL120065101

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.2
BioBTree
v2.0.2

Sources 73

This page pulls from 73 datasets indexed by BioBTree:

alphafoldantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetcivic_evidenceclingen_dosageclinical_trialsclinvarctd_gene_interactiondbsnpdepmapdiamond_similaritydoidefoensemblentrezesm2_similarityfantom5_genefantom5_promotergenccgenerifgogtopdbgtopdb_interactiongwasgwas_studyhgncicd11intactinterpromeddramedgenmeshmimmondomondochildmondoparentncitorphanetpatentpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assayreactomerefseqrhearnacentralsctidscxa_expressionscxa_gene_experimentsignorstring_interactiontranscriptufeatureumlsuniprot