graph LR
Chest_Tightness["Chest Tightness"]
Exercise_Intolerance["Exercise Intolerance"]
Sleep_Disturbance["Sleep Disturbance"]
Type_2_Immune_Response___Th2_Signaling["Type 2 Immune Response / Th2 Signaling"]
IL4["IL4"]
Wheezing["Wheezing"]
IL13["IL13"]
Airway_Inflammation["Airway Inflammation"]
Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception["Early-Life Rhinovirus Wheezing Illness and Asthma Inception"]
Rapid_Breathing["Rapid Breathing"]
Respiratory_Distress["Respiratory Distress"]
STAT3["STAT3"]
Coughing["Coughing"]
Bronchoconstriction["Bronchoconstriction"]
Reduced_Exercise_Tolerance["Reduced Exercise Tolerance"]
CDHR3["CDHR3"]
Anxiety["Anxiety"]
Airway_Remodeling["Airway Remodeling"]
Mucus_Overproduction["Mucus Overproduction"]
ADAM33["ADAM33"]
House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling["House Dust Mite Allergen Protease-Induced Epithelial Oxidant Signaling"]
Fatigue["Fatigue"]
Cyanosis["Cyanosis"]
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation["SIRT1-Mediated NAD+ Signaling and Protective Deacetylation"]
Airway_Inflammation --> Bronchoconstriction
Type_2_Immune_Response___Th2_Signaling --> Airway_Inflammation
Type_2_Immune_Response___Th2_Signaling --> Mucus_Overproduction
Bronchoconstriction --> Wheezing
Bronchoconstriction --> Chest_Tightness
Bronchoconstriction --> Rapid_Breathing
Bronchoconstriction --> Respiratory_Distress
Bronchoconstriction --> Cyanosis
Bronchoconstriction --> Exercise_Intolerance
Bronchoconstriction --> Reduced_Exercise_Tolerance
Bronchoconstriction --> Fatigue
Bronchoconstriction --> Anxiety
Mucus_Overproduction --> Coughing
Mucus_Overproduction --> Sleep_Disturbance
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Type_2_Immune_Response___Th2_Signaling
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Mucus_Overproduction
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Airway_Remodeling
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Bronchoconstriction
Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception --> Type_2_Immune_Response___Th2_Signaling
House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling --> Airway_Inflammation
Wheezing --> Respiratory_Distress
Wheezing --> Reduced_Exercise_Tolerance
IL4 --> Type_2_Immune_Response___Th2_Signaling
IL13 --> Type_2_Immune_Response___Th2_Signaling
ADAM33 --> Airway_Remodeling
STAT3 --> SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation
CDHR3 --> Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception
style Chest_Tightness fill:#fef3c7
style Exercise_Intolerance fill:#fef3c7
style Sleep_Disturbance fill:#fef3c7
style Type_2_Immune_Response___Th2_Signaling fill:#dbeafe
style IL4 fill:#f3e8ff
style Wheezing fill:#fef3c7
style IL13 fill:#f3e8ff
style Airway_Inflammation fill:#dbeafe
style Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception fill:#dbeafe
style Rapid_Breathing fill:#fef3c7
style Respiratory_Distress fill:#fef3c7
style STAT3 fill:#f3e8ff
style Coughing fill:#fef3c7
style Bronchoconstriction fill:#dbeafe
style Reduced_Exercise_Tolerance fill:#fef3c7
style CDHR3 fill:#f3e8ff
style Anxiety fill:#fef3c7
style Airway_Remodeling fill:#dbeafe
style Mucus_Overproduction fill:#dbeafe
style ADAM33 fill:#f3e8ff
style House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling fill:#dbeafe
style Fatigue fill:#fef3c7
style Cyanosis fill:#fef3c7
style SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation fill:#dbeafe
graph LR
Reduced_Female_Fertility["Reduced Female Fertility"]
Recurrent_Respiratory_Infections["Recurrent Respiratory Infections"]
Small_Airway_Obstruction["Small-Airway Obstruction"]
CFTR_Dysfunction["CFTR Dysfunction"]
Nasal_Polyposis["Nasal Polyposis"]
Exocrine_Pancreatic_Insufficiency["Exocrine Pancreatic Insufficiency"]
Intestinal_Obstruction["Intestinal Obstruction"]
Fat_Malabsorption["Fat Malabsorption"]
Osteoporosis["Osteoporosis"]
Impaired_Pancreatic_Organogenesis["Impaired Pancreatic Organogenesis"]
F508del_Phe508del["F508del (Phe508del)"]
Mucus_Plugging["Mucus Plugging"]
CFTR["CFTR"]
N1303K["N1303K"]
Patient_derived_airway_organoid_theratyping_model["Patient-derived airway organoid theratyping model"]
ENaC_Hyperactivity_and_Sodium_Hyperabsorption["ENaC Hyperactivity and Sodium Hyperabsorption"]
Hemoptysis["Hemoptysis"]
Short_Stature["Short Stature"]
Hyponatremic_Dehydration["Hyponatremic Dehydration"]
Chronic_Productive_Cough["Chronic Productive Cough"]
G542X["G542X"]
Vas_Deferens_Agenesis["Vas Deferens Agenesis"]
CF_Related_Diabetes["CF-Related Diabetes"]
Sinonasal_Disease["Sinonasal Disease"]
Sweat_Gland_Dysfunction["Sweat Gland Dysfunction"]
R117H["R117H"]
Pneumothorax["Pneumothorax"]
Exocrine_Pancreatic_Tissue_Destruction["Exocrine Pancreatic Tissue Destruction"]
Respiratory_Failure["Respiratory Failure"]
Fat_Soluble_Vitamin_Deficiency["Fat-Soluble Vitamin Deficiency"]
W1282X["W1282X"]
Rectal_Prolapse["Rectal Prolapse"]
Male_Infertility["Male Infertility"]
Neutrophil_Elastase_Mediated_Tissue_Injury["Neutrophil Elastase-Mediated Tissue Injury"]
Chronic_Sinusitis["Chronic Sinusitis"]
Airway_Remodeling["Airway Remodeling"]
CF_airway_on_chip_microphysiological_model["CF airway-on-chip microphysiological model"]
NuLi_CuFi_airway_epithelial_cell_line_model["NuLi/CuFi airway epithelial cell-line model"]
Protein_Calorie_Malnutrition["Protein-Calorie Malnutrition"]
Bronchiectasis["Bronchiectasis"]
Chronic_Bacterial_Infection["Chronic Bacterial Infection"]
Allergic_Bronchopulmonary_Aspergillosis["Allergic Bronchopulmonary Aspergillosis"]
Steatorrhea["Steatorrhea"]
Airway_Surface_Liquid_Depletion["Airway Surface Liquid Depletion"]
Gastroesophageal_Reflux["Gastroesophageal Reflux"]
Distal_Intestinal_Obstruction_Syndrome["Distal Intestinal Obstruction Syndrome"]
Focal_Biliary_Cirrhosis["Focal Biliary Cirrhosis"]
Meconium_Ileus["Meconium Ileus"]
Failure_to_Thrive["Failure to Thrive"]
Impaired_Mucociliary_Clearance["Impaired Mucociliary Clearance"]
Portal_Hypertension["Portal Hypertension"]
Delayed_Puberty["Delayed Puberty"]
Digital_Clubbing["Digital Clubbing"]
Hepatobiliary_Obstruction["Hepatobiliary Obstruction"]
Forced_Expiratory_Volume_in_1_Second_FEV1["Forced Expiratory Volume in 1 Second (FEV1)"]
CF_Bone_Disease["CF Bone Disease"]
Neutrophilic_Airway_Inflammation["Neutrophilic Airway Inflammation"]
Pancreatic_Duct_Obstruction["Pancreatic Duct Obstruction"]
G551D_Gly551Asp["G551D (Gly551Asp)"]
CFTR_Dysfunction --> Airway_Surface_Liquid_Depletion
CFTR_Dysfunction --> ENaC_Hyperactivity_and_Sodium_Hyperabsorption
CFTR_Dysfunction --> Impaired_Pancreatic_Organogenesis
CFTR_Dysfunction --> Pancreatic_Duct_Obstruction
CFTR_Dysfunction --> Intestinal_Obstruction
CFTR_Dysfunction --> Sweat_Gland_Dysfunction
CFTR_Dysfunction --> Vas_Deferens_Agenesis
CFTR_Dysfunction --> Hepatobiliary_Obstruction
CFTR_Dysfunction --> Sinonasal_Disease
CFTR_Dysfunction --> Reduced_Female_Fertility
ENaC_Hyperactivity_and_Sodium_Hyperabsorption --> Airway_Surface_Liquid_Depletion
Airway_Surface_Liquid_Depletion --> Impaired_Mucociliary_Clearance
Impaired_Mucociliary_Clearance --> Mucus_Plugging
Impaired_Mucociliary_Clearance --> Chronic_Productive_Cough
Mucus_Plugging --> Small_Airway_Obstruction
Mucus_Plugging --> Chronic_Bacterial_Infection
Mucus_Plugging --> Allergic_Bronchopulmonary_Aspergillosis
Small_Airway_Obstruction --> Bronchiectasis
Chronic_Bacterial_Infection --> Neutrophilic_Airway_Inflammation
Chronic_Bacterial_Infection --> Bronchiectasis
Chronic_Bacterial_Infection --> Recurrent_Respiratory_Infections
Neutrophilic_Airway_Inflammation --> Neutrophil_Elastase_Mediated_Tissue_Injury
Neutrophil_Elastase_Mediated_Tissue_Injury --> Airway_Remodeling
Airway_Remodeling --> Bronchiectasis
Bronchiectasis --> Respiratory_Failure
Bronchiectasis --> Hemoptysis
Bronchiectasis --> Pneumothorax
Respiratory_Failure --> Digital_Clubbing
Impaired_Pancreatic_Organogenesis --> CF_Related_Diabetes
Pancreatic_Duct_Obstruction --> Exocrine_Pancreatic_Tissue_Destruction
Pancreatic_Duct_Obstruction --> Exocrine_Pancreatic_Insufficiency
Exocrine_Pancreatic_Tissue_Destruction --> Exocrine_Pancreatic_Insufficiency
Exocrine_Pancreatic_Tissue_Destruction --> CF_Related_Diabetes
Exocrine_Pancreatic_Insufficiency --> Fat_Malabsorption
Exocrine_Pancreatic_Insufficiency --> Fat_Soluble_Vitamin_Deficiency
Exocrine_Pancreatic_Insufficiency --> Protein_Calorie_Malnutrition
Fat_Malabsorption --> Fat_Soluble_Vitamin_Deficiency
Fat_Malabsorption --> Protein_Calorie_Malnutrition
Fat_Malabsorption --> Steatorrhea
Fat_Soluble_Vitamin_Deficiency --> CF_Bone_Disease
Protein_Calorie_Malnutrition --> CF_Bone_Disease
Protein_Calorie_Malnutrition --> Rectal_Prolapse
Protein_Calorie_Malnutrition --> Gastroesophageal_Reflux
Protein_Calorie_Malnutrition --> Delayed_Puberty
Protein_Calorie_Malnutrition --> Failure_to_Thrive
Protein_Calorie_Malnutrition --> Short_Stature
Intestinal_Obstruction --> Meconium_Ileus
Intestinal_Obstruction --> Distal_Intestinal_Obstruction_Syndrome
Hepatobiliary_Obstruction --> Focal_Biliary_Cirrhosis
Hepatobiliary_Obstruction --> Portal_Hypertension
Sweat_Gland_Dysfunction --> Hyponatremic_Dehydration
Vas_Deferens_Agenesis --> Male_Infertility
Sinonasal_Disease --> Nasal_Polyposis
Sinonasal_Disease --> Chronic_Sinusitis
CF_Bone_Disease --> Osteoporosis
Patient_derived_airway_organoid_theratyping_model --> CFTR_Dysfunction
CF_airway_on_chip_microphysiological_model --> Airway_Surface_Liquid_Depletion
CF_airway_on_chip_microphysiological_model --> Impaired_Mucociliary_Clearance
CF_airway_on_chip_microphysiological_model --> Chronic_Bacterial_Infection
NuLi_CuFi_airway_epithelial_cell_line_model --> CFTR_Dysfunction
NuLi_CuFi_airway_epithelial_cell_line_model --> ENaC_Hyperactivity_and_Sodium_Hyperabsorption
Small_Airway_Obstruction -.-> Forced_Expiratory_Volume_in_1_Second_FEV1
F508del_Phe508del --> CFTR
G551D_Gly551Asp --> CFTR
G542X --> CFTR
W1282X --> CFTR
N1303K --> CFTR
R117H --> CFTR
style Reduced_Female_Fertility fill:#fef3c7
style Recurrent_Respiratory_Infections fill:#fef3c7
style Small_Airway_Obstruction fill:#dbeafe
style CFTR_Dysfunction fill:#dbeafe
style Nasal_Polyposis fill:#fef3c7
style Exocrine_Pancreatic_Insufficiency fill:#fef3c7
style Intestinal_Obstruction fill:#dbeafe
style Fat_Malabsorption fill:#dbeafe
style Osteoporosis fill:#fef3c7
style Impaired_Pancreatic_Organogenesis fill:#dbeafe
style F508del_Phe508del fill:#f3e8ff
style Mucus_Plugging fill:#dbeafe
style CFTR fill:#f3e8ff
style N1303K fill:#f3e8ff
style Patient_derived_airway_organoid_theratyping_model fill:#ccfbf1
style ENaC_Hyperactivity_and_Sodium_Hyperabsorption fill:#dbeafe
style Hemoptysis fill:#fef3c7
style Short_Stature fill:#fef3c7
style Hyponatremic_Dehydration fill:#fef3c7
style Chronic_Productive_Cough fill:#fef3c7
style G542X fill:#f3e8ff
style Vas_Deferens_Agenesis fill:#dbeafe
style CF_Related_Diabetes fill:#fef3c7
style Sinonasal_Disease fill:#dbeafe
style Sweat_Gland_Dysfunction fill:#dbeafe
style R117H fill:#f3e8ff
style Pneumothorax fill:#fef3c7
style Exocrine_Pancreatic_Tissue_Destruction fill:#dbeafe
style Respiratory_Failure fill:#dbeafe
style Fat_Soluble_Vitamin_Deficiency fill:#fef3c7
style W1282X fill:#f3e8ff
style Rectal_Prolapse fill:#fef3c7
style Male_Infertility fill:#fef3c7
style Neutrophil_Elastase_Mediated_Tissue_Injury fill:#dbeafe
style Chronic_Sinusitis fill:#fef3c7
style Airway_Remodeling fill:#dbeafe
style CF_airway_on_chip_microphysiological_model fill:#ccfbf1
style NuLi_CuFi_airway_epithelial_cell_line_model fill:#ccfbf1
style Protein_Calorie_Malnutrition fill:#dbeafe
style Bronchiectasis fill:#fef3c7
style Chronic_Bacterial_Infection fill:#dbeafe
style Allergic_Bronchopulmonary_Aspergillosis fill:#fef3c7
style Steatorrhea fill:#fef3c7
style Airway_Surface_Liquid_Depletion fill:#dbeafe
style Gastroesophageal_Reflux fill:#fef3c7
style Distal_Intestinal_Obstruction_Syndrome fill:#fef3c7
style Focal_Biliary_Cirrhosis fill:#fef3c7
style Meconium_Ileus fill:#fef3c7
style Failure_to_Thrive fill:#fef3c7
style Impaired_Mucociliary_Clearance fill:#dbeafe
style Portal_Hypertension fill:#fef3c7
style Delayed_Puberty fill:#fef3c7
style Digital_Clubbing fill:#fef3c7
style Hepatobiliary_Obstruction fill:#dbeafe
style Forced_Expiratory_Volume_in_1_Second_FEV1 fill:#e0e7ff
style CF_Bone_Disease fill:#dbeafe
style Neutrophilic_Airway_Inflammation fill:#dbeafe
style Pancreatic_Duct_Obstruction fill:#dbeafe
style G551D_Gly551Asp fill:#f3e8ff
name: com_Asthma__Cystic_Fibrosis
creation_date: '2026-06-26T00:00:00Z'
curation_status: CANDIDATE
notes: >-
Candidate comorbidity surfaced from an ICEES KG EHR signal (UNC primary
ciliary dyskinesia cohort) and corroborated by the well-documented high
prevalence of asthma signs, symptoms, and airway hyper-responsiveness in
cystic fibrosis. Directionality is left UNKNOWN: the ICEES signal direction
is inconsistent (MIXED across cohort-years/binning), and the association is
confounded by diagnostic overlap — asthma-like cough, wheeze, and
bronchial hyper-responsiveness in CF may reflect CF airways disease itself
rather than coexisting asthma. Mechanistic literature support is anchored on
the CFTR / airway smooth muscle axis; epidemiologic prevalence figures still
need dedicated quantitative curation.
disease_a:
slug: Asthma
preferred_term: asthma
term:
id: MONDO:0004979
label: asthma
disease_b:
slug: Cystic_Fibrosis
preferred_term: cystic fibrosis
term:
id: MONDO:0009061
label: cystic fibrosis
directionality: UNKNOWN
hypotheses:
- description: >-
Hypothesis: CFTR deficiency and the chronic neutrophilic/type-2 inflammatory
environment of the cystic fibrosis airway increase airway smooth muscle
contractility and bronchial hyper-responsiveness, producing an asthma-like
phenotype (and, in some patients, true coexisting asthma).
evidence:
- reference: PMID:24429094
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Among patients with cystic fibrosis there is a high prevalence (40-70%) of asthma signs and symptoms such as cough and wheezing and airway hyper-responsiveness to inhaled histamine or methacholine."
explanation: >-
Review documents the high prevalence of asthma-like airway
hyper-responsiveness among CF patients, the clinical basis of the
comorbidity signal.
- reference: PMID:24429094
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "Whether these abnormal airway responses are due to a primary deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) or are secondary to the inflammatory environment in the cystic fibrosis lungs is not clear."
explanation: >-
Supports the diagnostic-overlap caveat: the asthma-like phenotype may be
intrinsic to CF airways disease rather than a separate comorbid asthma,
justifying UNKNOWN directionality.
pathophysiology:
- name: CFTR-deficient airway smooth muscle hyper-responsiveness
description: >-
In CFTR-deficient airways, a proinflammatory milieu (IL-8-driven
neutrophilia, type-2 and IL-17 signalling) is proposed to increase airway
smooth muscle contractility, manifesting as the asthma-like bronchial
hyper-responsiveness observed clinically in cystic fibrosis.
biological_processes:
- preferred_term: airway smooth muscle contraction
term:
id: GO:0006939
label: smooth muscle contraction
evidence:
- reference: PMID:24429094
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A role for the CFTR in smooth muscle function is emerging, and alterations in contractile signalling have been reported in CFTR-deficient airway smooth muscle."
explanation: >-
Links CFTR loss to altered airway smooth muscle contractile signalling,
the proposed mechanism of the asthma-like phenotype.
association_signals:
- source: ICEES
method: EHR_COHORT_ASSOCIATION
signal_disorder_a_id: MONDO:0004979
signal_disorder_b_id: MONDO:0009061
population: >-
ICEES KG 8-20-2024, UNC Health primary-ciliary-dyskinesia (PCD) cohort
(condition-specific base population), patient-level chi-square contingency.
mapping_notes: >-
ICEES reports this pair as a MIXED correlation (both positively_ and
negatively_correlated_with edges across cohort-years/binning); the row
quoted below is a representative significant PCD cohort-year. Chi-square is
not multiple-testing corrected and is conditioned on the PCD base
population, so it corroborates rather than establishes the association.
directionality: UNKNOWN
limited_precision: true
statistics:
metrics:
- metric_type: CHI_SQUARE
metric_value: 16.033259562650493
p_value: 6.223947289683494e-05
notes: >-
ICEES PCD 2020 cohort co-occurrence of asthma and cystic fibrosis
(N=4753). Significant nominal association; direction reported
inconsistently across cohorts (see mapping_notes).
evidence:
- reference: ICEES:MONDO_0004979__MONDO_0009061
supports: SUPPORT
evidence_source: OTHER
snippet: "PCD_UNC_patient_2020_v6_binned_deidentified | 16.033259562650493 | 1 | 6.223947289683494e-05 | 4753"
explanation: >-
ICEES UNC EHR cohort shows a significant asthma-cystic fibrosis
co-occurrence in the 2020 PCD cohort.