Genetic Determinants Of Lung Function Flashcards
What are common respiratory conditions influenced by genetics?
Cystic fibrosis
Alpha-1 antitrypsin deficiency
Asthma
COPD
Lung cancer
What is Cystic Fibrosis?
Chronic genetic disease
Multi-organ involvement
Most common lethal autosomal recessive genetic disorder in Caucasians
Defect in long arm of chromosome 7 coding for the cystic fibrosis transmembrane regulator (CFTR) protein
What is the CFTR?
Transport protein on membrane of epithelial cells
Abnormal CFTR protein leads to disregulated epithelial fluid transport
80% Lung & GI involvement
15% Lung alone
How is Cystic Fibrosis diagnosed?
Genetic profile
Clinical symptoms – frequent infections, malabsorption, failure to thrive
Abnormal salt/chloride exchange – raised skin salt
Late diagnoses via infertility services – azoospermia or via GI team with recurrent pancreatitis/malabsorption
50% diagnosed by 6months, 90% diagnosed by 8 yrs of age
What is CF prevention management?
Segregation
Surveillance – frequent review minimum every 3 months
Airway clearance – physio & exercise
Nutrition – pancreatic enzymes, diet high calorie & fat, supplements including vitamins, percutaneous feeding
Psychosocial support
What are drugs used in CF prevention management ?
Suppression of chronic infections – antibiotic nebs
Bronchodilation – salbutamol nebs
Anti inflammatory – azithromycin, steroids
Diabetes – insulin
Vaccinations – influenza, pneumococcal
What is personalised medicine?
Individual tailored or targeted medicine
Move away from a ‘one size fits all’ approach
Stratified based on predicted response or risk of disease
Genetic information major factor
What are uses of personalised medicine in CF?
Monogenic disorder (i.e. is the result of mutation(s) in a specific gene)
Well-characterised pathophysiology with clear therapeutic targets
Genotype directed therapies
Targeted treatments based on infectious organisms and resistance patterns
What is Ivacaftor (Kalydeco)?
CFTR potentiator - potentiates chloride secretion via increased CFTR channel opening time
Class III mutations
What are challenges treating CF?
Adherence to treatment
High treatment burden
High cost of certain treatments
Allergies/intolerances to treatment
Different infectious organisms and their resistance to drugs
What is Alpha-1 antitrypsin deficiency (AATD)?
Autosomal recessive genetic disorder
80 different mutations of SERPINEA1 gene on chromosome 14
- Serum antiprotease
M phenotype normal and healthy
S and Z phenotypes major disease associations
What are consequences of AATD?
Early onset emphysema and bronchiectasis
- Unopposed action of neutrophil elastase in the lung
Where is the defect for CF?
Long arm of chromosome 7 coding for CFTR protein
What is the pathophysiology of cystic fibrosis in the pancreas?
Blockage of endocrine ducts
Early activation of pancreatic enzymes
Eventual auto destruction of exocrine pancreas
Patients will need supplemental pancreatic enzymes
What is the Class II mutation for cystic fibrosis?
CFTR protein is made but mis-folded (e.g F508del)
