Genetic Determinants Of Lung Function And Disease

Question 1

Asthma and genes

Answer 1

Asthma runs in families
Children of asthmatic parents are at increased risk of asthma

Asthma is not caused by a single mutation in one gene

Transmission of the disease through generations does not follow simple Mendelian inheritance typical of classic monogenic diseases

New genotyping technologies has made it possible to sequence the human genome for asthma-associated variants

Question 2

Asthma personalised medicine

Answer 2

Individualise pharmacotherapy based on genetic polymorphisms

Certain drugs are administered only to those patients who are most likely to respond

Harmful effects are avoided in patients who are most likely to experience toxicity and adverse reactions

Question 3

Cystic fibrosis

Answer 3

Defect in long arm of chromosome 7 coding for the cystic fibrosis transmembrane regulator (CFTR) protein (anion channel)

> 1600 mutations of CFTR gene identified

90% within a panel of 70 mutations

F508del most common mutation causing CF (will be asked about this)

Question 4

CFTR Protein

Answer 4

Transport protein on membrane of epithelial cells

Abnormal CFTR protein leads to dysregulated epithelial fluid transport

80% Lung and gastrointestinal involvement
15% Lung alone

Question 5

Pathophysiology- Vicious cycle

Answer 5

Cystic fibrosis results in microbial insults and defect in host defence, leading to respiratory tract infection.

This leads to bronchial inflammation

This leads to respiratory tract damage and so progressive lung disease which again leads to respiratory tract infection

Question 6

Cystic fibrosis diagnosis

Answer 6

Genetic profile and neonatal screening (day 5 IRT)

Clinical symptoms – frequent infections, malabsorption, failure to thrive

Abnormal salt / chloride exchange – raised skin salt

Late diagnoses via infertility services – azoospermia or via gastroenterology team with recurrent pancreatitis / malabsorption

Question 7

CF Pathophysiology

Answer 7

In the pancreas; blockage of exocrine ducts, early activation of pancreatic enzymes, and eventual auto-destruction of the exocrine pancreas
Most patients require supplemental pancreatic enzymes

In the intestine; bulky stools can lead to intestinal blockage

In the respiratory system; mucus retention, chronic infection, and inflammation that eventually destroy lung tissue
There are multiple hypotheses regarding the pathogenesis of lung disease, each of which is supported by data in vitro and in vivo
Lung disease is the most common cause of morbidity and mortality

Question 8

CF Genotype classification

Answer 8

Class I: no functional CFTR protein is made (e.g. G542X)

Class II: CFTR protein is made but it is mis-folded (e.g. F508del)

Class III: CFTR protein is formed into a channel but it does not open properly (e.g. G551D)

Class IV: CFTR protein is formed into a channel but chloride ions do not cross the channel properly (e.g. R347P)

Class V: CFTR protein is not made in sufficient quantities (e.g. A455E)

Class VI: CFTR protein with decreased cell surface stability (e.g. 120del123)

Class II is the most common

Question 9

Exam questions

Answer 9

Slide 18

Question 10

CF genetic treatment strategy

Answer 10

Maintenance and prevention management

Rescue

Personalised approaches

Question 11

CF prevention management

Answer 11

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

Suppression of chronic infections – antibiotic nebulisation

Bronchodilation – salbutamol nebulisation

Anti inflammatory – azithromycin, corticosteroids

Diabetes – insulin treatment

Vaccinations – influenza, pneumococcal, SARS CoV 2

Question 12

CF rescue antibiotics

Answer 12

2 week course IV antibiotics

Home vs hospital

Issues with frequent antibiotics
Allergies
Renal impairment
Resistance
Access problems

Question 13

Genotype directed therapies

Answer 13

Small molecule agents facilitate defective CFTR processing or function. Eg; Ivacaftor

Question 14

Ivacaftor (Kalydeco)

Answer 14

CFTR potentiator- potentiates chloride secretion via increased CFTR channel opening time

Class III mutations

Question 15

Lumacaftor

Answer 15

Lumacaftor is a CFTR corrector - corrects cellular misprocessing of CFTR (e.g. folding) to facilitate transport from the endoplasmic reticulum

Class II mutation - F508del/F508del

Question 16

Alpha-1 antitrypsin deficiency (AATD)

Answer 16

Autosomal recessive genetic disorder

80 different mutations of SERPINEA1 gene on chromosome 14

AAT is a type of Serum antiprotease

Alpha-1 antitrypsin is a protein produced in the liver that protects the body’s tissues from being damaged by infection

In AATD the body’s normal production of AAT is reduced, resulting in destruction of sensitive lung tissue

M phenotype normal and healthy

S and Z phenotypes major disease associations
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