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.
New genotyping technologies allows us to sequence the human genome for asthma-associated variants.

Question 2

Cystic fibrosis

Answer 2

Chronic genetic disease.
Multi-organ involvement.
In UK >10,000 people affected.
Median age of death improving.
Most common lethal autosomal recessive genetic disorder in Caucasians.
Static incidence with an increasing prevalence.

Question 3

Cystic fibrosis genes

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.

Question 4

CTFR 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

Cystic fibrosis diagnosis

Answer 5

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.
50% diagnosed @ 6 months
90% diagnosed @ 8 years of age

Question 6

CF pathophysiology

Answer 6

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 7

CF genotype classification

Answer 7

Class I: no functional CFTR protein is made.
Class II: CFTR protein is made but it is mis-folded.
Class III: CFTR protein is formed into a channel but it does not open properly.
Class IV: CFTR protein is formed into a channel but chloride ions do not cross the channel properly.
Class V: CFTR protein is not made in sufficient quantities.
Class VI: CFTR protein with decreased cell surface stability.