A L2.1 BP & Genetics

Question 1

Relationship b/w populations & genes

Answer 1

• Distribution remains similar
• Small genetic effect, mainly env

Question 2

3 sequence variances of genetic BP

Answer 2

• Extremely rare - major genetic diseases with big effect
• Rare - (<1/2000) coding mutations (coding = proteins altered) with modest effect (<5mmHg)
• Common (1/3) non-coding variant with small effect (<1mmHg)

Question 3

What is the missing heritability?

Answer 3

• All the BP loci discovered accounts for <5% of the heritability of BP

Question 4

Renin-angiotensin system (RAS)

Answer 4

• Renin (Kidneys) + Angiotensin (Liver) = Angiotensinogen I
• ANG I → ANG II (By ACE from (lungs)
• ANG II acts on → Adrenal → prod. Aldosterone (a mineralocorticoid - affects minerals i.e Na)
• Aldosterone acts on principal cells → Mineralocorticoid R. → Nucleus → ↑Epitheial Na+ channels (ENaC) → ↑Na influx & retention

Question 5

What is cortisol

Answer 5

• a glucocorticoid (affects metabolism)

Question 6

v. rare genetic diseases

Answer 6

• Liddle’s syndrome (pseudoaldosteronism)
• Apparent mineralocorticoid excess
• Glucocorticoid suppressible hyperaldosteronism
• Mineralocorticoid R. gene mutation
• Gordon’s syndrome
• Hypertension with brachydactyly

Question 7

Liddle’s syndrome

Answer 7

• (pseudoaldosteronism)
• Looks like aldosteronism (excess [aldosterone]), but [aldosterone] is low
• Mutations in SCNN1B & SCNN1G genes → activates ENaC
  
  • ↑Na & ↓K+ (hypokalemia) & ↓H+ → ↑fluid retention → ↑BP

Question 8

Apparent mineralocorticoid excess

Answer 8

• Reduced 11β-HSD2 enzyme (responsible for deactivation cortisol → cortisome)
• ↓ [aldosterone];
• ↑[cortisol] 1000% → access to mineralocorticoid R. → ↑BP → further ↓[aldosterone] (action not needed)

Question 9

Glucocorticoid suppressible hyperaldosteronism

Answer 9

• ↑[aldosterone]
• Chromosomal rearrangement → hybrid genes → create ACTH sensitive aldosterone synthase
  
  • No -ve feedback to turn it off
  • MC usually does not respond to ACTH (usually switched on by K+)
• GC suppressible → GC suppresses ACTH → turns off excessive aldosterone

Question 10

Mineralocorticoid R. gene mutation

Answer 10

• Abnormal stimulation of MR by progesterone
  
  • Normally deaf to progesterone

Question 11

Gordon’s syndrome

Answer 11

• Autosomal dominant
• Hyperkalemia AND Hypertension with NORMAL renal function
• WNK1 & WNK4 mutations (responsible for Na/K balance)
  
  • Disrupted normal control → Na & K retention

Question 12

Hypertension with brachydactyly

Answer 12

• Autosomal dominant
• Normal RAS
• Abnormal autonomic baroreceptor reflex function
  
  • Chromosome 12