C4 Preventing genetic destiny

Question 1

Variance components

Answer 1

• Individual
• Shared env
• Genes (~50%)

Question 2

Rare and common variance

Answer 2

• Rare coding sequence variance (1/1 000) → affects 2% protein coded (~5mmHg)
• Common non-coding variance (1/3) → <1mmHg

Question 3

How do variance come about

Answer 3

• Transcription factors
• Enhancers
• Silencers
• Insulators
• Non-coding RNAs (also interacts with env)
  
  • Epigenetics

Question 4

What is a tissue defined by?

Answer 4

• A tissue is defined by the expression of genes
• Each cell has the same 22 chrm, but gene expression is different

Question 5

Genetic predispositions of BP

Answer 5

• High parental and personal BP → have increased [renin]
  
  • But usually with hypertensive groups → except a low [renin]
  • Genetic influence may have created kidney problem
    
    • Leading to increased renal vascular resistance → renin-dependent renal abnormalities

Question 6

Interfering with RAS at the critical window?

Answer 6

• Treat with ACEi → lowered BP lifetime (changed genetic destiny)
  
  • Confirmed inhibiting RAS importance by:
    
    • Giving ANG II again → led to BP return to high normal levels

Question 7

Using other classes of drugs to treat hypertension during the critical window (e.g. Ca blockers)

Answer 7

• Other drug classes targeting other factors are ineffective
  
  • Decrease BP during treatment → but BP restored to normal hypertensive levels after
• Treatment not as effective in adulthood

Question 8

What are the different types of experimental rats?

Answer 8

• WKY rats → control rats (have similar BP levels)
• SHR rats (Good response to treatment of RAS during critical window)
  
  • increase in BP shows at adolescence ~4 weeks
  • Decrease GFR and increase renin → Has renin-dependent renal abnormalities (like in humans)
• Dahl rats (also responds to treatment of RAS during critical window)
  
  • Predisposed to sodium in diet → ↑BP
• Milan rats → does not share same genetic properties → not responsive to treatment

Question 9

What does the response of treatment of different rats signify?

Answer 9

• Dahl and SHR rats responding to RAS treatment:
  
  • Shows that Dahl rats and SHR rats have similar genetic properties
• Milan rats are unresponsive to treatment:
  
  • ∴shows that treatment is not yet directly applicable to humans (not even applicable to all rats)

Question 10

What may the RAS inhibition be changing?

Answer 10

• Vascular structures
• Decrease in SNS
• Decrease Angiotensinogen
• Renal function → decrease vascular resistance → improve renal BF

Question 11

What is the TROPHY trial?

Answer 11

• Human TROPHY trial (looked at prehypertension in adults ~48yo)
  
  • 2 years treatment and 2 years follow up
    
    • Lower BP during treatment and seemingly lowered lifetime (but unsure as it was not followed up)