Lecture 4: BP & Genes Flashcards
What are the three types of genetic variations that affect BP?
- Extremely rare major genetic diseases
- Rare (<1/2000) coding mutations with modest effect (5 mmHg)
- Common (1/3) non-coding variants with small effects (<1 mmgh) - normal, small effects, unmeasurable
What % of genetics contributes to BP?
40%
Rest is environmental
What is GWAS?
Genome wide associated studies
Needed to pick up small signals
200,000 people
Expensive
What is “missing” heritability?
All of the BP loci discovered to date account for less than 5% of the heritability of BP
What are the 3 groups of differences between individuals?
Inconsequential
Pathological
Physiological
How many difference in genes between people?
3 million
We differ 1 in every 1000 base pairs between individuals
What are 4 rare genetic causes of hypertension?
Genetic mutation usually in coding sequences
Amino acid substitution
Truncation of protein
major functional effects (on the proteins activity)
How much of the genome accounts for amino acids?
2% of the genome
20,000 genes code for amino acids
What are variants?
Sequences of genes that tend to be in non-coding parts
What are very rare genetic causes of hypertension?
Liddle’s syndrome
Syndrome of apparent mineralocorticoid excess (SAME)
Glucocorticoid suppression aldosteronism
Mineralocorticoid receptor gene mutation
Gordon’s syndrome
Hypertension with brachydactyly - odd one out, doesn’t involve abnormality of RAS.
What is Liddle’s syndrome?
Extremely rare - isolated familes in the world
Pseudoaldosteronism - looks like they’re going to have high aldosterone but they don’t
Mutations in SCNN1B and SCHH1G (b and y subunits of Na+ channel) = activation of lots of channels = lots of Na reabsorption = lose K and H ions
Shows increased conductance of renal epithelial Na+ channel
What is hypokalemia?
Trifecta of:
Na retention
H and K loss
What is Adrenocorticotropic hormone (ACTH)?
Hormone released from pituitary gland to switch on glucacorticoids
What is syndrome of apparent mineralocorticoid excess (SAME)?
Reduced activity of 11b-HSD2 enzyme Mutations of 11b-HSD2 High renal cortisol levels Not protecting kidney anymore Stimulation of renal mineralcorticoid receptor Low aldosterone levels
How can ACTH be switched off?
Tablets that trick the pituitary gland into thinking there is too much glucacorticoid around
Adrenal gland stops making cortisol
What is glucocorticoid suppressible hyperaldosteronism?
Aldosterone synthase gene controlled by ACTH-sensitive genetic promoter (from 11b-hydroxylase)
Results in:
- Gene duplication
- Chimeric gene
What is a mineralocorticoid receptor gene mutation?
Mutations of the mineralocorticoid receptor (MR) gene - changes receptivity of MR
Abnormal stimulation of MR by progesterone - activation causes high BP
Hypertension in pregnancy
Really rare!!
Problematic in pregnancy
What is Gordon’s syndrome?
Autosomal dominant Hypertension Hyperkalemia Volume expansion Normal GFR WNK 1 or WNK 4 (wink 1 or 4) mutations - controls series of channels - retain more Na and K
What is hypertension with brachydactyly?
In Turkish families Autosomal dominant Normal RAS function Abnormal autonomic baroreceptor reflex function Chromosome 12 Missense mutation in the PDE3A Increased TPR
What features of tumours causes aldosteronism?
Na retention High BP H+ excretion Alkolosis (pH > 7.4) Hypokalemia
Why does excretion of K and H occur?
Result of increased Na reabsorption in the distal nephron
What does stimulation of mineralocorticoid receptor (MR) cause?
Increases numbers of K channels and H/ATPase pumps in the luminal membrane
Why doesn’t cortisol activate the mineralocorticoid receptor (MR) in the body?
There is an enzyme in the kidney that prevents MR from receiving cortisol in circulation -
11/BHS2 converts cortisol into cortizone
