Lecture 4: BP & Genes

Question 1

What are the three types of genetic variations that affect BP?

Answer 1

1. Extremely rare major genetic diseases
2. Rare (<1/2000) coding mutations with modest effect (5 mmHg)
3. Common (1/3) non-coding variants with small effects (<1 mmgh) - normal, small effects, unmeasurable

Question 2

What % of genetics contributes to BP?

Answer 2

40%

Rest is environmental

Question 3

What is GWAS?

Answer 3

Genome wide associated studies
Needed to pick up small signals
200,000 people
Expensive

Question 4

What is “missing” heritability?

Answer 4

All of the BP loci discovered to date account for less than 5% of the heritability of BP

Question 5

What are the 3 groups of differences between individuals?

Answer 5

Inconsequential
Pathological
Physiological

Question 6

How many difference in genes between people?

Answer 6

3 million

We differ 1 in every 1000 base pairs between individuals

Question 7

What are 4 rare genetic causes of hypertension?

Answer 7

Genetic mutation usually in coding sequences
Amino acid substitution
Truncation of protein
major functional effects (on the proteins activity)

Question 8

How much of the genome accounts for amino acids?

Answer 8

2% of the genome

20,000 genes code for amino acids

Question 9

What are variants?

Answer 9

Sequences of genes that tend to be in non-coding parts

Question 10

What are very rare genetic causes of hypertension?

Answer 10

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.

Question 11

What is Liddle’s syndrome?

Answer 11

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

Question 12

What is hypokalemia?

Answer 12

Trifecta of:
Na retention
H and K loss

Question 13

What is Adrenocorticotropic hormone (ACTH)?

Answer 13

Hormone released from pituitary gland to switch on glucacorticoids

Question 14

What is syndrome of apparent mineralocorticoid excess (SAME)?

Answer 14

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

Question 15

How can ACTH be switched off?

Answer 15

Tablets that trick the pituitary gland into thinking there is too much glucacorticoid around
Adrenal gland stops making cortisol

Question 16

What is glucocorticoid suppressible hyperaldosteronism?

Answer 16

Aldosterone synthase gene controlled by ACTH-sensitive genetic promoter (from 11b-hydroxylase)
Results in:
- Gene duplication
- Chimeric gene

Question 17

What is a mineralocorticoid receptor gene mutation?

Answer 17

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

Question 18

What is Gordon’s syndrome?

Answer 18

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

Question 19

What is hypertension with brachydactyly?

Answer 19

In Turkish families
Autosomal dominant
Normal RAS function
Abnormal autonomic baroreceptor reflex function
Chromosome 12
Missense mutation in the PDE3A
Increased TPR

Question 20

What features of tumours causes aldosteronism?

Answer 20

Na retention
High BP
H+ excretion
Alkolosis (pH > 7.4)
Hypokalemia

Question 21

Why does excretion of K and H occur?

Answer 21

Result of increased Na reabsorption in the distal nephron

Question 22

What does stimulation of mineralocorticoid receptor (MR) cause?

Answer 22

Increases numbers of K channels and H/ATPase pumps in the luminal membrane

Question 23

Why doesn’t cortisol activate the mineralocorticoid receptor (MR) in the body?

Answer 23

There is an enzyme in the kidney that prevents MR from receiving cortisol in circulation -
11/BHS2 converts cortisol into cortizone