Genetics of hypertension

Question 1

What is hypertension defined as?

Answer 1

An elevated systolic and diastolic blood pressure

Continuous variable

Question 2

What causes essential hypertension?

Answer 2

As age increases as does blood pressure

Blood pressure does not rise with age in populations with very low sodium diet, thus other factors other than age that impact BP increase

BP genetic variability:
= 25-65%

BP heritability (twin studies):
Systolic 15-40%
Diastolic 15-30%

Sibling recurrence risk
= 1.2-1.5

Question 3

Essential hypertension can be either monogenic or polygenic.

True or false

Answer 3

True

Question 4

What are causes of monogenic hypertension?

Answer 4

1. Mineralocorticoid pathway
Familial Hyperaldosteronism
-Type 1 (Glucocorticoid-Remediable Aldosteronism) CYP11B1
-Type 2 ?7p22
-Type 3 KCNJ5

Apparent Mineralocorticoid Excess HSD11B2

Pseudohypoaldosteronism type 2 (Gordon syndrome) WNK4, WNK1, KLHL3, CUL3

Liddle syndrome SCNN1B,SCNN1G

2. Glucocorticoid pathway (CAH)
   CYP11B1, HSD3B2, CYP17A1, CYP11A1
3. Endocrine cancer genes
   RET, SDHB, SDHC, SDHD, VHL, KIF1B, PHD2, SDHAF2

*Protective loss-of-function variants
Bartter SLC12A1, KCNJ1, CLCNKB, BSND, CaSR, ClCK-A
Gitelman SLC12A3

Question 5

Describe the inheritance pattern in monogenic hypertension?

What is a key characteristic for diagnosis?

Answer 5

Recessive or dominant inheritance pattern

Low Renin levels. Renin increases level of angiotestin which in turn induce conversion of aldosterone, however in these patients, renin level is low as is suppressed by presence of hypertension, thus low renin does not drive hypertension

For all conditions there are particular groups of treatment considered most appropriate

Finding of low renin level leads to diagnosis

Question 6

What are significant pathways involved in monogenic hypertension?

Answer 6

Central pathway is mineralcorticoid receptor and its downstream effects, for AME or GRA all have effects that regulate mineralcorticoid receptor function

Liddle syndrome – sodium channel which is responsible for resorption of sodium is affected directly by a genetic mutation does not liked to mineralcorticoid receptor itself

Question 7

What is Glucocorticoid-remediablealdosteronism (GRA)(Familial hyperaldosteronism type I)?

Answer 7

Glucocorticoid-remediable Aldosteronism(GRA) is a rare form of primaryaldosteronism. The most common presentation of GRA is the discovery of asymptomatic severehypertension.

Pathway for synthesis of steroids in adrenal glands- Begins with cholesterol and ends with aldosterone production.

Pathway for synthesis of steroids in adrenal glands- Begins with cholesterol and ends with aldosterone production.

Gene for aldosterone synthase and gene for 11 beta hydroxylase are in tandem on same chromosome, each gene has its own promotor and coding sequence.

11 beta hydroxylase promotor responds to ACTH- hormone that drive steroid synthesis. Thus, ACTH in system activates promotor and this will drive transcription of 11 beta gene which increases cortisol production. As genes are in tandem crossing over events occur, meaning that rather than the attaining correct sequence of genes, a chimeric fusion gene product may occur meaning promotor of 11 beta hydroxylase fused to coding sequence of aldosterone synthesis, thus in this case when have ACTH rather than triggering production of 11 beta hydroxylase and thus cortisol, produce aldosterone synthase and thus aldosterone. Thus, response to low levels of steroids is to produce more aldosterone and that drives your blood pressure.

Question 8

What features describe Glucocorticoid-remediablealdosteronism (GRA) (Familial hyperaldosteronism type I) ?

Answer 8

Prevalence:
- up to 1:1,000 hypertensives?

Penetrance:
- ~90%

Often early-onset
Risk of haemorrhagic stroke

Refractory to standard treatment
Can respond to low-dose steroids (suppress ACTH)

Question 9

What does genetic testing of Glucocorticoid-remediablealdosteronism (GRA) (Familial hyperaldosteronism type I) involve?

Answer 9

Genetic testing criteria (UKGTN)
Cambridge, £99 / 10 days

Hypertension
AND
Primary hyperaldosteronism
AND
Any 2 of:
1) Dominant family history of hypertension
2) Family history of CVA under 60y
3) Urine 18-hydroxysteroid excess
4) Positive steroid suppression test
5) On >3 drugs for hypertension
6) Hypokalemia (esp. if on thiazide)

Question 10

What does Syndromic Hypertension refer?

Answer 10

Hypertension can be one symptom of a genetic condition which causes other symptoms

Question 11

GWAS does not examine specific genes, but at a given point in a genome, a polymorphism associated with BP

True or false

Answer 11

True

Question 12

What did studying genetic predisposition to high blood pressure and lifestyle factors conclude?

Answer 12

For those in a very high genetic group, if they have a healthy lifestyle their risk is lower than someone in low genetic risk score with a unfavourable lifestyle

Question 13

Why are polygenic risk scores not applied in clinics?

Answer 13

Polygenic risk score difficult to apply in clinic, and if were applied, unlikely that patients will follow

Question 14

What does the future of hypertension involve?

Answer 14

Epigenetics

• Methylation
• Histone modification
• RNA

Complex models

• Gene-gene interaction
• Gene-environment

Rare variants

Pharmacogenomics

Question 15

Current treatment for hypertension is what?

Answer 15

Empiric

Could pharmacogenomic personalised medicine improve treatment outcomes?