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Writer's Profile
Dr Nick Munro

Specialised Subjects

Biology, Education, Health, International Relations, International Studies, Medicine, Politics, Sciences, Statistics, Veterinary

I gained a PhD in life sciences from a work renowned UK University in 2006 and then joined the UK National Health Service as a clinical scientist. Through my work, I get to meet people from different backgrounds and cultures.

I very much enjoy reading and writing scientific articles and I occasionally teach biology to A-level students.

The genetics of Hypertension (elevated arterial blood pressure)

1.1 Introduction
Hypertension, or elevated arterial blood pressure, affects about 25% of the adult population in the developed world. Hypertension is a substantial public health problem, and a major risk factor for many common causes of morbidity and mortality including stroke, heart attacks, and renal diseases (Lifton 2001).

Of world deaths in 2000 attributable to selected leading risk factors, high pressure related death was the main risk factor (World Health Organisation).

According to WHO Guidelines, hypertension is defined as systolic blood pressure of equal or greater than 140 over 90 mmHg.

Individuals with uncontrolled levels of high blood pressure are:

  • On average seven times a higher risk of stroke
  • Exposed to higher risks of congestive heart failure
  • Six times more likely to have a heart attack

There is substantial proof indicating genetic causes for hypertension. Twin and population studies demonstrate greater similarity of family related blood pressure. This familial aggregation of blood pressure is not simply attributable to shared environmental effects. Studies conducted on adopted and biological siblings indicate a greater occurrence of hypertension in biologically related siblings than those adopted living in the same household (Lifton 2001).

For the vast majority of individuals (~90%) the phenotype reflects polygenic inheritance modulated by environmental factors i.e. it follows the same complex disease paradigm proposed for other common diseases such as diabetes and asthma. This form of hypertension is known as essential or primary or non-Mendelian. However, in about five per cent of cases hypertension causes are due to a single gene and this form of hypertension is referred to as secondary or Mendelian hypertension (O’Shaughnessy 2001). Monogenic syndromes are very rare, but unravelling their molecular genetics can provide major insights into the control of blood pressure and may identify targets and pathways for new approaches to treatment (Golbang et al., 2006).

Although blood pressure is known to have a strong genetic basis, the genes responsible for susceptibility are largely unknown. Researchers have shown greater concordance of hypertension with monozygotic than dizygotic twins, and population studies demonstrate greater similarity of blood pressure within families than between families (Lifton et al., 2001). Therefore identifying genes that contribute to hypertension can:

  • Help manage the use of drugs more efficiently and specifically to target the needs of individuals on the basis of their genotype.
  • Provide us with clues to understanding the physiological as well as biochemical pathways involved in hypertension and help elucidate the genes and environmental factors interactions.
  • Identify individuals who are at higher risk of developing the disease, before the occurrence of clinical symptoms, leading to new therapeutic approaches that target prevention rather than cure.

The molecular basis for most of the rare familial Mendelian forms of hypertension is becoming clearer and the success in this area contrasts sharply with the limited advances made in isolating the genes involved in non-Mendelian hypertension (Lifton 1996). Single genes can have a great influence on blood pressure, as demonstrated below by the examples of rare monogenic forms of blood pressure.

1.2 Examples of monogenic syndromes and their genetic basis:

1.2.1 Liddles’s syndrome
This autosomal dominant syndrome can be reversed by long-term amiloride therapy (Baker et al., 2002). In this syndrome, a specific mutation in the proline rich domain of ENaC (PPXY motif) prevents the binding of the physiologic repressor Nedd4-2, which normally promotes the endocytic retrieval of the channel. These mutations leads to ENaC channel retention at the cell surface that in turn leads to sodium and water increased reabsorption in the collecting tubules, leading to hypertension, hypokalemic alkalosis, suppressed renin activity, and low plasma aldosterone levels (Jentsch et al., 2004, O’Shaughnessy et al., 2004).

1.2.2 Apparent mineralocorticoid excess
An autosomal recessive disorder, which shows early onset of moderate to severe high blood pressure with hypokalemia and metabolic alkalosis. Mutations and sometimes deletion of 11?-hydroxysteroid dehydrogenase (11?-HSD) enzyme in these patients results in hypertension. Antagonists of mineralocorticoid receptor lower blood pressure in these patients (Lifton et al., 2001).

1.2.3 Gitelman’s syndrome
Gitelman’s syndrome is an autosomal recessive renal tubular disorder characterised by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. This disorder results from loss of function mutations in the thiazide sensitive NaCl co-transporter (NCCT) that consequently lead to salt wasting from the distal convoluted tubule (Jong et al., 2002, Reily et al., 2000).

1.2.4 Pseudohypoaldosteronism type I
There are two types of familial pseudohypoaldosteronism. Type one is a salt wasting, hypotensive syndrome presenting in infancy and caused by mutations in either ENaC, epithelial sodium channel or the mineralocorticoid receptor (Grunder et al., 1997).

1.2.5 Pseudohypoaldosteronism type II (PHA II)
PHA II is the mirror image of Gitelman’s syndrome. It is an autosomal dominant disorder characterised by hypertension (attributed to increased Na+ reabsorption in the distal nephron) and hyperkalemia (high serum potassium level due to reduced K+ excretion) (Lifton et al., 2001). The functional defect in Gordon’s resides in the distal convoluted tubule, and mutations in two genes are associated with PHA II. These two disease genes have been identified to be members of a newly discovered family of WNK (With No Lysine) kinases (Wilson et al., 2001).

The pathogenesis of hypertension remains largely unknown. Recently the application of genetic approaches to this disease has begun to highlight the molecular pathways underlying blood pressure variation, defining disease pathogenesis and identifying targets for therapeutic intervention. Several strategies have been used in identifying hypertension susceptibility genes. Three most common approaches are: Candidate gene approach, Genome-Wide Scan (GWS) and Comparative genomics.

1.3 Strategies used in finding the hypertension susceptibility genes

1.3.1 Candidate gene approach
An approach that takes the assumption that a specific gene or particular set of genes work together to cause high blood pressure. Genetic linkages and methods to indicate associations are widely used to study rare monogenic syndromes in this manner.
Fifteen loci have been detected to relate to hypertension (Golbang et al., 2005).

1.3.2 Genome-Wide Scan (GWS)
Genotyping of polymorphic markers through genome of individuals with or without a qualitative trait. Such research has shown linkages to various chromosomal regions. Levy and colleagues used individuals from the Framingham Heart Study to find great evidence of hypertension on chromosome number 17 (Tanira et al., 2005, Levy et al., 2000).

1.3.3 Comparative genomics
A method that uses studies on animals to target hypertension loci in humans. New et al., found a region on human chromosome 17, which was homologous to hypertension loci on chromosome 10 of rats, indicating that genes on human chromosome 17 maybe involved in essential hypertension (Turner et al., 2005).

1.4 Concluding remarks
This important disease affects a huge number of people worldwide, and therefore the study of the disease is of vital clinical importance. Hypertension is a genetically determined disease, with many other contributing factors. Research has expanded rapidly in this area, particularly over the last decade, and there are continuing advances in our understanding of the disease.