Related Experiment Videos
The causes of essential hypertension
1Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, UK.
Insights
Hypertension may stem from single-gene disorders, not just multifactorial causes. This study suggests new genetic approaches to understanding hypertension risk and its inheritance patterns.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Epidemiology
Background:
- Diagnostic criteria for hypertension can be confusing, potentially hindering research into its causes.
- Molecular genetics offers promise for understanding hypertension but requires large sample sizes and has limitations in complex disorders.
Purpose of the Study:
- To investigate the genetic basis of hypertension by analyzing familial aggregation.
- To challenge the traditional view of hypertension as a purely multifactorial condition.
- To identify potential single-gene contributions to hypertension susceptibility.
Main Methods:
- Analysis of sibling recurrence risk for hypertension in a cohort of 6000 patients.
- Examination of familial patterns within hypertensive sibships.
- Comparison of observed familial aggregation with expected patterns for multifactorial and Mendelian inheritance.
Main Results:
- A hypertension recurrence risk of approximately 3.5 was observed among siblings.
- Two-thirds of patients had no affected siblings; one-third had all affected siblings.
- A small subset (<10%) of patients had half their siblings affected, challenging continuous distribution models.
Conclusions:
- Hypertension may not solely be a continuous, multifactorial trait within normal blood pressure distribution.
- Findings suggest the existence of multiple single-gene disorders contributing to hypertension.
- Patterns in highly affected sibships indicate potential pre-zygotic gene selection influencing hypertension risk.
Abstract:
1. Confusion between the criteria for defining and diagnosing hypertension may have misled the search for the causes of hypertension. 2. The systematic approach of molecular genetics appears to offer the best chance of explaining hypertension, but the attractions are partly offset by the large numbers required, and unproven record of the genetic techniques in finding functional mutations in complex human disorders. 3. Part of the evidence for the polygenic nature of essential hypertension derives from the variable response to a large number of different anti-hypertensive agents. Systematic investigation of this variability may provide a basis for dividing patients into genetically more homogeneous sub-groups, within which smaller numbers will be required to detect the genes responsible for the susceptibility to hypertension. 4. The proportion of hypertensive patients with affected siblings has been studied in 6000 patients from Addenbrookes Hospital and local general practices. A recurrence risk for hypertension of approximately 3.5 was found. 5. Approximately two-thirds of patients have no known affected siblings. The next largest group, about one third, is patients whose siblings are all hypertensive. In a small group, < 10% of all patients, half the siblings are hypertensive. 6. We conclude from these surprising findings that hypertension is not a continuous, multifactorial part of the normal blood pressure distribution. They suggest that several more single-gene disorders causing hypertension will be found. The sibships where all members are hypertensive are inconsistent with the segregation of Mendelian genetics and suggest the selection of some genes linked to hypertension at the time of gamete maturation.