In a recent review published in the journal Pulse, David Curtis of the UCL Institute of Genetics, University College London, reviews historical and ongoing genetic variation research with a focus on hypertension. It tracks the progress studies have made in identifying genetic associations, revealing the functional mechanisms that support the roles of genetics in hypertension risk, and the clinical implications of these studies in guiding future risk assessment and disease interventions.
While its findings reveal associations between hundreds of common genetic variants and hypertension, with the effect of the former on the latter varying by gene, this review highlights the improbability of ongoing and future genetic variation research to discover a new drug or therapeutic street thus limiting the clinical relevance of the field.
Review: Genetic variants associated with hypertension risk: Progress and implications. Image credit: Shine Nucha / Shutterstock
Genetic variation, the role of natural selection and the need for this review
Despite the fact that all humans are 99.9% genetically identical, mutations caused by faulty DNA replication allow sequence variations to occur. In some cases, especially when mutations occur in coding genes, these variations can profoundly affect individuals’ susceptibility to disease. Research aimed at identifying these genetic variants and uncovering their clinical correlates envisions a future of personalized medicine and preventive gene therapy.
“Variations with zero or minimal effects that appeared early in human evolution can, through a process called genetic drift, become common so that they can be observed in a significant proportion of people today. In contrast, any variant that causes severe disruption of a vital physiological process will tend to be rapidly removed from the population by the process of natural selection, and therefore variants with large effects on disease risk are expected to be very rare.”
While genetic variation research has witnessed recent rapid developments, with techniques such as genome-wide association studies (GWASs) enabling the identification of thousands of variants implicating even more genes in many chronic diseases, this field unfortunately remains in its infancy. of, with a few reviews summarizing these developments and discussing their implications for both clinicians and the general public. The association between genetics and hypertension is a glaring omission in this regard, given that the condition and its comorbidities represent the leading cause of human mortality worldwide.
About the study
The present study seeks to gather literature on natural genetic variants and their associations with hypertension. It touches on the history of research in the field, while focusing on the results of recent major out-of-sequence projects. The review includes more than 35 publications spanning in vitro models, in vivo clinical trials and genome-exome association studies that identify hypertension-associated variants and subsequently reveal their mechanistic underpinnings. Finally, it discusses the clinical implications of past and present genetic variation research and what this means for the layperson of the future.
Research on genetic associations
Prior to the current large-scale association studies, investigations into the association of genetic diseases with hypertension were targeted. Conversely, these investigations have led to the discovery of rare genetic variants associated with diseases such as congenital adrenal hyperplasia, pseudopoaldosteronism, and familial hyperaldosteronism that may not have been discovered by current methods, the latter of which sacrifices sensitivity for broader coverage. .
Despite their difficulties in detecting rare variants, genome-wide and exome-wide association studies are representative of the population and have enabled the discovery of thousands of genetic loci associated with hypertension risk and pathology, the most notable of which are studies that were made by the United Kingdom (UK) Biobank. The largest of these studies included more than 1 million individuals and revealed 901 associated genetic loci.
“The ability to perform exome sequencing on large samples has now made it possible to identify every coding variant in every gene, rather than just those variants predefined on the Exome Chip or those in specific genes identified in targeted studies.”
So far, more than 20 genes with single-variant hypertension associations with substantial positive or negative effects on risk and disease progression have been discovered.
Research on functional mechanisms
Despite its specificity, research on the functional mechanisms underlying gene-hypertension interactions is substantially rarer than that aimed at establishing these genetic associations, genes, particularly those involved in blood pressure control, have been investigated for their mechanisms of action. Studies mainly in mice (mice) models have shown that the expression of certain genetic loci can alter specific levels of natriuretic peptides, altering blood pressure and, subsequently, the risk of hypertension.
The nitric oxide (NO) signaling pathway and its associated genes have been studied through the lens of systolic blood pressure, culminating in its role in blood pressure regulation, vasodilation, and pulmonary hypertension. Mechanisms supporting the role of the DBH gene encoding dopamine beta-hydroxylase have been similarly elucidated. Some genes, such as ASXL1, FES, SMAD6, GEM and INPPL1, are known to play a role in hypertension, but the mechanisms underlying their mode of action remain unknown. Fortunately, research continues to fill this knowledge gap.
Clinical implications of hypertension genetic variant research
There are three potential ways in which genetic variation research can translate into beneficial clinical outcomes – 1. New insights into pathogenic mechanisms, 2. Improved risk quantification, and 3. Improved treatment guidance. Unfortunately, while genetic variation research elucidates new mechanisms of interaction and, in rare cases, discovers previously unknown loci associated with hypertension, historical and current research results suggest that genetic variation research is unlikely to lead to new drugs or clinical interventions .
While future clinical trials may allow for better disease prediction and inform treatment modalities, the current age of the field means that these trials may be years or even decades away, highlighting that the clinical implications of genetic variation research in the treatment of hypertension are limited, at best. .
