Home Medizin Genetische Studien geben Aufschluss über das Bluthochdruckrisiko, können jedoch keine neuen Behandlungsmöglichkeiten aufzeigen

Genetische Studien geben Aufschluss über das Bluthochdruckrisiko, können jedoch keine neuen Behandlungsmöglichkeiten aufzeigen

von NFI Redaktion

In a recent review published in the journal, ImpulsDavid Curtis from the UCL Genetics Institute at University College London provides an overview of historical and ongoing research on genetic variants focusing on hypertension. He outlines the progress studies have made in identifying genetic associations, unraveling the functional mechanisms underlying the role of genetics in hypertension risk, and the clinical implications of these studies for guiding future risk assessments and disease interventions.

While his findings reveal the associations between hundreds of common genetic variants and hypertension, with the effects of the former on the latter varying depending on the gene, this review highlights the unlikely possibility that ongoing and future genetic variant research will discover a new medication or therapeutic pathway. This limits the clinical relevance of the field.

Looking back: Genetic variants associated with hypertension risk: Progress and impact. Image credit: Shine Nucha / Shutterstock Genetic variation, the role of natural selection, and the need for this overview. Although all humans are 99.9% genetically identical, mutations caused by faulty DNA replication allow for the generation of sequence variations. In some cases, especially when mutations occur in coding genes, these variations can have profound effects on an individual’s susceptibility to disease. Research aiming to identify these genetic variants and elucidate their clinical associations envisions a future of personalized medicine and preventive gene therapy. „Variants with minimal or no impact that occurred early in human evolution can become widespread through a process called genetic drift, to the extent that they can be observed in a significant portion of individuals today.“ In contrast, any variant causing a severe disruption of a vital physiological process tends to be quickly purged from the population through the process of natural selection, thus it is expected that variants with significant impacts on disease risk are very rare.“

While genetic variant research has made rapid progress in recent years, with techniques like genome-wide association studies (GWASs) enabling the identification of thousands of variants responsible for numerous chronic diseases, this field is still in its infancy and there are few reviews summarizing these advancements and discussing their implications for both physicians and the general public. The connection between genetics and hypertension is a glaring omission in this respect, as the disease and its comorbidities are the leading cause of death worldwide. About the study The aim of the present study is to compile literature on naturally occurring genetic variants and their association with hypertension. It touches on the history of research in this field while focusing on the results of recent large-scale exome sequencing projects. The review encompasses over 35 publications from various years, including in vitro models, in vivo clinical studies, as well as genome- and exome-wide association studies identifying variants associated with hypertension and subsequently decoding their mechanistic basis. Finally, the clinical implications of past and current genetic variant research and their significance for the layperson of the future are discussed. Research on genetic associations Prior to the current large-scale association studies, investigations into the connections between genetic diseases and hypertension were at the forefront. Contrary to intuition, these studies led to the discovery of rare genetic variants associated with diseases such as congenital adrenal hyperplasia, pseudohypoaldosteronism, and familial hyperaldosteronism, which may not have been detected with current methods, sacrificing sensitivity for broader coverage. Despite their challenges in detecting rare variants, genome- and exome-wide association studies are representative of the population and have enabled the discovery of thousands of genetic loci associated with the risk and pathology of hypertension. The most notable of these are the UK Biobank studies conducted in the United Kingdom. The largest of these studies included over a million individuals and identified 901 associated genetic loci. „The ability to conduct exome sequencing in large samples has now made it possible to identify every coding variant in every gene, not just the variants pre-specified on the exome chip or those sequenced in targeted studies in specific genes.“ To date, more than 20 genes have been discovered with monogenic hypertension associations having significant positive or negative effects on disease risk and progression. Exploring functional mechanisms While research on the functional mechanisms underlying the interactions between genes and hypertension is less explored due to its specificity compared to those targeting the identification of these genetic associations, genes, especially those involved in blood pressure control, have been investigated for their mechanisms of action. Studies predominantly in mouse models have shown that the expression of some genetic loci can alter the concentration of specific natriuretic peptides and thus modify blood pressure and hence the risk of hypertension. The nitric oxide (NO) signaling pathway and associated genes have been examined from the perspective of systolic blood pressure. The highlight is its role in blood pressure modulation, vasodilation, and pulmonary hypertension. The mechanisms underlying the role of the DBH gene encoding for dopamine beta hydroxylase have also been elucidated. While some genes such as ASXL1, FES, SMAD6, GEM, and INPPL1 are known to play a role in hypertension, the mechanisms governing their actions are still unclear. Fortunately, research is currently underway to close this knowledge gap. Clinical implications of genetic variant hypertension research There are three ways in which genetic variant research can lead to beneficial clinical outcomes: 1. new insights into pathogenic mechanisms, 2. improved risk quantification, and 3. enhanced treatment guidance. While genetic variant research elucidates new interaction mechanisms and in rare cases discovers previously unknown hypertension-associated loci, historical and current research results unfortunately suggest that genetic variant research is unlikely to lead to new medications or clinical interventions. While future clinical studies may enable better disease prediction and suggest treatment options, the current state of the field means these studies could still be years or even decades away, highlighting that the clinical impact of genetic variant research in treating hypertension is limited at best.

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