STUDY. Genetic causes of arterial hypertension, elucidated. Risk could be assessed by polygenic scores

In a study conducted by the National Institutes of Health (NIH), 100 new genomic regions associated with mechanisms by which blood pressure (BP) is regulated are described. The study, published in Nature Genetics, is one of the largest genome-wide investigations of AD, drawing on data from more than one million participants. The results could be the basis for the development of polygenic risk scores for the assessment of the risk of hypertension (HT). Up to 12% of the variation in hypertension can be explained by genetic factors.

Data from four GWAS studies that assessed the genetic component of HTN were integrated. The analysis indicated over 2,000 genomic loci linked to TA, including 113 novel regions.

Several of these new regions are associated with genes involved in iron metabolismreinforcing previous findings showing that iron accumulation may contribute to cardiovascular disease.

• The TMPRSS6 gene has been identified as a potential therapeutic target. Variations in this gene are associated with markers of iron overload. This gene encodes a protein that has been linked to attenuating dietary iron overload in cardiac tissue, leading to cardioprotective effects.
• The SMAD7 gene modulates the expression of hepcidin, a key regulator of intestinal iron absorption.
• The GSTM1 gene has also been implicated in cardiomyopathy resulting from iron overload.

The study also confirmed the relationship between variants in the ADRA1A gene and BP, highlighting the potential for new therapeutic targets for HTN. The ADRA1A gene encodes the alpha-1A adrenergic receptor, a protein located on the surface of smooth muscle cells, including in the walls of blood vessels. This receptor responds to norepinephrine and epinephrine (adrenaline), triggering vasoconstriction, which increases vascular resistance and raises blood pressure. Thus, the gene plays a key role in regulating blood pressure, and genetic variations can affect its response to neurotransmitters, influencing a person’s risk of developing hypertension.

Research has also led to development of scores of polygenic risk, which combines the effects of all genomic variants to assess HTN risk.

The scores showed that people with the highest genetic risk had, on average, systolic blood pressure levels about 17 mmHg higher than those with the lowest genetic risk, as well as a 7 times higher risk of hypertension.

These polygenic risk scores are publicly accessible and can be used by the global research community to explore the contributions of blood pressure to various conditions.

The project was led by NHGRI researchers in collaboration with Queen Mary University of London, Vanderbilt University Medical Center in Nashville, Tenn., the University of Groningen in the Netherlands, and other institutions as part of International Blood Pressure Consortium.

Although the study was mainly based on data from participants of European descent, it also showed that the polygenic risk score was applicable to people of African descent. This finding was confirmed by data from the All of Us project, which aims to create a diverse biomedical data resource to advance human health research.

More than 30% of adults worldwide suffer from hypertension, which is a major modifiable risk factor for cardiovascular disease. Hypertension is defined by high levels of systolic blood pressure (SBP) and/or diastolic blood pressure (DBP). SBP, the maximum blood pressure exerted during heartbeats, increases continuously with age, while DBP, the blood pressure between heartbeats, gradually stabilizes in midlife. Pulse pressure, defined as the difference between SBP and DBP, is an indicator of arterial stiffness. Blood pressure has an important heritable component, and several GWAS studies have highlighted its complex and polygenic architecture.

A polygenic risk score (PRS) is a numerical value that quantifies an individual’s genetic risk for a particular trait or disease, based on the combined effect of several genetic variants. These scores are calculated by summing the effects of various single nucleotide polymorphisms (SNPs) associated with a particular trait or disease, often weighted by their effect sizes obtained from genome-wide association studies (GWAS).

Many complex diseases, including hypertension, are influenced by a multitude of genetic variants, each contributing to a small degree to the overall risk. A PRS captures this polygenic architecture by aggregating the effects of numerous variants, providing a comprehensive genetic assessment of risk. For HTN, a high PRS may indicate a higher likelihood of high blood pressure or related complications, allowing for early intervention and monitoring.

The use of PRSs illustrates the potential of personalized medicine by tailoring prevention, monitoring and treatment strategies according to genetic risk. For hypertension, this could include lifestyle interventions or pharmacological treatments aimed at reducing blood pressure.

By aggregating genetic risk factors, PRSs can help researchers and decision-makers understand the distribution of disease risk in populations, thereby guiding public health strategies and resource allocation, especially for widespread pathologies such as hypertension.

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