Uncovering New Drivers of Heart Disease, Brain Vessel Disorders

How genetic changes in cells that line blood vessels fuel cardiac disease, brain vessel malformations

By BRIGHAM AND WOMEN’S/BROAD INSTITUTE COMMUNICATIONS February 7, 2024 Research

4 min read

Image: Rasi Bhadramani/iStock/Getty Images Plus

At a glance:

Research shows how genetic alterations can affect the biology of cells that line the walls of blood vessels to magnify heart disease risk.
The study identifies a gene involved both in brain vessel malformations, a rare condition, and heart disease, the number one cause of death worldwide.
The findings can inform the design of new diagnostic tools and precision-targeted treatments for these conditions.

Over the past 15 years, scientists have pinpointed hundreds of regions in the human genome linked to heart attacks, but they have not been able to determine precisely how genetic variants can alter biologic function and culminate in cardiovascular disease. This has precluded the design of precision-targeted therapies that treat heart disease at its very root — in the cells of the blood vessel wall where the disease arises.

Now, a new approach — developed by Harvard Medical School scientists at Brigham and Women’s Hospital and colleagues at the Broad Institute of MIT and Harvard and Stanford Medicine — promises to close this gap.

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The new technique, the variant-to-gene-to-program, combines several tools of genetic analysis to reveal how changes in gene structure can alter the biology and function of epithelial cells that line the walls of blood vessels and cause them to malfunction.

The research, which was done in human blood vessel cells and published Feb. 7 in Nature, establishes a way to connect genetic changes to biologic function and dysfunction. Just as important, it hints at possible therapies that prevent and treat the malfunction that affects the cells lining blood vessels and leads to disease.

Additionally, the study found that alterations in one particular gene — a previously unsuspected player in cardiovascular illness — can drive both the development of heart disease, the number one cause of death in the United States, as well as the formation of rare but often fatal brain vessel malformations.

“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said study co-senior author Rajat Gupta, HMS assistant professor of medicine and a physician in genetics and cardiovascular medicine at Brigham and Women’s Hospital.

“We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function,” he added.

Melding gene-editing, AI, and more to find the drivers of mischief

The researchers started out by looking at areas on the human genome previously linked to coronary artery disease and then connecting these areas to the function of specific genes.

Then, using a tool called CRISPRi-Perturb-seq, developed at the Broad Institute, the team “deleted” thousands of genes linked to heart disease, one at a time and in individual cells. Doing so allowed scientists to determine how each individual gene deletion affected the activity of all the other genes in a given cell.

In total, the researchers analyzed 215,000 blood-vessel lining cells to determine how 2,300 deletions influenced expression of 20,000 other genes in each cell. Then, with the help of AI, researchers were able to link which changes in the biologic function of blood vessels consistently appeared together with gene variants already linked with heart disease.

The analysis showed that 43 of 306 gene variants linked to heart disease were also linked to genes involved in the development of cerebral cavernous malformations, a group of rare but devastating vascular disorders marked by abnormally formed and poorly functioning blood vessels in the brain.

The researchers hypothesized that subtler mutations in the genes involved in brain vessel malformations may also contribute to heart disease by fueling blood-vessel inflammation and blood-clotting and by interfering with the structural integrity of the blood-vessel walls.

New genetic cross-links between heart disease and brain vessel malformations

Moreover, the researchers found that one specific gene, TLNRD1 — whose biologic function had thus far been unclear — appears to play a dual role in the development of brain vessel malformations and heart disease.

Armed with these new findings, the researchers plan to study patients with gene variants that appear to be linked both to heart disease and brain vessel malformations.

The ultimate goal of these efforts would be to design genetic tests to identify those at risk for either disorder and to develop treatments that target each condition at its root — the molecular level of dysfunction.

Blood vessel inflammation and clogging caused by abnormalities in cholesterol metabolism are well-known drivers of blood vessel damage that leads to heart disease. But in recent years, it’s become increasingly clear that heart disease also could arise from mechanisms other than high cholesterol. Abnormalities in the cells that line the walls of blood vessels play a distinct role in the development of heart disease not caused by high cholesterol.

“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease. Perhaps now we can better describe the risk factors and pathways that drive the rare cerebrovascular disease as well.”

Beyond heart disease and brain vessel malformations, the researchers say that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell type relevant to that disease can be genetically modified in the lab.

“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said Jesse Engreitz, assistant professor of genetics at Stanford Medicine and co-senior author on the paper.

Authorship, funding, disclosures

Gavin R. Schnitzler (Brigham and Women’s; Broad Institute) and Helen Kang (Stanford Medicine) are co-first authors of this study.

Additional authors include Shi Fang, Ramcharan S. Angom, Vivian S. Lee-Kim, X. Rosa Ma, Ronghao Zhou, Tony Zeng, Katherine Guo, Martin S. Taylor, Shamsudheen K. Vellarikkal, Aurelie E. Barry, Oscar Sias-Garcia, Alex Bloemendal, Glen Munson, Philine Guckelberger, Tung H. Nguyen, Drew T. Bergman, Stephen Hinshaw, Nathan Cheng, Brian Cleary, Krishna Aragam, Eric S. Lander, Hilary K. Finucane, and Debabrata Mukhopadhyay.

This work was supported by the Variant-to-Function Initiative at the Broad Institute, the National Heart, Lung, and Blood Institute (R01HL159176, R01HL164811, U01HL166060), the National Human Genome Research Institute (UM1HG011972, R35HG011324), the Gordon and Betty Moore Foundation, the Basic Sciences and Engineering Initiative at the Lucile Packard Children’s Hospital at Stanford University, National Institutes of Health (K99HG009917, R00HG009917, DP2HL152423, HL70567, K08DK129824), the Novo Nordisk Foundation (NNF21SA0072102); the Harvard Society of Fellows; a Khoury Innovation Award and Braunwald Scholar Award; the Broad Institute, a Florida Department of Health Cancer Research Chair’s Fund Grant (3J-02 and (M.S.T.).

Engreitz is a shareholder of Illumina and 10X Genomics, has received materials from 10X Genomics unrelated to this work, is an equity holder in and consultant for Martingale Labs, and has received guest speaker honoraria from GSK. Taylor holds equity and has received consulting fees from ROME Therapeutics, which is not related to this work. Schnitzler, Gupta, Engreitz, Kang, and Ma are inventors on a provisional patent related to this work.

Adapted from a Brigham and Women’s/Broad Institute news release.