Genetic variant common among West African descendants contributes to large cardiovascular disease burden

Among cardiologists, it’s known that transthyretin cardiac amyloidosis, a type of heart disease, is caused by the misfolding of a protein called transthyretin, which builds up in the walls of the heart, causing the muscle to get thicker and stiffer. One reason this can happen is because of a genetic mutation caused by the gene variant V142I, which is commonly found in people of West African descent. In a new study published Sunday in the Journal of the American Medical Association, researchers found that the 3%-4% of self-identified Black individuals carrying this variant had an increased risk for heart failure and death.

Heart failure affects African Americans at nearly twice the rate that it affects white people in the U.S. — and the reason may in part be due to ancestry, not race. But even though the link between V142I and heart failure is well known, researchers did not know how the variant affects people’s risk of heart failure and its association with preserved heart function. Previously, researchers would study patients who already had the disease and came in for treatment. In this study, researchers from Brigham and Women’s Hospital and Duke University School of Medicine looked at the natural history of the disease by drawing on data from four National Institutes of Health-funded studies in the U.S. Their findings suggest an opportunity to provide more genetic counseling and screening for African Americans.

Notably, these studies were not designed to look at amyloid heart disease specifically, but to obtain genotyping data in healthy women and individuals with various risk factors, such as stroke and atherosclerosis. 

“It would inform us and clinicians and patients regarding the likelihood that an individual at a given time in their life who has this genetic mutation might develop this disease. And the reason that’s becoming more important is that there are now some therapies that are available for the first time, really only in the last few years, that are available for amyloid heart disease,” said Scott Solomon, senior author of the paper and professor of medicine at Brigham and Women’s Hospital and Harvard Medical School.

Using this large dataset, the researchers analyzed data from 23,338 self-reported Black individuals, out of whom 754, or a little over 3% of them, carried the V142I variant. They found that the genetic variant increased the risk for heart failure hospitalization by age 63 and the risk of death by age 72.

“That’s earlier than we thought,” said Senthil Selvaraj, the paper’s first author and an advanced heart failure physician-scientist at Duke University School of Medicine. Previously, researchers had thought that risk of hospitalization occurred in the 70s. 

He added that they found that men and women also have a similar risk for disease, which suggests that women are fairly likely to be underdiagnosed with this form of amyloid heart disease. Women in general tend to have less thick walls, which means that even though amyloid heart disease thickens the walls, it could still be missed. The researchers also were unable to determine, among people who had the variant, whether they were hospitalized because of the condition or some other risk factor or combination of risk factors, such as high blood pressure or diabetes. 

The researchers also looked at the burden this mutation has on a person’s life span. On average, people who carry the variant live two to two and a half years less than a non-carrier. Approximately 13 million Black Americans are over the age of 50, and the researchers estimated that nearly half a million people over 50 are carriers of the variant. “This means that the contemporary population of Black Americans will live about a million fewer years due to the variant,” Selvaraj said. That might even be a conservative estimate, according to the editorial published with the study written by Clyde Yancy, professor and chief of cardiology at Northwestern University Feinberg School and Medicine and deputy editor for JAMA Cardiology.

Yet the implications for screening and genetic counseling are not obvious. While this variant is found in people with West African ancestry, the increased risk of heart failure and death does not only affect people who self-identify as Black.

“This kind of work is incredibly important, because we have to accept the evident truth that we as scientists understand: Race does not infer biology. Period. Hard stop. No modifiers, no adjectives. Race is a social variable, and relates to culturation, it relates to experiences, but does not infer biology. Period,” Yancy told STAT. The color of your skin does not protect you from having this variant. He gave an example of a “delightful” white patient under his care who is currently being treated for amyloid heart disease and has the V1421 gene.

Selvaraj acknowledged that since the variant is found in people with West African ancestry, this is a global disease and people with various ethnic backgrounds may carry the variant as well.

It’s impossible to know the worldwide burden of disease, “but, in some ways, this is sort of the tip of the iceberg,” Selvaraj said. 

“I think it was a well-done study,” said Evan Kransdorf, an assistant professor of cardiology and a member of the cardiogenetics team at Cedars-Sinai in Los Angeles, who was not part of the study. Besides increasing screening, he said there’s also an opportunity to pursue other areas of research. “We would like to know how treatment would affect and modify the outcome, but obviously, that is a whole different study and can be difficult because in the last few years there’s been a lot of rapid advancements in the field in the treatment of amyloidosis.” One treatment is the drug tafamidis, which prevents the misfolding of the protein transthyretin. A gene-editing therapy is currently in clinical trials.

Yancy, who wrote one of the two editorials accompanying this study, said it’s the presence of the V1421 gene itself that gives “reason to heighten surveillance — not because of race, but because of detectable genetic risk variables.” Screening for the mutations should be made available for all people with a suitable disease phenotype, he argued in his editorial. This would be a similar practice to the “race-agnostic” screening for APOL1 in kidney disease.

“We have to figure out, how do we get a reluctant patient cohort to agree to this kind of sophisticated genetic screening? First, that is counseling, and then the genetic testing, and how do we pay for it?” he said. According to Yancy’s editorial, outside of commercial payers, patients on Medicare are only able to get cancer screenings, and Medicaid in most states does not cover genetic testing. “It could be that these kinds of conversations will encourage CMS to revisit coverage decisions, wouldn’t that be a really wonderful outcome?” Yancy said.

In order to convince a reluctant patient, Kransdorf said that education is important. “I say ‘Hey, there’s an 80% chance that I’m not going to be giving you any useful information, but there’s a 20% chance I’m going to be giving you very useful information.”’ Keeping that information in mind, a patient can decide on whether the odds are worth possibly confirming a genetic link to their disease.

As science moves toward race-agnostic research, Kransdorf believes that focusing on genetics will be a big component to developing individualized or precision medicine. “Obviously, we’re not quite there yet, but I think maybe in five or 10 years, we’ll be starting to get there.” He added robust genetic testing should pave the way. “Actual testing will be able to give us much more precise abilities to diagnose and potentially treat people. … I think that we will be able to use genetic information to get past these kind of crude estimates.”