Researchers at Brigham and Women’s Hospital have published research in JAMA showing that a genetic variant present in 3% to 4% of Black people in the United States increases their risk of developing transthyretin amyloidosis. Carriers of the V142I mutation are also more likely to develop subsequent heart failure and to die about two years earlier than non-carriers.
“Given our estimations, there are about 500,000 Black Americans who live with this mutation, making it potentially one of the most common genetic diseases of people of African descent,” says Scott D. Solomon, MD, the Edward D. Frohlich Distinguished chair in Cardiovascular Pathophysiology at the Brigham.
He and his colleagues want healthcare practitioners to be more aware of this “common rare disease” so they can counsel patients about genetic screening and make more appropriate treatment recommendations.
“We treat this differently than we treat generic heart failure,” Dr. Solomon says. “There are therapies coming on the market designed specifically for transthyretin amyloidosis that can dramatically improve outcomes in patients with this disease. So it is worth understanding the differences.”
Understanding Transthyretin Amyloidosis and Cardiac Amyloidosis
Amyloidosis occurs when certain kinds of proteins in the blood misfold, clump up, and deposit in various parts of the body. Transthyretin amyloidosis is a particular type of cardiac amyloidosis involving misfolding of the transthyretin protein. This protein is produced in the liver and normally carries thyroxine, a thyroid hormone, throughout the body.
There are two types of transthyretin amyloidosis. One mostly affects the nervous system, leading to peripheral neuropathy and difficulty with bodily sensations such as touch, pain, heat, and sound, and involuntary bodily functions such as blood pressure, heart rate, and digestion. The other type is cardiac amyloidosis, which occurs when the misfolded proteins clump up and deposit in the heart. Some people have both types and therefore manifestations of both.
The transthyretin protein can begin to misfold due to aging in a process that is not well understood, causing what is known as wild-type transthyretin amyloidosis. The condition may also be caused by a genetic mutation in the DNA that encodes the protein.
“Ultimately, enough of these amyloid fibrils get deposited that the heart becomes stiff, dysfunctional, and can’t pump as well,” Dr. Solomon explains. “These patients develop heart failure and then are at high risk for hospitalizations and death.”
Amyloidogenic V142I Variant of the TTR Gene
One of the mutations that can cause transthyretin amyloidosis is the amyloidogenic V142I variant of the transthyretin (TTR) gene. Research has shown that the mutation is quite common in people with West African heritage (which is the most common heritage of Black individuals in the United States).
Notably, the presence of the variant does not guarantee that a person will develop the disease, Dr. Solomon says, and those who do develop the disease often do so later in life. Therefore, he and his colleagues wanted to understand what factors may influence whether a carrier goes on to develop the disease.
In the JAMA study, Dr. Solomon and colleagues examined long-term data on more than 23,000 Black people in the general population. Of that group, 754 had the V142I variant (3.2%).
When the researchers analyzed rates of heart failure and all-cause mortality between people with and without the V142I variant, they discovered that carriers died an average of two to two-and-a-half years earlier than non-carriers. On a population level, these numbers extrapolate to about a half-million Black Americans older than age 50 who are carriers of this mutation, Dr. Solomon says.
The researchers also found that age was the only factor associated with the development of heart failure in V142I carriers. Risk increased by about age 63, and mortality significantly increased at age 72.
“We looked at all the other things about this population to try to figure out what might have contributed to an increased risk. For example, we looked at gender, diabetes, and hypertension. But the only thing that increased the relative risk of developing heart failure and death was age,” Dr. Solomon says.
Screening for Transthyretin Amyloidosis Genetic Mutation
Dr. Solomon stops short of recommending that all people of West African descent have genetic testing to screen for the V142I variant. He adds that the mutation is “almost unheard of” in people who are not of African descent.
However, those with a family history of amyloidosis or heart failure, especially at an earlier age, might consider genetic testing. The information can help prevent misdiagnosis in people who do go on to develop heart failure. And it can direct patients and clinicians toward more effective treatment that is specifically designed for this type of disease.
“When people present with heart failure, transthyretin amyloidosis isn’t necessarily the first thing clinicians think of. So, patients often get treated for other conditions that are better understood, such as hypertension and diabetes, and they may not be accurately diagnosed and treated,” Dr. Solomon notes.
There are therapies specifically designed for transthyretin amyloidosis. For example, tafamidis (brand names Vyndaqel® and Vyndamax®) is an oral medication for cardiomyopathy and peripheral neuropathy caused by transthyretin amyloidosis in adults. Several other medications are currently being tested for the disease, such as silencers (which lower the amount of transthyretin in the blood), drugs that remove amyloid from the heart, and gene editing technology.
Mass General Brigham has a robust program treating this patient population and participates in many of the studies exploring risk factors and potential treatments.
“If you put together our incredibly strong patient care with our deep commitment to the research in both understanding the disease and exploring potential therapies for the disease, it makes us a unique center that deeply understands this disease,” Dr. Solomon says.