Article

Relatively Common Genetic Variant Linked to Cardiovascular Disease and Death in Black Americans

Cohort study finds V142I transthyretin variant contributes to nearly 1 million years of life lost

Cardiology & Heart Surgery
By
Jordan McCollum
Published
September 3, 2024
Portrait of a doctor listening to an elderly woman patient's heartbeat

A new study published in the Journal of the American Medical Association determined the cardiovascular burden of the V142I transthyretin (TTR) genetic variant. The study, led by physicians from Duke and Brigham and Women’s Hospitals, found that patients with this variant died on average 2.5 years earlier than those without, according to Duke cardiologist and study lead author Senthil Selvaraj, MD, MS, MA.

Occurring among 3-4% of the Black population in the U.S., the V142I variant causes cardiac amyloidosis (CA) and heart failure (HF). Using population data from the U.S. Census, the study authors extrapolated that the U.S. Black population aged 50 to 95 years are projected to lose more than 950,0000 years of life due to this genetic variant.

Cardiac Amyloidosis Clinical Trials at Duke
  • MAGNITUDE: Testing CRISPR/Cas9-based genome therapy to edit TTR in hepatocytes
  • DepleTTR-CM: Testing recombinant human monoclonal IgG1 antibody to target TTR protein
  • ACT-EARLY: Testing prophylactic intervention for TTR variant carriers without clinical evidence of amyloidosis

V142I mechanism for HF

A known cause of CA, the V142I variant causes the amyloid protein to misfold, ultimately depositing in the body’s tissues. The malformed protein accumulates, causing musculoskeletal symptoms including carpal tunnel syndrome and lumbar spinal stenosis, as well as a stiff heart.

The study determined how early patients with the V142I variant carried a higher cardiovascular risk. “If you’re a carrier,” says Selvaraj, “your risk of being hospitalized for heart failure in the next ten years starts to increase by age 63. Your increased risk of death starts as early as 72. Those are younger ages than we’d previously estimated.”

Duke Cardiac Amyloidosis Clinic Director Michel G. Khouri, MD, study co-author, emphasizes the importance of early diagnosis: “This variant plays a major role in Black Americans who develop transthyretin amyloidosis. Too often, they’re not diagnosed until they have moderate to advanced disease, and that limits the efficacy of existing therapies.”

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New findings about V142I

Previously, the V142I variant was believed to cause more HF among men, and when the variant resulted in HF, the disease presented with a preserved ejection fraction. However, study data indicated that patients with the variant were more likely to have reduced ejection fraction by the time carriers were hospitalized, and men and women were equally affected by the variant. “This means we’ve probably been underdiagnosing women,” says Selvaraj.

The study also helped to define better screening guidelines for the variant. “We found a heart failure signal in the early 60s,” says Khouri, “so we should consider screening patients at age 50 and above. As the variant is hereditary, cascade genetic screening for family members can also help to identify relatives who will need surveillance for the condition.”