FAP V122I Mutation Associated with Heart Failure in African, Hispanic People, Study Finds

The V122I gene mutation, found primarily in people of African descent with hereditary transthyretin amyloidosis (ATTR), is associated with heart failure in individuals of African or Hispanic/Latino descent, a study found.

The study, “Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry,” was published in the Journal of the American Medical Association.

Hereditary ATTR (hATTR), also known as familial amyloid polyneuropathy (FAP), is caused by the buildup of a protein called transthyretin in certain tissues or organs, which damages them and impairs their function. The process is triggered by genetic mutations in the TTR gene, which provides instructions to make transthyretin.

While polyneuropathy (nerve pain) is the most common symptom in people with hATTR, some patients can also develop cardiomyopathy (hATTR-CM), a condition in which heart muscles weaken and compromise the heart’s ability to pump blood. Patients with hATTR-CM often develop heart failure and arrhythmia (abnormal heart rhythm).

One of the most common genetic causes of hATTR-CM is the mutation known as TTR V122I, primarily found in individuals of African descent.

“Despite having … characteristics of hATTR-CM, very few individuals of African ancestry with heart failure underwent evaluation for hATTR-CM or genetic testing for TTR V122I in standard clinical practice,” the researchers wrote.

“Furthermore, for the minority that were diagnosed, there were lengthy delays in obtaining a molecular diagnosis of hATTR-CM,” they said.

The study was based on clinical and genetic data of individuals of African and Hispanic/Latino ancestry who were enrolled in either the Penn Medicine Biobank (PMBB) or the Icahn School of Medicine at Mount Sinai BioMe biobank.

The researchers analyzed electronic health record data from carriers and non-carriers of the TTR V122I variant of African descent, ages 50 and older, who enrolled in the Penn Medicine Biobank between 2008 and 2017.

They looked at 3,724 individuals of African ancestry with a median age of 64. Some 116 of them were carriers of the TTR V122I variant (3.1%), and 1,121 individuals (30%) had heart failure.

Investigators found that almost half (44%) of the TTR V122I carriers had heart failure, while only a third (30%) of non-carriers had the condition, indicating the TTR V122I mutation was associated with a 1.7-fold increased risk of heart failure.

They also analyzed data from people who enrolled in the Mount Sinai biobank between 2007 and 2015, some 2,307 of whom were of African ancestry and 3,663 of Hispanic/Latino origin. The median age was 73.

In this group, there were 1,376 cases of heart failure. The remaining 4,594 people had no clinical diagnosis of heart failure, and were used as a control group for the primary analysis.

Among the combined group of individuals of African and Hispanic/Latino origin, 36 of the 1,376 (2.6%) who had heart failure and 82 of the 4,594 (1.8%) of controls carried the TTR V122I variant.

“This translated into V122I carriers having significantly higher odds of heart failure [1.8-fold higher] than non-carriers among individuals of self-reported African and Hispanic/Latino ancestry,” the investigators wrote.

Across both sets of analyses, there were a total of 92 people who carried the V122I variant and had a clinical diagnosis of heart failure. However, only 10 (11%) of these carriers with heart failure were found to have hATTR-CM. Among these patients, the median time from symptom presentation to clinical diagnosis was three years.