A physician-scientist at the University of Alabama at Birmingham led a national genetic study examining the role of genetic variations in titin, TTN, and genes in Black people. In their research, Nature cardiovascular research They found that black people with these gene mutations were at increased risk of developing atrial fibrillation and heart failure.

“Titin is an essential protein required for the contraction and relaxation of the heart,” said lead author Naman S. Shetty, MD, a research scientist in the UAB Division of Cardiovascular Disease.

Shetty explains that the TTN gene, which codes for the protein titin, is one of the largest genes in humans.

“Because the genes are so large, genetic mutations are more likely to occur,” Shetty said. “However, not all mutations in the titin gene cause disease. A particular subset of mutations known as high-ratio splice-in (hiPSI) titin truncation variants (TTNtv) are responsible for diseases such as atrial fibrillation and heart disease. These hiPSI TTNtvs variants are a unique set of mutations that are expressed more than 9 out of 10 times in the Titin protein and disrupt the structure of the protein. ”

Previous studies have shown that these variants increase the risk of atrial fibrillation, heart failure, and dilated cardiomyopathy in Caucasians.

“DCM is a rare type of heart disease in which the chambers of the heart expand in size, making the heart unable to effectively pump blood to other parts of the body,” Shetty said. “The role of hiPSI TTNtv in the development of atrial fibrillation, heart failure, and DCM could not be established in black people because black people are underrepresented in genetic studies.”

Shetty and his team leveraged data from the All of Us Research Program to examine whether hiPSI TTNtv is associated with adverse cardiovascular events in Black people. The All of Us Research program aims to accelerate precision medicine research by recruiting diverse populations from across the United States and providing researchers with access to genetic and phenotypic data.

“Race is primarily thought of as a social construct, so we used genetic data to confirm each individual’s genetic ancestry,” Shetty said. “Using genetic ancestry, we conducted an analysis among individuals of African descent. Individuals of African descent who carry hiPSI TTNtv have a two-fold increased risk of developing atrial fibrillation, DCM, and heart failure. I understand.”

This study generated comparative data for individuals with European ancestry.

“Consistent with previous studies, we found that carriers of hiPSI TTNtv were at increased risk of developing atrial fibrillation, DCM, and heart failure,” said Pankaj Arora, lead author and associate professor in the UAB Division of Cardiovascular Diseases and Medicine. said the doctor. “Notably, the increased risk of atrial fibrillation, DCM, and heart failure in carriers was similar in individuals of African and European ancestry.”

Arora heads the UAB Cardiogenomics Clinic and is regularly involved in the care of DCM patients, and the study grew out of observations in the clinic that the majority of DCM patients have mutations in the titin gene. He said he noticed that. of their race. However, supporting evidence in the literature was lacking.

“Our study highlights that hiPSI TTNtv is equally pathogenic in any ancestral group,” Arora said. “The All of Us Research Program gave us access to a large group of diverse ethnic backgrounds and allowed us to examine the role of hiPSI TTNtv in the pathogenesis of cardiovascular disease across two ancestral groups.”

“Our findings support the role of genetic screening for hiPSI TTNtv in both European and African ancestry,” Arora said. “Identifying these individuals may allow for regular monitoring and preventive measures to delay the onset of the disease. Additionally, identifying carriers may help identify those likely to carry the same gene. It may also facilitate cascade screening in which first-degree relatives of carriers undergo genetic screening for the variant. “

Arora highlights the need to raise awareness about the role of hiPSI TTNtv in the pathogenesis of DCM and to develop and implement population screening for hiPSI TTNtv.