A large national study by UAB researchers found that black people with genetic mutations in the TTN gene are at increased risk for adverse clinical outcomes.A University of Alabama at Birmingham physician-scientist led a national genetic study examining the role of genetic variations in the titin (TTN) gene in Black people. A study in Nature Cardiovascular Research found that black people with these genetic variations are 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 failure. 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 is an NIH-funded program that advances precision medicine research by recruiting diverse populations from across the United States and providing researchers with access to genetic and phenotypic data. The purpose is

Naman Shetty, MD (left) and Pankaj Arora, MD (right) are UAB researchers involved in this study.“Race is primarily thought of as a social construct, so we used genetic data to confirm each individual’s genetic ancestry,” Shetty said. “We conducted an analysis in individuals of African descent using genetic ancestry. We found that people of African descent with hiPSI TTNtv had twice the risk of developing atrial fibrillation, DCM, and heart failure. I found it to be expensive.”

This study generated comparative data for individuals with European ancestry.

“Similar to previous studies, we found that carriers of hiPSI TTNtv were at increased risk of developing atrial fibrillation, DCM, and heart failure,” said Pankaj Arora, senior author and associate professor of medicine in the UAB Division of Cardiovascular Diseases. says Dr. “Notably, the increased risk of atrial fibrillation, DCM, and heart failure in carriers was also similar in people of African and European ancestry.”

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

“Our study highlights that hiPSI TTNtv is equally pathogenic in all ancestral groups,” 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. “Identification of these individuals may allow for regular monitoring and preventive measures to delay the onset of the disease. Additionally, identification of carriers may help identify those who carry the same genetic mutation. This potential could also facilitate cascade screening in which first-degree relatives of carriers undergo genetic screening.”

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.