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'All of Us' Sequencing Data Links Titin Mutations, Heart Conditions in African Ancestry Individuals

NEW YORK – By digging into genetic data generated for the All of Us Research Program, a team from the University of Alabama at Birmingham and the Birmingham Veterans Affairs Medical Center linked several heart conditions to specific mutations in the TTN gene coding for a heart contraction-related protein called titin in participants of African or European ancestry.

The alterations, dubbed "high-proportion spliced-in titin truncating variants," or hiPSI TTNtvs, were previously implicated in enhanced atrial fibrillation, dilated cardiomyopathy (DCM), and heart failure risk in European ancestry individuals, senior and corresponding author Pankaj Arora, a cardiovascular disease researcher at the University of Alabama at Birmingham and Birmingham VA Medical Center, and his colleagues wrote in a research letter in Nature Cardiovascular Research on Monday.

Even so, "similar data in individuals of African ancestry are lacking," they explained, prompting an analysis of alterations found in the titin-coding gene TTN in 38,154 African ancestry participants in the All of Us study.

Based on whole-genome sequence data for the participants, the team flagged hiPSI TTNtv alterations in 169 individuals of African ancestry, representing 0.4 percent of participants profiled.

As reported in those of European ancestry in the past, the researchers explained, the presence of the hiPSI TTNtvs coincided with significant upticks in each of the heart conditions considered — from a 2.82-fold uptick in DCM to 2.07-fold rise in heart failure risk and 2.32-fold increase in the number of atrial fibrillation cases in their adjusted hazard ratio analyses.

Overall, the hiPSI TTNtvs turned up in 1.1 percent of the 1,699 African ancestry individuals diagnosed with atrial fibrillation, but in just 0.4 percent of the unaffected African ancestry participants. Similar patterns turned up in analyses of 1,573 DCM and 3,179 heart failure cases in the African ancestry-focused analyses.

Such findings prompted the investigators to take a closer look at the specific domains of the TTN gene that contained hiPSI TTNtv alterations. They also compared hiPSI TTNtv and related heart disease patterns in 105,904 European ancestry participants in the All of Us Research Program, where atrial fibrillation, DCM, and heart failure risk was again elevated in the hiPSI TTNtv carriers.

Given these findings, the authors suggested that "genetic testing of hiPSI TTNtvs may permit early identification of carriers and support preventive measures to reduce the likelihood of heart failure development both in individuals of European ancestry and in individuals of African ancestry."

"The risks for the development of atrial fibrillation, DCM, and heart failure conferred by hiPSI TTNtvs were similar across ancestry groups," they explained. "Future research should focus on assessing the contribution of environmental factors in the development of DCM in carriers of hiPSI TTNtvs."