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Titin variants may affect LVEF despite cardiomyopathy status
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Patients of European ancestry with proportion spliced in truncating variants in the titin, or TTN, gene had an abnormal phenotype exemplified by lower left ventricular ejection fraction regardless of their cardiomyopathy status, according to a study published in Circulation.
“This gene, we know, is found to be mutated in about 10% to 20% of people who have dilated cardiomyopathy,” Zoltan P. Arany, MD, PhD, director of the cardiovascular metabolism program and professor of medicine at University of Pennsylvania Perelman School of Medicine, told Cardiology Today. “We were interested in understanding a little bit more about that and asking questions about what it means to have that mutation or not have that mutation.”
Bio Bank data
Christopher M. Haggerty, PhD, co-director of the cardiac imaging technology laboratory and assistant professor in the department of imaging science and innovation at Geisinger in Danville, Pennsylvania, and colleagues analyzed whole-exome sequence data from 61,040 samples from the Geisinger MyCode Community Health Initiative and 10,289 samples from the Penn Medicine BioBank. Researchers also analyzed patients with truncating variants in the Titin gene in exons that were highly expressed in the heart, in addition to patients from the Jackson Heart Study.
Truncating variants in the TTN gene in a highly expressed exon were seen in 1.2% of patients from the Penn Medicine BioBank and 0.6% of those from the Geisinger MyCode Community Health Initiative.
“We find that having mutations in titin is rare, but it’s not that rare,” Arany told Cardiology Today.
Patients with European ancestry with truncating variants in the TTN gene in a highly expressed exon were more likely to have dilated cardiomyopathy, as shown in the Penn Medicine (OR = 18.7; 95% CI, 9.1-39.4) and the Geisinger groups (OR = 10.8; 95% CI, 7-16). This was not seen in patients of African ancestry, although they had a high prevalence of dilated cardiomyopathy (OR = 1.8; 95% CI, 0.2-13.7).
Among the 244 patients of European ancestry with dilated cardiomyopathy from the Penn Medicine group, those who were carriers of truncating variants in the TTN gene in a highly expressed exon had an increased LV diameter (beta = 0.65 cm; P = 9 x 10-3) and a lower LVEF (beta = –12%; P = 3 x 10-7). Patients in the Geisinger group with truncating variants in the TTN gene in a highly expressed exon without cardiomyopathy had lower LVEF (beta = –3.4%; P = 1 x 10-7), more HF (OR = 3.8; 95% CI, 2.4-6) and more atrial fibrillation (OR = 2.4; 95% CI, 1.6-3.6).
Future research
“Having such a mutation, even though it increases your odds of getting cardiomyopathy by 20- or 30-fold, it doesn’t write it in stone that you’re going to have cardiomyopathy,” Arany said in an interview. “There’s something else going on in the people who do, and we don’t know what that something else is, so that’s fodder for future studies.” – by Darlene Dobkowski
For more information:
Zoltan P. Arany, MD, PhD, can be reached at 3400 Civic Blvd., Philadelphia, PA 19104; email: zarany@pennmedicine.upenn.edu.
Disclosures: Haggerty and Arany report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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