Association Between TTN Gene Variants and Circulating Cardiac Biomarkers in Iraqi Patients with Congestive Heart Failure

Abstract

Background: Titin(TTN) is the most significant sarcomeric protein and the most commonly identified gene involved in inherited dilated cardiomyopathy. There is, however, a lack of studies aimed at uncovering the relationship between different localized TTN mutations and circulating pro-inflammatory cardiac biomarkers in Middle-Eastern cohorts. Hence, this study proposes to assess the changes in cardiac biomarkers in association with genetic mutations in the TTN gene among Iraqi patients with heart failure.

Methods: This hospital-based case-control study included 70 patients with CHF and 30 age- and sex-matched healthy controls. Serum concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), high-sensitivity cardiac troponin I (hs-cTnI), endothelin-1 (ET-1), interleukin-6 (IL-6), and insulin were measured. Genomic DNA was extracted, the TTN gene was amplified by polymerase chain reaction, and selected amplicons underwent Sanger sequencing for variant identification.

Results: Patients with CHF demonstrated significantly higher CRP concentrations, whereas NT-proBNP, hs-cTnI, and insulin levels were significantly lower than those of healthy controls (P<0.05). No significant differences were observed for ET-1 or IL-6. Sanger sequencing identified four TTN variants, including two recurrent likely pathogenic variants (A70V and G77*) detected in 70% of sequenced samples. Carriers of likely pathogenic TTN variants exhibited significantly higher CRP and significantly lower hs-cTnI and insulin concentrations than variant-negative patients, while NT-proBNP, ET-1, and IL-6 showed no significant associations.

Conclusions: TTN gene variants were associated with distinct inflammatory and metabolic biomarker profiles in Iraqi patients with CHF. Integrating molecular genetic analysis with circulating biomarkers may improve genotype–phenotype characterization and support future personalized risk stratification in congestive heart failure