The genetics of cardiac failure: Role of a G protein-coupled receptor polymorphism in therapeutic response in an Indian population

BACKGROUND AND AIM: The incidence of heart failure (HF) is rising to epidemic proportions in developing countries like India. A lack of adequate Indian studies underscores the importance of pursuing research into HF in an Indian population. G protein-coupled receptor kinase 5 (GRK5) Gln41>Leu (rs2230345) polymorphism was reported as a genetic modifier associated with survival in HF patients. A prospective study was conducted to investigate the association of GRK5 Gln41>Leu polymorphism with response to β-blocker therapy in Indian HF patients. METHODS: HF patients (n=584) were recruited for the study. The patients were genotyped by tetra-primer based allele specific polymerase chain reaction and confirmed with Sanger sequencing. The HF patients were evaluated for GRK5 gene expression and followed up for ~3 years. Drug dosages, cardiac output and hospitalization-free survival were evaluated as study outcomes. HF subgroups (i.e. systolic or diastolic dysfunction, biventricular dysfunction and pulmonary artery hypertension) were also analyzed in association with hospital-free survival. RESULTS: HF patients showed genotype frequencies of AT (15%) and TT (1%). AT/TT genotype carriers showed downregulated GRK5 gene expression and significant reduction in carvedilol drug dosage (p=0.0001). Moreover, AT/TT genotype carriers on β-blockers showed improved ejection fraction from 27% to 36% (p=0.0007) and increased hospitalization-free survival in comparison to other HF patients. HF patients with AA genotype showed an increased rate of hospital admission in comparison with patients with the AT/TT genotype. HF subgroups with the AT/TT genotype showed an increased hospitalization-free survival versus subgroups with the AA genotype. CONCLUSIONS: GRK5 Gln41>Leu polymorphism in response to β-blocker therapy improved cardiac function in HF patients. RELEVANCE FOR PATIENTS: This study presents a comprehensive clinicofunctional pharmacogenetic characterization of GRK5 Gln41>Leu polymorphism in a cohort of Indian HF patients. GRK5 Gln41>Leu polymorphism can confer improved cardiac function and reduce hospitalization, thus improving the quality of life in HF patients.