Hypertrophy-Associated Polymorphisms Ascertained in a Founder Cohort Applied to Heart Failure Risk and Mortality

• Published in: Clinical and translational science 2011-02, Vol.4 (1), p.17-23
• Main Authors: Parsa, Afshin, Chang, Yen-Pei C., Kelly, Reagan J., Corretti, Mary C., Ryan, Kathleen A., Robinson, Shawn W., Gottlieb, Stephen S., Kardia, Sharon L.R., Shuldiner, Alan R., Liggett, Stephen B.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Base Sequence; Cardiomegaly - complications; Cardiomegaly - diagnostic imaging; Cardiomegaly - genetics; Cohort Studies; Demography; Ethnic Groups - genetics; Female; Founder Effect; Genetic Predisposition to Disease; genetics; heart failure; Heart Failure - complications; Heart Failure - diagnostic imaging; Heart Failure - genetics; Heart Failure - mortality; Heart Ventricles - pathology; Humans; hypertrophy; Male; Middle Aged; mortality; Organ Size; Polymorphism, Single Nucleotide - drug effects; Polymorphism, Single Nucleotide - genetics; Risk Factors; Sequence Homology, Nucleic Acid; Short Interspersed Nucleotide Elements - genetics; signal transduction; Ultrasonography; Young Adult
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/j.1752-8062.2010.00251.x

A three‐stage approach was undertaken using genome‐wide, case‐control, and case‐only association studies to identify genetic variants associated with heart failure mortality. In an Amish founder population (n = 851), cardiac hypertrophy, a trait integral to the adaptive response to failure, was found to be heritable (h2= 0.28, p = 0.0002) and GWAS revealed 21 candidate hypertrophy SNPs. In a case (n = 1,610)‐control (n = 463) study in unrelated Caucasians, one of the SNPs associated with hypertrophy (rs2207418, p = 8 × 10−6), was associated with heart failure, RR = 1.85(1.25–2.73, p = 0.0019). In heart failure cases rs2207418 was associated with increased mortality, HR = 1.51(1.20–1.97, p = 0.0004). There was consistency between studies, with the GG allele being associated with increased ventricular mass (˜13 g/m2) in the Amish, heart failure risk, and heart failure mortality. This SNP is in a gene desert of chromosome 20p12. Five genes are within 2.0 mbp of rs2207418 but with low LD between their SNPs and rs2207418. A region near this SNP is highly conserved in multiple vertebrates (lod score = 1,208). This conservation and the internal consistency across studies suggests that this region has biologic importance in heart failure, potentially acting as an enhancer or repressor element. rs2207418 may be useful for predicting a more progressive form of heart failure that may require aggressive therapy. Clin Trans Sci 2011; Volume 4: 17–23