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

Abstract

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.

Mapping Genetic Contributions to Cardiac Pathology Induced by Beta-Adrenergic Stimulation in Mice

“…We explored whether the loci we identified overlap with human GWAS results by examining the top twelve previously identified significant and suggestive human loci 6,7,37 . The human loci were mapped onto the mouse genome using the NCBI Homologene resource and compared to a set of loci identified for the weight traits based on a slightly relaxed stringency (P<1E-05, MAF>5%) from the HMDP study.…”

“…Only two heart-failure related loci 5 have reached accepted levels of genome-wide significance, despite meta-analyses of tens of thousands of patients 6,7 . The challenge of performing GWAS in human HF is likely due to the very complex nature of the disease, which can arise as a result of multiple underlying etiologies, such as myocardial infarction, hypertension or metabolic disorders, each of which are complex traits with significant environmental confounders 1 .…”

A functional variant in the coding region of CAMTA2 is associated with left ventricular hypertrophy by affecting the activation of Nkx2.5-dependent transcription

“…Cardiac hypertrophy, defined as an increase in the size and/or thickness of the ventricles in the heart, is an important compensatory mechanism for pathophysiological states and an independent predictor of cardiovascular morbidity and mortality [20,21]. Recently, several genomewide association studies (GWASs) for LVH have been reported [22][23][24][25][26][27]; however, the association of rs238234 in CAMTA2 with LVH did not reach genome-wide significance levels. There are some reasons to explain: first, many variants with the biological characteristics are filtered out because GWASs employed the rigorous statistics correction and P value to identify the most statistically significant single-nucleotide polymorphisms between case and control.…”

Characterization of the genetic and environmental factors driving gene expression variability

“…This SNP was in LD with another SNP, also associated with three transcripts, that was located in an intergenic region and was a GWAS hit for cardiac hypertrophy [351]. TRIM10 itself is involved in differentiation of RBCs [363].…”

“…One of these SNPs was a GWAS hit for human immunodeficiency virus (HIV) infection [350], indicating a potential link between erythroid cells and infecting virus. The second SNP was associated with cardiac hypertrophy (Table 4.5) [351].…”