TY - JOUR
T1 - Hypertrophy-associated polymorphisms ascertained in a founder cohort applied to heart failure risk and mortality
AU - Parsa, Afshin
AU - Chang, Yen Pei C.
AU - Kelly, Reagan J.
AU - Corretti, Mary C.
AU - Ryan, Kathleen A.
AU - Robinson, Shawn W.
AU - Gottlieb, Stephen S.
AU - Kardia, Sharon L.R.
AU - Shuldiner, Alan R.
AU - Liggett, Stephen B.
PY - 2011/2
Y1 - 2011/2
N2 - 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.
AB - 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.
KW - Genetics
KW - Heart failure
KW - Hypertrophy
KW - Mortality
KW - Signal transduction
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U2 - 10.1111/j.1752-8062.2010.00251.x
DO - 10.1111/j.1752-8062.2010.00251.x
M3 - Article
C2 - 21348951
AN - SCOPUS:79951887844
SN - 1752-8054
VL - 4
SP - 17
EP - 23
JO - Clinical and translational science
JF - Clinical and translational science
IS - 1
ER -