Clinical and Genetic Modifiers of Long-Term Survival in Heart Failure

Cresci, Sharon; Kelly, Reagan; Cappola, Thomas P.; Diwan, Abhinav; Dries, Daniel L.; Kardia, Sharon L.R.; Dorn, Gerald W.

doi:10.1016/j.jacc.2009.05.009

Cited by 108 publications

(106 citation statements)

References 53 publications

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“…Because the HSPB7 heart failure-associated SNPs do not alter protein coding or cardiac gene expression, we hypothesized that the HSPB7 risk variants marked heart failure risk alleles within the broader genetic region. Accordingly, we resequenced all 19 coding exons and intron-exon boundaries of the adjacent CLCNKA gene in 1,742 DNA samples from the Cincinnati Heart Failure Study (18,19). (Detailed clinical characteristics of the study populations are in Table S1.)…”

Section: Resultsmentioning

confidence: 99%

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Cappola

Matkovich

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Common heart failure has a strong undefined heritable component. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of the HSPB7 gene as being associated with heart failure. HSPB7 resequencing identified other risk alleles but no functional gene variants. Here, we further show no effect of the HSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, suggesting that the SNP marks the position of a functional variant in another gene. Accordingly, we used massively parallel platforms to resequence all coding exons of the adjacent CLCNKA gene, which encodes the K a renal chloride channel (ClC-K a ). Of 51 exonic CLCNKA variants identified, one SNP (rs10927887, encoding Arg83Gly) was common, in linkage disequilibrium with the heart failure risk SNP in HSPB7, and associated with heart failure in two independent Caucasian referral populations (n = 2,606 and 1,168; combined P = 2.25 × 10 −6). Individual genotyping of rs10927887 in the two study populations and a third independent heart failure cohort (combined n = 5,489) revealed an additive allele effect on heart failure risk that is independent of age, sex, and prior hypertension (odds ratio = 1.27 per allele copy; P = 8.3 × 10 −7). Functional characterization of recombinant wild-type Arg83 and variant Gly83 ClC-K a chloride channel currents revealed ≈50% loss-of-function of the variant channel. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. The variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardiorenal axis.cardiomyopathy | genetic association

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Section: Resultsmentioning

confidence: 99%

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Cappola

Matkovich

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…To catalog nucleotide variations within the 4 target gene exons, we amplified and resequenced 5 loci covering 9.4 kb of nonamplified genomic DNA archived from 2,606 individuals -1,742 Caucasians and 864 African Americans -who had participated in a longitudinal study of systolic heart failure (20). The coding regions for ADRA1A, ARDB2, HSPB7, and PLN were comprehensively examined ( Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease

Matkovich¹,

Booven²,

Hindes³

et al. 2010

J. Clin. Invest.

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Sporadic heart failure is thought to have a genetic component, but the contributing genetic events are poorly defined. Here, we used ultra-high-throughput resequencing of pooled DNAs to identify SNPs in 4 biologically relevant cardiac signaling genes, and then examined the association between allelic variants and incidence of sporadic heart failure in 2 large Caucasian populations. Resequencing of DNA pools, each containing DNA from approximately 100 individuals, was rapid, accurate, and highly sensitive for identifying common and rare SNPs; it also had striking advantages in time and cost efficiencies over individual resequencing using conventional Sanger methods. In 2,606 individuals examined, we identified a total of 129 separate SNPs in the 4 cardiac signaling genes, including 23 nonsynonymous SNPs that we believe to be novel. Comparison of allele frequencies between 625 Caucasian nonaffected controls and 1,117 Caucasian individuals with systolic heart failure revealed 12 SNPs in the cardiovascular heat shock protein gene HSPB7 with greater proportional representation in the systolic heart failure group; all 12 SNPs were confirmed in an independent replication study. These SNPs were found to be in tight linkage disequilibrium, likely reflecting a single genetic event, but none altered amino acid sequence. These results establish the power and applicability of pooled resequencing for comparative SNP association analysis of target subgenomes in large populations and identify an association between multiple HSPB7 polymorphisms and heart failure.

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“…It was shown that patients receiving beta-blockers with the Gln41Gln genotype but Leu41 carriers exhibited improvement in survival compared to Glu41 carriers (79). The other larger study did not confirm this (80).…”

Section: Beta-blockersmentioning

confidence: 86%

The Pharmacogenetics of Cardiovascular Drugs / FARMAKOGENETIKA KARDIOVASKULARNIH LEKOVA

Stanković¹,

Ašanin²,

Majkić-Singh³

2014

Journal of Medical Biochemistry

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Summary This article will primarily summarize the current knowledge of the pharmacogenetics of commonly used drugs for the cardiovascular system: oral anticoagulants, antiplatelet therapy and statins. Coumarin anticoagulants are widely used to treat and prevent thromboembolisms. Variations in the CYP2C9 and VKORC1 genes influence the pharmacodynamic response to coumarins. Genetic variation makes an important contribution to the variation in the response to clopidogrel, the most commonly prescribed antiplatelet treatment. Genetic polymorphisms in the CYP2C19 gene as in the paraoxonase 1 gene are associated with clopidogrel effectiveness and have shown an association with excess of ischemic events such as myocardial infarction and stent thrombosis, but also with serious threat of bleeding. Statin pharmacogenetics has the potential to improve the safety and effectiveness of lipid-lowering therapy by statins. Genetic variations in apolipoprotein E, cholesterol ester transfer protein, kinesin-like protein 6, statin transporter OATP1B1 etc. could partly explain the interindividual variation in statins therapeutic response and adverse reactions. Finally, we comment on the pharmacogenetics of other cardiovascular drugs that have been extensively studied, but for which data are conflicting or that have not yet seen clinical implementation. Based on the available data, it could be expected that in the future genome-tailored drug prescription and use of defined algorithms will contribute to the successful drug action, lowering the frequency of adverse events, and will have greater clinical relevance.

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Clinical and Genetic Modifiers of Long-Term Survival in Heart Failure

Cited by 108 publications

References 53 publications

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease

The Pharmacogenetics of Cardiovascular Drugs / FARMAKOGENETIKA KARDIOVASKULARNIH LEKOVA

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