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Common variants in HSPB7 and FRMD4B associated with advanced heart failure.
MedLine Citation:
PMID:  20124441     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Heart failure results from abnormalities in multiple biological processes that contribute to cardiac dysfunction. We tested the hypothesis that inherited variation in genes of known importance to cardiovascular biology would thus contribute to heart failure risk.
METHODS AND RESULTS: We used the ITMAT/Broad/CARe cardiovascular single-nucleotide polymorphism array to screen referral populations of patients with advanced heart failure for variants in approximately 2000 genes of predicted importance to cardiovascular biology. Our design was a 2-stage case-control study. In stage 1, genotypes in Caucasian patients with heart failure (n=1590; ejection fraction, 32+/-16%) were compared with those in unaffected controls (n=577; ejection fraction, 67+/-8%) who were recruited from the same referral centers. Associations were tested for independent replication in stage 2 (308 cases and 2314 controls). Two intronic single-nucleotide polymorphisms showed replicated associations with all-cause heart failure as follows: rs1739843 in HSPB7 (combined P=3.09x10(-6)) and rs6787362 in FRMD4B (P=6.09x10(-6)). For both single-nucleotide polymorphisms, the minor allele was protective. In subgroup analyses, rs1739843 associated with both ischemic and nonischemic heart failure, whereas rs6787362 associated principally with ischemic heart failure. Linkage disequilibrium surrounding rs1739843 suggested that the causal variant resides in a region containing HSPB7 and a neighboring gene, CLCNKA, whereas the causal variant near rs6787362 is probably within FRMD4B. Allele frequencies for these single-nucleotide polymorphisms were substantially different in African Americans (635 cases and 714 controls) and showed no association with heart failure in this population.
CONCLUSIONS: Our findings identify regions containing HSPB7 and FRMD4B as novel susceptibility loci for advanced heart failure. More broadly, in an era of genome-wide association studies, we demonstrate how knowledge of candidate genes can be leveraged as a complementary strategy to discern the genetics of complex disorders.
Thomas P Cappola; Mingyao Li; Jing He; Bonnie Ky; Joan Gilmore; Liming Qu; Brendan Keating; Muredach Reilly; Cecelia E Kim; Joseph Glessner; Edward Frackelton; Hakon Hakonarson; Faisel Syed; Anna Hindes; Scot J Matkovich; Sharon Cresci; Gerald W Dorn
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-02-02
Journal Detail:
Title:  Circulation. Cardiovascular genetics     Volume:  3     ISSN:  1942-3268     ISO Abbreviation:  Circ Cardiovasc Genet     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-21     Completed Date:  2010-07-27     Revised Date:  2013-06-13    
Medline Journal Info:
Nlm Unique ID:  101489144     Medline TA:  Circ Cardiovasc Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  147-54     Citation Subset:  IM    
Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, USA.
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MeSH Terms
Adaptor Proteins, Signal Transducing / genetics*
Case-Control Studies
European Continental Ancestry Group / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
HSP27 Heat-Shock Proteins / genetics*
Heart Failure / genetics*
Middle Aged
Polymorphism, Single Nucleotide
Grant Support
P50 HL077101/HL/NHLBI NIH HHS; P50 HL077113/HL/NHLBI NIH HHS; R01 HL059888-01A1/HL/NHLBI NIH HHS; R01 HL059888-02/HL/NHLBI NIH HHS; R01 HL059888-03/HL/NHLBI NIH HHS; R01 HL059888-04/HL/NHLBI NIH HHS; R01 HL059888-05/HL/NHLBI NIH HHS; R01 HL059888-06/HL/NHLBI NIH HHS; R01 HL059888-07/HL/NHLBI NIH HHS; R01 HL059888-08/HL/NHLBI NIH HHS; R01 HL059888-09A1/HL/NHLBI NIH HHS; R01 HL059888-09A1W1/HL/NHLBI NIH HHS; R01 HL059888-10/HL/NHLBI NIH HHS; R01 HL059888-11/HL/NHLBI NIH HHS; R01 HL059888-12/HL/NHLBI NIH HHS; R01 HL080008-01A1/HL/NHLBI NIH HHS; R01 HL080008-02/HL/NHLBI NIH HHS; R01 HL080008-03/HL/NHLBI NIH HHS; R01 HL080008-04/HL/NHLBI NIH HHS; R01 HL080008-05/HL/NHLBI NIH HHS; R01 HL080008-06/HL/NHLBI NIH HHS; R01 HL087871/HL/NHLBI NIH HHS; R01 HL087871-01/HL/NHLBI NIH HHS; R01 HL087871-02/HL/NHLBI NIH HHS; R01 HL087871-03/HL/NHLBI NIH HHS; R01 HL087871-04/HL/NHLBI NIH HHS; R01 HL087871-05/HL/NHLBI NIH HHS; R01 HL087871-06/HL/NHLBI NIH HHS; R01 HL088577/HL/NHLBI NIH HHS; R01 HL088577/HL/NHLBI NIH HHS; R21 HL092379/HL/NHLBI NIH HHS; RC2 HL102222/HL/NHLBI NIH HHS; RC2 HL102222-01/HL/NHLBI NIH HHS; RC2 HL102222-02/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/FRMD4B protein, human; 0/HSP27 Heat-Shock Proteins; 0/HSPB7 protein, human

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