title: Common variants in HSPB7 and FRMD4B associated with advanced heart failure.
abstract: 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.
  
  
  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.
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, USA. thomas.cappola@uphs.upenn.edu
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Bonnie
authors.initials: B
authors.lastname: Ky
authors.forename: Joan
authors.initials: J
authors.lastname: Gilmore
authors.forename: Liming
authors.initials: L
authors.lastname: Qu
authors.forename: Brendan
authors.initials: B
authors.lastname: Keating
authors.forename: Muredach
authors.initials: M
authors.lastname: Reilly
authors.forename: Cecelia E
authors.initials: CE
authors.lastname: Kim
authors.forename: Joseph
authors.initials: J
authors.lastname: Glessner
authors.forename: Edward
authors.initials: E
authors.lastname: Frackelton
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Faisel
authors.initials: F
authors.lastname: Syed
authors.forename: Anna
authors.initials: A
authors.lastname: Hindes
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.forename: Sharon
authors.initials: S
authors.lastname: Cresci
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006333:Heart Failure / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C439674:FRMD4B protein, human; D055551:HSP27 Heat-Shock Proteins; C550985:HSPB7 protein, human