title: CREB1 is a strong genetic predictor of the variation in exercise heart rate response to regular exercise: the HERITAGE Family Study.
abstract: BACKGROUND
  A genome-wide linkage scan identified a quantitative trait locus for exercise training-induced changes in submaximal exercise (50 W) heart rate (DeltaHR50) on chromosome 2q33.3-q34 in the HERITAGE Family Study (n=472).
  
  
  RESULTS
  To fine-map the region, 1450 tag SNPs were genotyped between 205 and 215 Mb on chromosome 2. The strongest evidence of association with DeltaHR50 was observed with 2 single-nucleotide polymorphisms (SNPs) located in the 5' region of the cAMP-responsive element-binding protein 1 (CREB1) gene (rs2253206: P=1.6x10(-5) and rs2360969: P=4.3x10(-5)). The associations remained significant (P=0.01 and P=0.023, respectively) after accounting for multiple testing. Regression modeling of the 39 most significant SNPs in the single-SNP analysis identified 9 SNPs that collectively explained 20% of the DeltaHR50 variance. CREB1 SNP rs2253206 had the strongest effect (5.45% of variance), followed by SNPs in the FASTKD2 (3.1%), MAP2 (2.6%), SPAG16 (2.1%), ERBB4 (3 SNPs approximately 1.4% each), IKZF2 (1.4%), and PARD3B (1.0%) loci. In conditional linkage analysis, 6 SNPs from the final regression model (CREB1, FASTKD2, MAP2, ERBB4, IKZF2, and PARD3B) accounted for the original linkage signal: The log of the odds score dropped from 2.10 to 0.41 after adjusting for all 6 SNPs. Functional studies revealed that the common allele of rs2253206 exhibits significantly (P<0.05) lower promoter activity than the minor allele.
  
  
  CONCLUSIONS
  Our data suggest that functional DNA sequence variation in the CREB1 locus is strongly associated with DeltaHR50 and explains a considerable proportion of the quantitative trait locus variance. However, at least 5 additional SNPs seem to be required to fully account for the original linkage signal.
authors.affiliation: Human Genomics Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808-4124, USA. rankint@pbrc.edu
authors.forename: Tuomo
authors.initials: T
authors.lastname: Rankinen
authors.forename: George
authors.initials: G
authors.lastname: Argyropoulos
authors.forename: Treva
authors.initials: T
authors.lastname: Rice
authors.forename: D C
authors.initials: DC
authors.lastname: Rao
authors.forename: Claude
authors.initials: C
authors.lastname: Bouchard
mesh_terms: D000483:Alleles; D002889:Chromosomes, Human, Pair 2; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D015444:Exercise; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012044:Regression Analysis
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein
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