CREB1 Is a Strong Genetic Predictor of the Variation in Exercise Heart Rate Response to Regular Exercise

Background— A genome-wide linkage scan identified a quantitative trait locus for exercise training–induced changes in submaximal exercise (50 W) heart rate (ΔHR50) on chromosome 2q33.3-q34 in the HERITAGE Family Study (n=472). Methods and 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 ΔHR50 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 =1.6×10 −5 and rs2360969: P =4.3×10 −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 ΔHR50 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≈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 ΔHR50 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.