CREB1 is a strong genetic predictor of the variation in exercise heart rate response to regular exercise: The HERITAGE Family Study

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 2_q33.3 _-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.