TITIN IS A CANDIDATE GENE FOR STROKE VOLUME RESPONSE TO ENDURANCE TRAINING

PURPOSE A quantitative trait locus (QTL) for endurance training —induced change in submaximal exercise stroke volume was identified on chromosome 2q31.1 in a genome-wide linkage scan performed in the HERITAGE Family Study. Here we report a further characterization of the QTL and provide evidence that titin is most likely the candidate gene involved. METHODS The original QTL covered approximately 25 million base pairs (Mb) and the linkage was detected with two markers (D2S335 and D2S1391). We added 12 microsatellite markers in the region resulting in an average marker density of one marker per 2.3 Mb. RESULTS The evidence of linkage increased from p = 0.006 in the original scan to p = 0.0002 and 0.00001 in the multi- and singlepoint analyses, respectively. The strongest evidence of linkage was seen with two markers in and near the titin gene. Transmission/disequilibrium test with the same marker set provided evidence for association only with one of the titin markers (D2S385; p = 0.004). CONCLUSION Titin is a major contributor to the elasticity of cardiomyocytes and a key regulator of the Frank-Starling mechanism. The gene encoding titin is the largest in the human genome (363 exons, about 300 kb). The challenge is to identify the DNA sequence variants contributing to the interindividual differences in cardiac adaptation to endurance training.