Titin is a candidate gene for stroke volume response to endurance training: the HERITAGE Family Study

A genome-wide linkage scan for endurance training-induced changes in submaximal exercise stroke volume (ΔSV50) in the HERITAGE Family Study revealed two chromosomal regions (2q31–q32 and 10p11.2) with at least suggestive evidence of linkage among white families. Here we report a further characterization of the quantitative trait locus (QTL) in chromosome 2q31 and provide evidence that titin ( TTN) is likely a candidate gene involved. The original linkage was detected with two markers ( D2S335 and D2S1391), and the QTL covered ∼25 million base pairs (Mb). We added 12 microsatellite markers resulting in an average marker density of one marker per 2.3 Mb. The evidence of linkage increased from P = 0.006 to P = 0.0002 and 0.00002 in the multi- and single-point analyses, respectively. The strongest evidence of linkage was seen with two markers in and near the TTN gene. Transmission/disequilibrium test (TDT) with the same marker set provided evidence for association with one of the TTN markers ( D2S385; P = 0.004). TTN is a major contributor to the elasticity of cardiomyocytes and a key regulator of the Frank-Starling mechanism. Since TTN is the largest gene in the human genome, the challenge is to identify the DNA sequence variants contributing to the interindividual differences in cardiac adaptation to endurance training.