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Physiol. Genomics (July 15, 2003). doi:10.1152/physiolgenomics.00147.2002
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Submitted on November 1, 2002
Accepted on July 13, 2003

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

Tuomo Rankinen1*, Treva Rice2, Anik Boudreau1, Arthur S Leon3, James S Skinner4, Jack H Wilmore5, D C Rao6, and Claude Bouchard1

1 Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
2 Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
3 School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, MN, USA
4 Department of Kinesiology, Indiana University, Bloomington, IN, USA
5 Department of Health and Kinesiology, Texas A & M University, College Station, TX, USA
6 Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA; Departments of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

* To whom correspondence should be addressed. E-mail: rankint{at}pbrc.edu.

A genome-wide linkage scan for endurance training-induced changes in submaximal exercise stroke volume ({Delta}SV50) 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 approximately 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 singlepoint analyses, respectively. The strongest evidence of linkage was seen with two markers in and near the TTN gene. Transmission/disequilibrium (TDT) test 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.




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