An extensive search for linkage between DNA markers and the response of VO2max to training has recently been launched in the HERITAGE Family Study. This is the first report on a genome-wide search strategy to locate chromosomal regions and positional candidate genes for cardiorespiratory endurance phenotypes. Linkage between seven markers spanning chromosome 22 spaced approximately 10 cM apart (D22S264, D22S274, D22S301, D22S304, D22S421, IL2RB, and PDGFB) and VO2max at baseline, as well as its response to endurance exercise training, was examined using the sib-pair linkage method. Markers were genotyped in at least 210 sib-pairs derived from 128 adult brothers (25 +/- 6 yr; mean +/- SD) and 138 sisters (24 +/- 6 yr) from 86 Caucasian families. VO2max, maximal heart rate, and maximal oxygen pulse were measured during stationary cycle tests before and after a standardized 20-wk endurance training program. On average, the initial VO2max was 2654 +/- 767 mL.min-1 while training increased VO2max significantly by 430 +/- 239 mL.min-1 or 16% (P < 0.0001). The VO2max response was adjusted for age and initial VO2max. No evidence of linkage was found between any of these markers on chromosome 22 and VO2max or its trainability.