In a large cohort of middle-aged subjects, an interaction effect between objectively measured physical activity level and β2- adrenergic receptor gene Gly16Arg polymorphism on plasma nonesterified fatty acids (NEFA) was reported (65). Suppression of plasma NEFA levels was found in Arg16Arg subjects with increasing physical activity level. Similar results were reported from a small, uncontrolled study with female subjects (61), in which submaximal physical exercise resulted in a blunted response in lipolysis and fat oxidation acutely in subjects homozygous for the Glu27 allele.
One study was reported on the modifying response of beta fibrinogen genotype to acute heavy physical exercise (13). This study was undertaken in young army recruits after an exercise-training program for 11 wk. Carriers of the A allele of the −455 G>A polymorphism were found to display higher plasma fibrinogen levels postexercise compared with GG homozygote subjects. However, no differences in plasma fibrinogen between genotypes were found according to the −854 G>A polymorphism.
During the year 2002, two studies reported mutations in nuclear genes, and four studies found mutations in mitochondrial genes associated with exercise intolerance (Table 12). Two mutations in the alpha-sarcoglycan gene were found in a young male patient who had developed progressive muscle weakness and exercise intolerance since his early teens (66). The patient was a compound heterozygote for the Glu137Lys and Arg284Cys mutations. Vladutiu and coworkers (129) reported a detailed genetic, metabolic, and neuromuscular study of a family with carnitine palmitoyltransferase II (CPT2) deficiency. Two of the four daughters manifested exercise intolerance, whereas the remaining two daughters and parents did not. Genetic analyses showed that the daughters with exercise intolerance were compound heterozygotes for two disease-causing mutations in the CPT2 gene (S113 L and Q413fs). Other family members were heterozygous for only one of the two mutations (129).
This review constitutes the 2002 update of the human gene map for physical performance and health-related phenotypes and is based on scientific papers published by the end of 2002. Association studies with candidate genes, genome-wide scans with polymorphic markers, and single gene defects causing exercise intolerance to variable degrees are included. The genes and markers with evidence of association or linkage with a performance or fitness phenotype in sedentary or active people, in adaptation to acute exercise or for training-induced changes are positioned on the genetic map of all autosomes and the X chromosome. By the end of 2000, 29 gene entries and QTL were depicted on the map. The 2001 map included 71 entries on the autosomes and two on the X chromosome. Among these genes, 24 were from prior publications on exercise intolerance and four related to other pathologies. In addition, variants in 13 mitochondrial genes were shown to influence relevant fitness and performance phenotypes. By the end of December 2002, the gene map contains 90 gene entries and QTL on the autosomes, two on the X chromosome, plus 14 mitochondrial genes.
An encouraging trend is that of using well-defined samples of patients (e.g., heart failure, COPD, etc.) and controls to define the role of candidate genes and mutations in health-related fitness and performance phenotypes. Although such studies represent major challenges primarily because of sample size and disease heterogeneity issues, they can contribute significantly to our understanding of the role of genetic variation in the predisposition to specific diseases and in the acute response to exercise or the adaptation to exercise training.
Appropriately designed expression studies are needed to generate new and better-justified candidate genes. Genome-wide scans based on large numbers of polymorphic markers followed by extensive positional cloning efforts are needed to evidence new candidate genes. These explorations of the genome should be undertaken not only on cohorts of human families but also with informative rodent crosses. Transgenic mice overexpressing a targeted gene in relevant tissues are needed to refine our understanding of the role of potential candidate genes. Similarly, engineered mice in which specific genes have been knocked out would be useful for the definition of their roles on fitness and performance phenotypes. Candidate gene studies need to move to a higher level of sophistication not only in terms of study design and appropriate sample sizes but also by more detailed exploration of DNA variation in exons, splicing sequences, and promoter regions. Whether we recognize it or not, overall progress in exercise science and sports medicine will be closely related to our understanding of the genetic and molecular basis of fitness and performance phenotypes and their responses to long-term exposure to exercise. These yearly updates of the fitness and performance human gene map reveal that advances in the field are currently registered at a very modest pace.
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