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(Hypertension. 2007;50:1120.)
© 2007 American Heart Association, Inc.

Original Articles

Effect of Endothelin 1 Genotype on Blood Pressure Is Dependent on Physical Activity or Fitness Levels

Tuomo Rankinen; Timothy Church; Treva Rice; Nathan Markward; Arthur S. Leon; Dabeeru C. Rao; James S. Skinner; Steven N. Blair; Claude Bouchard

From the Human Genomics Laboratory (T.Rankinen, N.M., C.B.) and Preventive Medicine Laboratory (T.C.), Pennington Biomedical Research Center, Baton Rouge, La; Division of Biostatistics (T.Rice, D.C.R.) and Departments of Genetics and Psychiatry (D.C.R.), Washington University School of Medicine, St Louis, Mo; Laboratory of Physiological Hygiene and Exercise Science (A.S.L.), School of Kinesiology, University of Minnesota, Minneapolis; Department of Kinesiology (J.S.S.), Indiana University, Bloomington; Department of Exercise Science (S.N.B.), Arnold School of Public Health, University of South Carolina, Columbia.

Correspondence to Tuomo Rankinen, Human Genomics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA 70808. E-mail rankint{at}pbrc.edu

Contributions of the DNA sequence variation at the endothelin 1 locus to the risk of hypertension and to endurance training–induced changes in blood pressure were investigated in the Aerobics Center Longitudinal Study and the Health, Risk Factors, Exercise Training and Genetics Family Study cohorts. We identified 586 normotensive control subjects and 607 incident hypertensive case subjects from the Aerobics Center Longitudinal Study cohort (all whites) who were normotensive and healthy at their first clinic visit. The case subjects were diagnosed with hypertension during an average follow-up of 9.5 years, whereas the control subjects remained normotensive. The allele and genotype frequencies of 5 endothelin 1 haplotype tagging single nucleotide polymorphisms did not differ significantly between the case and control subjects. However, we observed a significant (P=0.0025) interaction between the endothelin 1 rs5370 (G/T; Lys198Asn) genotype and cardiorespiratory fitness level on the risk of hypertension: among low-fit subjects, the rs5370 minor allele (T; 198Asn) was associated with higher risk of hypertension (odds ratio: 1.95; 95% CI: 1.36 to 2.81; P=0.0003), whereas the risk did not differ among genotypes in high-fit subjects. In the white Health, Risk Factors, Exercise Training and Genetics subjects (N=480), the rs5370 T allele was associated with blunted systolic blood pressure (P=0.0046) and pulse pressure (P=0.0016) responses to a 20-week endurance training program. The Lys198Asn variant of the endothelin 1 locus is associated with blood pressure phenotypes in whites. However, the expression of the genotype effect is modulated by physical activity or cardiorespiratory fitness level. Our study provides an illustrative example of how physical activity and fitness level modifies the associations between a candidate gene and outcome phenotype.

Key Words: genotype • exercise training • cardiorespiratory fitness • gene-environment interaction • HERITAGE Family Study • HYPGENE Study