Exercise, genetics, and blood pressure: Focus on "Physical exercise and blood pressure with reference to the angiotensinogen M235T polymorphism" and on "Angiotensinogen M235T polymorphism associates with exercise hemodynamics in postmenopausal women"

Larry A. Sonna1,2, Susan B. Glueck3 and Xavier Jeunemaître4,5

1 United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
2 Brigham and Women’s Hospital, Boston, Massachusetts
3 Deputy Editor, Physiological Genomics, Hôpital Europeen Georges Pompidou AP-HP 75015, France
4 Departement de Genetique, Hôpital Europeen Georges Pompidou AP-HP 75015, France
5 College de France-Institut National de la Santé et de la Recherche Médicale, Paris 75005, France

BLOOD PRESSURE is a complex trait that is influenced by a number of hereditary, environmental, and culturally transmissible factors (3). Genetic factors are estimated to account for ~30% of the variance in blood pressure in adult populations, and it appears likely that this hereditary contribution is polygenic in nature (3, 6, 18). Furthermore, there is evidence that the genetic factors contributing to resting blood pressure also affect blood pressure during exercise (19).

Angiotensinogen (AGT) has attracted attention as a candidate gene contributing to blood pressure. AGT is a pro-hormone produced by the liver (and other tissues) that is converted to angiotensin I by renin. In turn, angiotensin I is converted to its active form, angiotensin II, by angiotensin converting enzyme (ACE). Angiotensin II raises systemic blood pressure by serving both as a vasoconstrictor and a stimulus (both direct and by way of aldosterone) for sodium retention by the kidney. Several studies have implicated angiotensinogen polymorphisms in the genetics of hypertension in adults and include reports of linkage (1, 4, 5, 10) and association (5, 10). By contrast, with the exception of the angiotensin II type 1 receptor gene, for which both association with (2) and linkage to (14) blood pressure have been reported, there is little evidence to suggest an independent role for other components of the renin-angiotensin system in the genetics of human blood pressure (3, 8, 9).

Two papers in this release of Physiological Genomics (Refs. 12 and17; see pages 63 and 71, respectively, in this release) examine the effect of a common polymorphism in the angiotensinogen gene on blood pressure phenotypes. The polymorphism in question (M235T) involves a T-for-C substitution at nucleotide 704, which leads to a methionine-for-threonine substitution at codon 235. This polymorphism is an attractive candidate for study because of its high prevalence [with allele frequencies in the population of 0.4 and 0.6, respectively, for the T and M variants in whites (6)] and because of evidence implicating angiotensinogen in the genetics of hypertension (as noted). Furthermore, it has been reported that presence of the T allele correlates with slightly increased plasma angiotensinogen levels (reviewed in Ref. 6). However, the phenotypic effects of the M235T polymorphism may not be due to the amino acid substitution itself, but rather to a functionally significant A-6G polymorphism in the AGT gene promoter that is in linkage disequilibrium with the M235T polymorphism (reviewed in Ref. 6).

The first study, by McCole and colleagues (12), examines the role of the AGT M235T polymorphism in the cardiovascular responses to exercise, in a cohort of postmenopausal women. Because of the known effect of training on blood pressure, the authors were careful to stratify their analysis by level of habitual activity in this cross-sectional study. Among their findings was a significant effect of AGT genotype on blood pressure during exercise that was dependent on level of habitual activity. In the sedentary women, but not in other subgroups, there was a statistically significant effect of AGT genotype on maximal systolic blood pressure during exercise, with subjects homozygous for the M allele (who would be expected to have the lowest levels of plasma angiotensinogen at baseline) exhibiting significantly lower maximal systolic blood pressures during exercise than subjects who were homozygous for the T allele or who were heterozygous. Importantly, the genotype-specific differences in the blood pressure during exercise in the susceptible group were quite large, with the maximum systolic pressure achieved averaging between 195 and 200 mmHg in the two sedentary women homozygous for the T allele and about 150 mmHg in the six sedentary women homozygous for the M allele. In middle-aged men, cardiovascular mortality risk has been reported to increase with rising systolic blood pressure during exercise (7, 13), even after controlling for habitual activity (7). If a similar epidemiological association exists in postmenopausal women, then differences in exercise systolic pressure of the magnitude reported by McCole et al., if confirmed, may be of clinical importance. However, the results of this study must be interpreted cautiously in light of the relatively small number of subjects (as the authors point out) and the well-known hazards of subgroup analysis. A larger, confirmatory, and longitudinal follow-up study is warranted.

The second study, by Rauramaa et al. (17), examines the effect of exercise and AGT genotype on age-related gains in resting blood pressure in a cohort of middle-aged men in Finland. Subjects were randomized to no intervention or an exercise program of moderate intensity (resulting in an estimated energy expenditure of 1,300 kcal/wk, the equivalent of a 70-kg man walking a total of 3.7 h/wk at a 15 min/mile pace). The authors achieved excellent compliance with the study program and were able to obtain follow-up data on 120 of their 140 randomized subjects over a 6-yr period. Their results revealed a significant interaction between physical activity and AGT genotype. Specifically, subjects homozygous for the M allele who engaged in exercise did not demonstrate the age-related gains in resting systolic blood pressure that occurred in individuals of other AGT genotypes (heterozygotes and individuals homozygous for the T allele) who exercised and in individuals of the same AGT genotype (homozygous for the M allele) who belonged to the control (no intervention) group. Furthermore, subjects homozygous for the M allele who exercised experienced a decrease in resting diastolic blood pressure over time, whereas subjects homozygous for this allele in the control group exhibited a gain in resting diastolic blood pressure (a difference that was statistically significant). By contrast, among heterozygous subjects and those homozygous for the T allele, there were no significant differences in the changes in resting diastolic blood pressure over time between individuals who exercised and those in the control group. The observation that AGT genotype influences the effect of aerobic training on longitudinal changes in resting blood pressure over the course of several years is novel and may potentially be of clinical value, especially if confirmed in larger cohorts and other ethnic groups.

The results of these and other studies suggest that the angiotensinogen M235T polymorphism influences blood pressure but that the effect is highly sensitive to environmental context (Table 1). In four of these five studies, being homozygous for the M allele correlated with lower blood pressure (systolic, diastolic, or both) in at least one subgroup, although the specific subgroup and conditions in which the effect was observed did vary somewhat from study to study (Table 1). Importantly, the effect of AGT genotype on blood pressure appears to be affected by physical activity, but here again, the precise nature of the interaction appears to be complex. Two studies (12, 15) found that physical training or habitual activity can mask the effects of AGT genotype on blood pressure during maximal exercise. However, the beneficial effect of training on resting (17) and submaximal exercise (15) diastolic blood pressure in males has also been found to be greatest in [and in one study (17), limited to] subjects homozygous for the M allele. Such apparent discrepancies are not necessarily surprising. As shown in Table 1, there were substantial methodological differences in the studies that have examined the relationship between AGT genotype, exercise, and blood pressure. As noted, blood pressure is a complex trait that is influenced by a number of genetic and nongenetic factors. Thus the effects of unmeasured genotypes and other confounding factors (such as salt intake, alcohol use, etc.) might significantly influence the effect of AGT in any given study. For example, AGT has been found to interact significantly with the angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism (15) in the response of submaximal exercise diastolic blood pressure to training in men and with body fat mass in women with respect to both resting and submaximal exercise diastolic blood pressure (16).


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Table 1. Association studies of M235T AGT genotype, blood pressure, and exercise

 
Much remains to be learned about the role that this and other candidate genes play in blood pressure in adults. The studies presented here illustrate how genetic polymorphisms that individually account for a small part of the variance in blood pressure in the population at large might nevertheless produce potentially important effects in select subgroups. Further understanding of these genetic effects, and how they interact with environmental factors, may some day enable physicians to use genetic information to tailor preventive and therapeutic interventions to individual characteristics.

FOOTNOTES

Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: L. A. Sonna, Thermal and Mountain Medicine Division, US Army Research Institute of Environmental Medicine, 42 Kansas St., Natick, MA 01760 (E-mail: Larry.Sonna{at}NA.AMEDD.ARMY.MIL).

10.1152/physiolgenomics.00081.2002.

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