Aldosterone Synthase Gene T−344C Polymorphism, Sodium and Blood Pressure in a Free-Living Population: A Community-Based Study

497 Hypertens Res Vol.30 (2007) No.6 p.497-502 Original Article Aldosterone Synthase Gene T–344C Polymorphism, Sodium and Blood Pressure in a Free-Living Population: A Community-Based Study Kazumasa YAMAGISHI1), Takeshi TANIGAWA1), Renzhe CUI1),2), Minako TABATA1), Ai IKEDA3),4), Masayuki YAO1),5), Takashi SHIMAMOTO5), and Hiroyasu ISO3) There have been few epidemiological studies on the gene-environmental interaction between the aldosterone synthase gene (CYP11B2) T– 344C polymorphism and sodium in relation to blood pressure in a freeliving general population. We hypothesized a priori that persons with the T allele of CYP11B2 would have elevated blood pressure levels in response to a higher sodium intake, and thus the association between the T–344C polymorphism and blood pressure would be more evident among persons with a high sodium intake than among those with a low sodium intake. Study subjects were 2,823 men and women aged 30–74 in a Japanese community. We examined the associations between the T– 344C polymorphism and blood pressure levels, stratified by sodium variables estimated by 24-h urinary sodium excretion and a dietary questionnaire. There was no significant difference in blood pressure levels among the CC, TC and TT groups for either or both sexes. However, among persons with higher sodium excretion, mean systolic blood pressure levels tended to be higher in those with the TC ( + 3.0 mmHg, p = 0.06) and TT ( + 2.9 mmHg, p = 0.07) genotypes than in those with the CC genotype, but this tendency was not seen among those with lower sodium excretion ( – 4.0 mmHg, p = 0.03 for TC vs. CC; – 3.0 mmHg, p = 0.11 for TT vs. CC; p for interaction = 0.006). In conclusion, we found no association between CYP11B2 and blood pressure for total subjects or for persons with a higher sodium intake. However, a possible gene–blood pressure association among persons with higher sodium intake needs to be explored further. (Hypertens Res 2007; 30: 497–502) Key Words: CYP11B2, gene-environment interaction, salt-sensitivity, epidemiology Introduction Aldosterone is synthesized by CYP11B2, a mitochondrial cytochrome P450 enzyme. Recent biological studies suggest that increase in aldosterone and thereby in epithelial Na+ channel (ENaC) activity may play an important role in the etiology of hypertension (1). T−344C polymorphism (thymidine-to-cytosine substitution at position −344 in the regulatory region) of the CYP11B2 gene was extensively From the 1)Department of Public Health Medicine, Graduate School of Comprehensive Human Sciences, and Institute of Community Medicine, University of Tsukuba, Tsukuba, Japan; 2)Department of Epidemiology and Community Medicine, Medical College of Nankai University, Tianjin, P.R. China; 3) Public Health, Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, Suita, Japan; 4)Department of Society, Human Development and Health, Harvard School of Public Health, Boston, USA; and 5)Osaka Medical Center for Health Science and Promotion, Osaka, Japan. This study was supported by a Grant-in-Aid for Exploratory Research from the Japan Society for the Promotion of Science, Japan (No. 11877069 in 1999–2000 and 19659160 in 2007–2009) and a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (No. 17790382 in 2005–2007). Address for Reprints: Kazumasa Yamagishi, M.D., Ph.D., Department of Public Health Medicine, Graduate School of Comprehensive Human Sciences, and Institute of Community Medicine, University of Tsukuba, 1–1–1 Tennodai, Tsukuba 305–8575, Japan. E-mail: Received October 6, 2006; Accepted in revised form January 12, 2007. 498 Hypertens Res Vol. 30, No. 6 (2007) examined as a candidate gene of hypertension because high levels of aldosterone increase subsequent risk of hypertension (2). Some studies (3–6), but not all (7–12), reported that the T allele was associated with blood pressure/hypertension, especially for low-renin hypertension (4, 5, 13), which is considered to correspond to salt-sensitive hypertension (14). However, no community-based study has been conducted to examine the genetic association between CYP11B2 and saltsensitive hypertension, probably due to the difficulty in identifying this type of hypertension in community-based samples. Therefore, we conducted a large community-based observational study of 2,823 Japanese men and women to examine associations of CYP11B2 polymorphism with blood pressure levels, stratified by sodium variables. Our a priori hypothesis was that persons with the T allele of CYP11B2 would have elevated blood pressure in response to high sodium intake, and thus the association between T−344C polymorphism and blood pressure levels would be more evident among persons with high sodium intake. Methods Study Population Subjects were free-living residents of a farming community of Kyowa (census population in 2000: n= 17,145), which was similar to that examined in our previous studies (15–17). Briefly, we recruited subjects aged 30–74 years who had participated in the 2001 cardiovascular risk survey (n= 2,972). Physicians explained the protocol to all participants, and obtained written informed consent from 95% (n= 2,823) of them. The data of these 2,823 persons were used in the present study. The study protocol was approved by the Medical Ethics Committee of the University of Tsukuba. Population Surveys The population surveys have been performed annually since 1981. Details of the surveys have been described elsewhere (15–17). Well-trained blood pressure observers measured arterial systolic blood pressure (SBP) and fifth-phase diastolic blood pressure (DBP) using standard mercury sphygmomanometers (with a cuff 14 cm wide and 51 cm long) on the right arm of quietly seated participants after a period of at least 5-min rest. When the SBP was ≥ 140 mmHg and/or the DBP was ≥ 90 mmHg, the measurement was repeated and the average of the two readings was used in the analyses; otherwise the single reading was used. The methods of blood pressure measurement were standardized uniformly across the surveys, and blood pressure measurement training for blood pressure observers was provided before each annual survey. Hypertension was defined as an SBP of ≥ 140 mmHg and/or DBP of ≥ 90 mmHg, and/or use of antihypertensive medication. Some participants collected all urine over 24 h between the 1982 and 2005 surveys (15). Subjects who provided urine samples of < 500 mL and/or for < 20 h, or those with incomplete collections based on records were excluded from the analyses. Consequently, 1,920 subjects completed the 24-h urine collection. In addition, all participants were asked to complete a self-administered dietary questionnaire to estimate present and past sodium intake at the 2001 survey, and 99% of the subjects successfully completed the questionnaire; the method was described in detail and validated elsewhere (17). (...truncated)