981 Hypertens Res Vol.28 (2005) No.12 p.981-986 Original Article T1198C Polymorphism of the Angiotensinogen Gene and Antihypertensive Response to Angiotensin-Converting Enzyme Inhibitors Huimin YU, Shuguang LIN, Guozhang LIU*, Yuqing ZHANG*, Chunyu DENG, and Wenjun MA* This study examined the association between T1198C polymorphism of the angiotensinogen (AGT) gene and the blood pressure response to ACE inhibitors in a Chinese hypertensive cohort. After a 2-week single- blind placebo run-in period, benazepril (10–20 mg/day) or imidapril (5–10 mg/day) was administered for 6 weeks to 509 patients with mild-to-moderate essential hypertension. Polymerase chain reaction combined with restriction enzyme digestion was used to detect the polymorphism, and the patients were classified as having the TT, TC, or CC genotype. The achieved changes in systolic and diastolic blood pressure (SBP and DBP) were analyzed to determine their association with genotypes at the AGT gene locus. In the total 509 patients, the TT genotype was observed in 44 patients (8.7%), the TC genotype in 214 patients (42.0%), and the CC genotype in 251 patients (49.3%). The SBP reductions in patients with the TT genotype, TC genotype, and CC genotype were -15.3±12.7 mmHg, -14.0±12.7 mmHg, and -14.4±12.4 mmHg, respectively (p=0.809). The DBP reductions in patients with the TT genotype, TC genotype, and CC genotype were -8.5±8.1 mmHg, -8.3±7.5 mmHg, and -8.9±6.6 mmHg, respectively (p=0.638). There were no significant dif- ferences in the changes in SBP or DBP after treatment among the three genotype groups. In conclusion, these results suggest that the AGT genotype does not predict the blood pressure-lowering response to anti- hypertensive treatment with ACE inhibitors in Chinese hypertensive patients. (Hypertens Res 2005; 28: 981– 986) Key Words: hypertension, angiotensinogen, treatment, genes extent of EH. The RAAS has drawn substantial attention as a 1−5 Introduction cardinal source of candidate genes for EH ( ). It is reason- able to hypothesize that variation in genes of the system may Essential hypertension (EH) is a complex syndrome deter- be predictive of variation in blood pressure (BP) response. mined by both genetic and environmental factors. The Variation in genes of the RAAS has been investigated in rela- response of patients to antihypertensive therapy is variable. It tion to antihypertensive response to angiotensin-converting has long been suspected that interindividual variation in the enzyme (ACE) inhibitors, β-blockers, calcium channel block- efficacy and side effects of medications may be influenced by ers, and angiotensin type 1-receptor blockers (ARB). How- genetic factors. The renin-angiotensin-aldosterone system ever, previously published studies have had somewhat (RAAS) plays an important role in the development and conflicting results (6−16). From the Department of Cardiology, Guangdong Provincial People’s Hospital and Guangdong Cardiovascular Institute, Guangzhou, P.R. China; and *Division of Hypertension, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, P.R. China. Address for Reprints: Shuguang Lin, M.D., Guangdong Provincial People’s Hospital and Guangdong Cardiovascular Institute, Guangzhou 510100, P.R. China. E-mail: [email protected] Received August 12, 2005; Accepted in revised form October 17, 2005. 982 Hypertens Res Vol. 28, No. 12 (2005) Table 1. Clinical Characteristics of the Benazepril and Imidapril Groups Benazepril Imidapril p value† Number of patients (n1/n2) 250 (71/179) 259 (84/175) 0.323 Sex (male/female) 141/109 165/94 0.092 Age (years) 56.3±10.0 54.8±9.7 0.098 BMI (kg/m2) 26.2±3.1 26.2±3.2 0.801 Creatinine (mg/dl) 82.1±20.4 85.7±21.2 0.054 Sodium (mmol/l) 141.7±4.1 141.8±3.9 0.657 Potassium (mmol/l) 4.4±0.4 4.4±0.5 0.900 Chloride (mmol/l) 103.5±3.6 103.8±3.6 0.387 Glucose (mmol/l) 5.3±1.0 5.2±1.0 0.494 Uric acid (μmol/l) 298.3±97.9 306.7±99.6 0.340 Total cholesterol (mmol/l) 5.1±1.0 5.1±1.0 0.604 Triglyceride (mmol/l) 1.3±0.4 1.3±0.4 0.913 HDL cholesterol (mmol/l) 1.7±0.8 1.7±0.8 0.870 GPT (U/l) 26.4±14.0 26.7±13.3 0.820 Pretreatment SBP (mmHg) 155.3±12.4 153.9±12.4 0.183 Posttreatment SBP (mmHg) 140.5±12.8* 140.1±13.0* 0.694 Pretreatment DBP (mmHg) 97.1±5.3 96.7±5.3 0.351 Posttreatment DBP (mmHg) 88.3±8.0* 88.3±7.2* 0.961 Pretreatment HR (bpm) 75.0±8.6 75.4±8.5 0.584 Posttreatment HR (bpm) 74.6±8.2 74.8±8.5 0.828 Fall in SBP at 6 weeks (mmHg) 14.8±13.1 13.8±12.0 0.361 Fall in DBP at 6 weeks (mmHg) 8.8±7.4 8.4±6.8 0.457 Change in HR at 6 weeks (bpm) 0.4±9.0 0.6±8.3 0.741 Data are presented as the mean±SD. n1, number of patients who received benazepril 10 mg/day or imidapril 5 mg/day over the entire 6- week treatment period; n2, number of patients who received benazepril 20 mg/day or imidapril 10 mg/day during the last 3 weeks of treatment; BMI, body mass index; HDL, high density lipoprotein; GPT, glutamic-pyruvic transaminase; SBP and DBP, systolic and diastolic blood pressure; HR, heart rate. †p value calculated by ANOVA for continuous variables and χ2 test for categorical variables. *p<0.001 between pretreatment and posttreatment. The angiotensinogen (AGT) gene, the source of the RAAS Hypotensive Efficacy and the Cough Occurrence of Imidapril generated mainly in the liver, has been implicated in EH. versus Benazepril (24), which is a randomized and double- Polymorphisms within the AGT gene have been linked to blind trial performed in 20 centers in 12 cities in P.R. China. hypertension, in particular the T1198C polymorphism in exon Both male and female patients who met the following crite- 2 (17−19). The AGT T1198C variant has not only been ria were included: age, 18−79 years; a history of EH; and shown to be associated with hypertension but is also related to diastolic BP (DBP) 90−109 mmHg or systolic BP (SBP) 140− salt-sensitive hypertension and circulating AGT levels; how- 179 mmHg. The exclusion criteria were secondary hyperten- ever, these associations remain controversial (20−23). sion or known renal artery stenosis; congestive heart failure, The aim of the present study was to investigate the associa- cerebrovascular accident, transient ischemic attacks or myo- tion between T1198C polymorphism of the AGT gene and the cardial infarction within the past year; a documented history BP response to benazepril or imidapril and the distribution of of unstable angina pectoris within the past 6 months; clini- the polymorphism in Chinese essential hypertensive patients. cally important cardiac arrhythmia; uncontrolled diabetes For this purpose, we employed data from a randomized and mellitus (fasting blood glucose [FBG]>180 mg/dl); any clin- double-blind trial which compared the clinical effect of treat- ically important abnormal laboratory finding, such as ment with benazepril and imidapril in Chinese hypertensive glutamic-pyruvic transaminase (GPT)/creatinine twice the patients. upper limit of normal; a history or suspicion of alcohol or drug abuse; pregnancy or lactation in females; concomitant Methods use of any agent that may cause an alteration of BP; or known hypersensitivity or contraindication to ACE inhibition. The appropriate ethics committees approved this study. All of the Study Patients participating patients gave their informed consent. The material studied comes from the Comparative Study of Yu et al: AGT Gene and Blood Pressure Response 983 Study Design Results All antihypertensive agents were withdrawn before the start of a 2-week single-blind placebo run-in period. At the end of At the end of the placebo period, a total of 250 qualified the placebo period, a total of 640 qualified patients were allo- patients were allocated randomly to the benazepril group to cated randomly to groups to receive either 5 mg imidapril or receive 10 mg benazepril orally once daily for 3 weeks, after 10 mg benazepril orally once daily for 3 weeks. After that, which 71 patients whose BP was <140/ 90 mmHg continued patients whose BP was <140/90 mmHg continued the same with the same dose regimen for another 3 weeks. In the 179 dose regimen for another 3 weeks. In patients whose BP was patients whose BP was not adequately controlled (BP≥140/ not adequately controlled (BP≥140/90 mmHg), the dose of 90 mmHg), the dose of benazepril was doubled (20 mg/day) either regimen was doubled for the following 3 weeks. Five for the following 3 weeks. A total of 259 qualified patients hundred and sixty-six patients completed the 6-week trial, were allocated randomly to the imidapril group to receive 5 and their data were used for the present study. The DNA of mg imidapril orally once daily for 3 weeks, after which the 84 509 patients was successfully extracted for further analysis. patients whose BP was <140/90 mmHg continued with the BP was measured by trained doctors using a mercury same dose regimen for another 3 weeks. In the 175 patients sphygmomanometer after the patient had rested for at least 10 whose BP was not adequately controlled (BP≥140/90 min in a seated position, and was determined as the average of mmHg), the dose of imidapril was doubled (10 mg/day) for three measurements taken 1 min apart.