Background
Hypertension is a complex disease caused by multiple environmental and genetic factors. According to the recent nationwide hypertension survey from 2012 to 2015, the prevalence of hypertension among China adults (≥ 18 years old) is 27.9% [
1]. If hypertension is not well controlled, it would inevitably become a severe public health problem in the country in the coming decades. To our knowledge, an effective way to control hypertension is to improve blood pressure management. Although hundreds of compounds representing distinct drug classes have been approved for the treatment of hypertension, the control rate of hypertension in Chinese population remains as low as 15.3% [
2]. The patients with hypertension have suffered from trial–error switching of drug classes due to interindividual variations that are attributed to genetic and environmental factors [
3,
4].
As a major isoform of CYP superfamily, CYP2C9 accounts for approximately 20% of the total CYP protein in the liver. Allele variants of CYP2C9 may underlie the decreased activities of CYP2C9 enzyme in the populations. Although about 30 variant alleles of
CYP2C9 have been reported, only
CYP2C9*2 (Arg144Cys) and
CYP2C9*3 (Ile359Leu) are well studied with respect to their reduced metabolic activities compared with the wild type counterpart
CYP2C9*1 (Arg144Ile359). It has been reported that the allele frequencies of
CYP2C9*2 and
CYP2C9*3 range from 4 to 16% in the Caucasian populations [
5], while in the Asian population,
CYP2C9*2 is absent, and the frequency of
CYP2C9*3 varies from 0.07 to 6.0% [
6‐
9]. Yu et al. found that in the Chinese population, the allele frequency of
CYP2C9*3 was 1.5% in hypertensive patients and 4.9% in healthy controls [
10]. Losartan is a selective angiotensin II receptor antagonist and has been used in hypertension treatment to reduce the risk of cardiovascular events. As a prodrug, losartan needs to be oxidized by CYP2C9 to be an active metabolite showing the most antihypertensive effect [
11]. Numerous studies reveal that
CYP2C9*3 allele can reduce oxidation of losartan, thus decreasing its antihypertensive function [
11,
12]. Unlike losartan, irbesartan, another angiotensin II receptor antagonist, requires CYP2C9 to be converted to inactive metabolite. Besides, the blood concentrations of irbesartan have been found to be higher in
CYP2C9*3 allele carriers compared with other allele carriers [
13]. Moreover, studies have shown that the plasma concentration of irbesartan in Chinese hypertensive patients carrying
CYP2C9*3 allele is significantly elevated 6 h after dosing [
14,
15]. Thus,
CYP2C9*3 allele is involved in an individual’s response to antihypertensive drugs.
Angiotensin II is an important effector controlling blood pressure in the cardiovascular system. Type 1 angiotensin II receptor (AGTR) is encoded by the
AGTR1 gene.
AGTR1 polymorphisms are found to be associated with blood pressure response to the inhibition of renin-angiotensin system (RAS) in the hypertensive population [
16,
17]. A1166C (rs5186) SNP of
AGTR1 may be involved in posttranscriptional modification and angiotensin II receptor-mediated cell signaling [
18]. A1166C has been extensively studied in hypertension and is associated with the end-point phenotypes [
16,
17]. Sun et al., found that in Chinese population, A1166C polymorphism of
AGTR1 was associated with antihypertensive response to candesartan, and individuals with AC genotype displayed a significantly reduction in SBP after taking candesartan [
19].
It has been documented that genetic polymorphisms of CYP2C9 and AGTR1 are involved in the determination of the individual variation in response to antihypertensive effect of angiotensinIIreceptor antagonist. The prevalence of genetic polymorphisms varies remarkably among different geographical regions, nationalities, and races. In this study, we aimed to determine the allele frequency and genotype distribution of CYP2C9 and AGTR1, and explore the relationships between hypertension and combined genotypes and phenotypes of CYP2C9 (CYP2C9*3, Ile359Leu, rs1057910, A1075C) and AGTR1 (rs5186, A1166C) in Han Chinese population using angiotensin II receptor antagonist. This study may provide valuable information for guiding the selection of angiotensin II receptor antagonist such as losartan, irbesartan, and candesartan.
Discussion
This study showed that the frequency of
CYP2C9*3 allele was 3.49%, and
CYP2C9*1/*1 was the major
CYP2C9 genotype with a frequency of 93.30% in Han hypertensive patients. Importantly, a genotype frequency of 0.29% for mutant-type homozygotes
CYP2C9*3/*3 was noticed in the hypertensive patients, whereas
CYP2C9*3/*3 genotype was not detected in the normotensive Han population. On the contrary, one recent research has indicated that the frequency of
CYP2C9*3/*3 is 0.1% in the normotensive Han population [
20]. These inconsistent conclusions may be due to different samples sizes. The present study had large hypertensive population and small normotensive population. Hiltunen et al. have stated that, small sample size has insufficient power to detect a SNP with minor allele frequency [
21].
In addition, the frequency of AA genotype was 90.41% and that of CC genotype of
AGTR1 was 0.29% in Han Chinese hypertension patients. Previous studies report a frequency of 93.4% or 89.6% for the AA genotype in the Han hypertensive population [
19,
22]. Collectively, these results indicated that the AA genotype of
AGTR1 was common in Han hypertensive patients.
In this study, we further identified *1/*1 + AA as the most frequent genotype of combined
CYP2C9 and
AGTR1 in Han hypertensive population. There was no significant association between the genotype distribution of
CYP2C9 or
AGTR1 and hypertension grade in Han hypertensive patients. Besides, no significant difference in the genotype distribution and allele frequency of
AGTR1 and
CYP2C9 was detected between Han normotensives and hypertensive patients. Under strictly controlled conditions, Hiltunen et al. do not identify the association between
AGTR1 and
CYP2C9 polymorphisms and antihypertensive effect of angiotensin receptor antagonists by using GWAS technology. However, they find that the SNPs of
LRPPRC, PPM1B and
NPHS1 are significantly associated with the response to angiotensin receptor antagonists. Hypertension is a multifactorial disorder, and various parameters such as age, ethnicity, disease type, and gene–gene interactions can affect the antihypertensive response. Different ethnic group may contribute to these contradictory results. Of the top 20 SNPs associated with losartan response in GENRES study, few SNPs could be replicated in other 4 studies in Hiltunen et al. research [
21], which reconfirm the complexity nature of the antihypertensive response.
Several researches have clarified that the
AGTR1 and
CYP2C9 polymorphisms are associated with the antihypertensive function of angiotensin II receptor antagonists [
11‐
15,
18,
19]. Angiotensin II receptor antagonists are mainly metabolized by CYP2C9, and AGTR1 is implicated in the sensitivity of angiotensin II receptor antagonists. Based on these clinical studies and the present results, we speculated that most the Han Chinese hypertensive patients had normal clearance (irbesartan) or activation (losartan) function, and normal sensitivity for angiotensin II receptor antagonist. Because of the multigenic and multifactorial nature of the antihypertensive drug response, and sometimes contradictory results, prospective clinical researches are required to establish reliable recommendations.
Limitations
The current study provided valuable information about personalized blood pressure control, but a few limitations should be considered. First, only dominant variants of CYP2C9 (rs1057910, A1075C) and AGTR1 (rs5186, A1166C) were detected because of their high frequencies in Han Chinese. Second, there were a large number of hypertensive patients in the present study, but the sample size of normotensive controls was relatively small. Finally, the pharmacokinetics of angiotensin II receptor antagonist among individuals with different CYP2C9 and AGTR1 genotypes were not evaluated.
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