The CYP17A1 gene, which encodes17α-hydroxylase and 17,20-lyase, has been identified as a common hypertension susceptibility locus in a European population. However, the association between CYP17A1 polymorphisms and hypertension is unclear in the Chinese population as well as in the role of serum 25(OH) D levels. Six single nucleotide polymorphisms (SNPs) in CYP17A1 were genotyped in two stages in a Han Chinese population, and the serum 25(OH) D levels were measured. Analysis in stage 1 showed that the rs1004467 minor G-allele and rs11191548 minor C-allele in CYP17A1 were significantly associated with a decreased risk of hypertension and higher serum 25(OH) D levels (all P < 0.05). The larger sample in stage 2 also showed that a mutation in rs11191548 was significantly associated with a decreased risk of hypertension (adjusted OR = 0.707, 95% CI: 0.553–0.904, P = 0.006). The rs11191548 minor C-allele was associated with higher serum 25(OH) D levels in hypertensive subjects (βadj ± SEM = 0.094 ± 0.949, P = 0.003) and controls (βadj ± SEM = 0.128 ± 1.025, P < 0.001). In conclusion, the rs11191548 CYP17A1 gene mutation was associated with hypertension and the serum 25(OH) D levels in Han Chinese.
Essential hypertension (EH) has become a major public health problem globally [1, 2]. In 2000, the estimated number of people with hypertension was 972 million (ranging from 957 to 987 million). By 2025, the number of individuals with hypertension will increase to 1.56 billion (ranging from 1.54 to 1.58 billion) . EH is thought to be a multifactor-related disease including genetic factors and environmental factors, such as dietary sodium intake, obesity, excessive drinking, and smoking history . According to recent publications, vitamin D deficiency was also considered as a risk factor for hypertension [4,5,6]. In several genome-wide association studies (GWAS), various genetic variants were associated with hypertension and high blood pressure (BP) [7, 8]. A recent GWAS meta-analysis has identified 66 (17 new) significant loci for hypertension in 342,415 individuals from a European population . It has also been estimated that nearly 30–50% of the blood pressure variation in populations is attributed to genetic factors .
There are 18 cytochrome P450 (CYP) families that encode 57 genes in the human genome . CYP genes and enzymes have an important role in many critical life processes. For example, CYP7A1 is a key enzyme in bile acid biosynthesis; CYP17A1, CYP21A1, and CYP11B2 are key enzymes involved in steroidogenesis; and CYP27A1 catalyses important reactions in both cholesterol homeostasis and vitamin D metabolism (Supplementary Figure 1). Therefore, specific mutations in those genes will result in specific diseases. Several CYP17A1 polymorphisms have been reported to be associated with hypertension in European and Asian populations [12, 13]. Nevertheless, the contribution of these loci to hypertension in Han Chinese and serum 25(OH) D levels remain unknown.
The aim of our study was to evaluate the association between single nucleotide polymorphisms (SNPs) located in the CYP17A1 gene and hypertension and 25(OH) D levels in Han Chinese.
Materials and methods
A two-stage designed study was used to evaluate whether genetic variations in the CYP17A1 gene were associated with 25(OH) D and hypertension in a Chinese population. In stage 1, we screened for six SNPs in 157 cases diagnosed with EH and 159 controls from the First Affiliated Hospital of Nanjing Medical University in Jiangsu Province in 2016. In stage 2, a larger sample including 570 cases with EH and 570 controls were recruited. Individuals with an systolic blood pressure (SBP) ≥ 140 mmHg and/or a diastolic blood pressure (DBP) ≥ 90 mmHg or those who take any anti-hypertension drugs were included. Individuals with no diagnosis of hypertension and with an SBP < 140 mmHg and DBP < 90 mmHg were selected as controls. Individuals with secondary hypertension, cancer, or any history of chronic diseases or thyroid dysfunction were excluded from the study. All experimental protocols were approved by the First Affiliated Hospital of Nanjing Medical University (No. 2017-SR-108). Informed written consent was obtained from each subject.
Information from each participant was recorded in a standardized questionnaire, including name, sex, age, nationality, history of diseases, and smoking history. Blood pressure measurements were repeated three times with a 20 minutes rest in a quiet environment. BMI was calculated by dividing weight (kg) by height squared (m2). The serum levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and fasting blood glucose (GLU) were measured. The serum levels of 25(OH) D were determined simultaneously using batched specimens with commercially available kits (Eagle Biosciences, Nashua, NH, USA) and were conducted in accordance with the manufacturer’s instructions in prior studies, which confirmed the validity of the test. Vitamin D inadequacy is defined by serum 25(OH) D levels < 20 ng/ml . Individuals with age < 55 years were selected for the middle-aged group, whereas individuals with age ≥ 55 years were selected for the old-aged group.
The CYP17A1 gene (gene ID: 1586) is located on chromosome 10 at q24.32. SNPs tagged with a minor allele frequency ≥ 0.10 in the Chinese HapMap database and with an r2 ≥ 0.80 using the linkage disequilibrium method were selected as candidate SNPs (Supplementary Figure 2). Other SNPs in or near CYP17A1 that have been reported to be associated with hypertension were also selected for further study. Finally, six SNPs were selected for use in the present study. Detailed information on these SNPs is provided in Supplementary Table 1.
Genomic DNA was extracted from peripheral blood leukocytes from each subject using the Tiangen Blood DNA Kit (TIANamp blood DNA Kit, Tiangen, Biotech, Beijing, China). The selected SNPs in the CYP17A1 gene were genotyped using TaqMan Genotype assays (Applied Biosystems, USA) according to the supplier’s recommendations. Duplicate genotyping for ~5% of samples was applied for quality control.
Expression quantitative trait loci (eQTL)
Publicly available RNA-seq and genotyping data from 399 normal thyroid samples and 225 testis samples from the Genotype-Tissue Expression project (GTEx Portal, https://www.gtexportal.org/home/) were used to assess the Gene Expression Quantitative Trait Loci (eQTL) for CYP17A1 mRNA expression and candidate the SNPs rs4919686, rs1004467, rs4919687, and rs11191548 .
All data were analyzed using the SPSS software, version 13.0 (SPSS, Chicago, IL, USA). Variables are shown as the mean ± SD or a percentage. Differences between groups were assessed with the Student’s t-test or χ2 test. The Hardy–Weinberg equilibrium was calculated for controls using the χ2 test. The association between the SNPs and hypertension was tested by logistic regression analysis. The association between the SNPs and serum 25 (OH) D levels was assessed by multivariate linear regression. All of the models used in the study were adjusted for age, sex, BMI,TG, TC, LDL-C, HDL-C, GLU, and smoking unless otherwise noted. Bonferroni correction (0.05/number of tests performed) was applied for multiple measures.
The clinical characteristics of the hypertensive patients and controls are summarized in Table 1. The mean age and gender distribution were similar between the hypertension and control groups. The levels of SBP, DBP, TG, and GLU were higher in the hypertension groups than in the controls (all, P < 0.05), and the levels of HDL-C and 25(OH) D were lower in the hypertension groups than in the controls (all, P < 0.05).
25(OH) D inadequacy was significantly associated with hypertension (OR = 1.740, 95% CI: 1.125–2.691, P = 0.013) after adjusting for confounding factors. Furthermore, stratified analysis on serum 25 (OH) D levels was performed according to the subjects’ age and gender. We detected that 25(OH) D inadequacy was inversely associated with a risk of hypertension in old-aged adults (age ≥ 55 years) (OR = 1. 915, 95% CI: 1.114–3.418, P = 0.019) and females (OR = 2.299, 95% CI: 1.135–4.657, P = 0.021). However, there was no association between 25(OH) D inadequacy and hypertension in the middle-aged group (age < 55 years) (OR = 1.214, 95% CI: 0.575–2.564, P = 0.612) and males (OR = 1.438, 95% CI: 0.082–2.522, P = 0.205) (Supplementary Table 2).
The stage 1 analysis showed that rs1004467 (P = 0.009), rs743572 (P = 0.003), and rs11191548 (P = 0.006) in CYP17A1 showed a significant association with hypertension (Supplementary Table 3). Three other selected SNPs were excluded because hypertension and BP levels were not affected (P ≥ 0.05). The rs1004467 G-allele (βadj ± SEM = 0.095 ± 1.194, P = 0.016) and rs11191548 C-allele (βadj ± SEM = 0.080 ± 1.209, P = 0.043) were associated with higher 25 (OH) D levels after adjusting for age, sex, BMI, and smoking history.
In stage 2, the rs1004467 minor G-allele (OR = 0.707, 95% CI: 0.557–0.898, P = 0.004) and the rs11191548 minor C-allele (OR = 0.707, 95% CI: 0.553–0.904, P = 0.006) were still associated with a decreased risk for hypertension (Tables 2 and 3). The genotype distributions for each SNP complied with Hardy–Weinberg equilibrium values in the controls. Rs1004467 was significantly associated with hypertension in both the dominant (OR = 0.736, 95% CI: 0.577–0.940, P = 0.014) and recessive (OR = 0.641, 95% CI: 0.450–0.914, P = 0.014) models. Rs11191548 was also significantly associated with hypertension in both the dominant (OR = 0.712, 95% CI: 0.554–0.915, P = 0.008) and recessive (OR = 0.603, 95% CI: 0.425–0.856, P = 0.005) models. Although there were few differences in the distribution of the genotypes between stages 1 and 2, we still found significant associations between hypertension and these two SNPs (rs1004467 and rs11191548) in the dominant model in both research stages (Tables 2 and 3).
Furthermore, we analyzed the association between the two SNPs (rs1004467 and rs11191548) and serum 25 (OH) D levels. The stratifying analysis was performed according to the two subgroups (the hypertension groups and controls) (Table 4). The rs1004467 minor G-allele was significantly associated with increased 25 (OH) D levels (βadj ± SEM = 0.089 ± 1.025, P = 0.003) in the controls, but not in the hypertensive groups (βadj ± SEM = 0.058 ± 0.964, P = 0.065). Subjects with the rs11191548 TC/TT genotype had lower 25 (OH) D levels than the CC genotype in both the hypertension (P = 0.001) and control (P = 0.002) groups. Adjusted for confounding factors, the rs11191548 minor C-allele was associated with higher 25 (OH) D levels in hypertensive (βadj ± SEM = 0.094 ± 0.949, P = 0.003) and normotensive (βadj ± SEM = 0.128 ± 1.025, P < 0.001) subjects. These results were still statistically significant after Bonferroni correction.
The Genotype-Tissue Expression project was used to assess the eQTLs for CYP17A1 and candidate SNP mRNA expression. The eQTL data revealed that the mutations in rs4919686 (P = 6.6 × 10−5) and rs4919687 (P = 2.6 × 10−5) were associated with high CYP17A1 expression in thyroid tissues (Fig. 1a, c). In addition, low CYP17A1 expression levels were significantly associated with the rs1004467 minor G-allele (P = 4.3 × 10−9) and the rs11191548 minor C-allele (P = 1.3 × 10−7) (Fig. 1b, d).
This is the first study to explore the association between SNPs located in the CYP17A1 gene with hypertension and 25(OH) D levels in Han Chinese from Jiangsu Province. We found that the rs11191548 and rs1004467 CYP17A1 mutations were strongly associated with a decreased risk for hypertension. We also found that the rs11191548 mutation was significantly related to higher serum 25(OH) D levels after adjusting for potential factors.
Several publications have reported the relationship between the rs11191548 and rs1004467 polymorphisms and the development of hypertension in different populations. Some studies completed on Han Shanghai and Japanese populations reported that the rs1004467 A-allele was a risk factor for hypertension [16, 17], which were similar to our results. Others showed insignificant associations between rs1004467 and hypertension or BP levels in Japanese and Yunnan, Xinjiang Han populations [13, 18, 19]. The inconsistency could be attributed to the different genetic backgrounds, living habits, and environmental factors.
GWAS studies from the CHARGE consortium and the Global BPgen Consortium first reported that the rs11191548 major T-allele was associated with increased hypertension risk and BP levels in a European population [12, 20]. Similar studies were performed in Asian populations and showed the same results [13, 18, 21, 22]. Some studies have reported that the rs11191548 minor C-allele is associated with an increased hypertension risk and BP levels [16, 23,24,25]. However, in our study, the rs11191548 C-allele was less susceptible to hypertension than the T-allele. Our results were in accordance with those in most previous studies [12, 13, 18, 20,21,22]. Nearly 30–50% of blood pressure (BP) variation in the populations is attributed to genetic factors .
CYP17A1 encodes both 17α-hydroxylase and 17,20-lyase, which are key enzymes for glucocorticoid biosynthesis. Mutations in the CYP17A1 gene result in 17α-hydroxylase deficiency (17-OHD); important characteristics in 17-OHD patients include hypertension, hypokalemia, suppressed plasma renin activity (PRA), and low-to-normal plasma aldosterone (ALD) levels [26,27,28,29]. A study showed that the rs11191548 mutation was associated with lower K+ and PRA levels in 1102 hypertensive patients, which suggests this variant may decrease CYP17A1 enzymatic activity . The analysis in our study showed that the rs11191548 mutation leads to low CYP17A1 expression levels and was associated with higher serum 25(OH) D levels. It is possible that the rs11191548 mutation decreases CYP17A1 enzymatic activity and increases 25(OH) D biosynthesis.
Epidemiological data have shown that lower serum 25(OH) D levels are strongly associated with the risk of hypertension [30,31,32,33]. Similarly, our study also showed that 25 (OH) D inadequacy was significantly associated with hypertension, especially in older-aged adults and females. This association is possibly explained by the activation of the renin–angiotensin system and macrophage ER stress [34, 35].
In conclusion, our results suggest that subjects with the rs11191548 C-allele near the CYP17A1 gene are significantly associated with both a decreased risk of hypertension and increased 25(OH) D levels in a Chinese population. These data suggest a role for this mutation in the pathogenesis of hypertension through the accumulation of 25(OH) D. Owing to the small sample size in our study, further investigation with a large-scale sample size and different races is recommended to confirm these findings.
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The research was supported by the Technology project of Jiangsu province (#2014085) and the Jiangsu province health commission (#201402). This research was also supported by the National Natural Science Foundation of China (#81570810).
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Zhang, N., Jia, J., Ding, Q. et al. Common variant rs11191548 near the CYP17A1 gene is associated with hypertension and the serum 25(OH) D levels in Han Chinese. J Hum Genet 63, 731–737 (2018). https://doi.org/10.1038/s10038-018-0435-x