The authors have declared that no competing interests exist.
Conceived and designed the experiments: LS S-JZ. Performed the experiments: H-CY J-HL JL LY JQ. Analyzed the data: H-CY JL B-XH LL D-PD. Contributed reagents/materials/analysis tools: JL B-XH. Wrote the paper: H-CY.
CYP4A11 oxidizes endogenous arachidonic acid to 20-hydroxyeicosatetraenoic acid, a renal vasoconstrictor and natriuretic in humans. Previous studies demonstrated an association between a functional variant (T8590C) of
Associations between the T8590C polymorphism and essential hypertension were examined in 328 unrelated cases and 297 age-matched controls in Han Chinese individuals. High-resolution melting was used to identify the
The frequency of the
This meta-analysis suggests there is a significant association between the
Hypertension is a major risk factor for cardiac, renal and cerebrovascular morbidity and mortality
Hypertension has a substantial heritability that is likely to be of polygenic origin. To date, several variants have been identified by genome-wide association studies (GWASs) to be associated with essential hypertension
Cytochrome P450 (CYP) is a superfamily of cysteine-heme enzymes that are key mediators of the oxidative transformation of endogenous and exogenous molecules. Cytochrome P450 enzymes are classified into families, subfamilies and individual isoenzymes based on similarities in their amino acid sequences. Human CYP4A11, which belongs to the cytochrome P450 family 4, catalyzes the conversion of endogenous arachidonic acid to 20-tetrahydrocannabinol acid (20-HETE)
Given the role of 20-HETE in the regulation of hypertension, CYP4A11 is the subject of much research interest. The human
Patients diagnosed with essential hypertension were recruited at Guangzhou General Hospital of Guangzhou Military Command from 2008 to 2011. Three hundred and twenty-eight essential hypertension patients and 297 age-matched controls were enrolled in the study. BP was measured twice in each participant while seated, after 5 min of rest. Essential hypertension was diagnosed based on the following criteria: seated systolic BP greater than 140 mmHg or diastolic BP greater than 90 mmHg on three occasions within 2 months after the first BP reading, or current use of antihypertensive agents. Individuals with secondary hypertension, cancer, chronic kidney or hepatic disease, stroke, diabetes mellitus or severe psychiatric illness were excluded. All individuals enrolled were from the Han population in China. Diagnosis of diabetes was based on the history of treatment for hypoglycemia and/or confirmed fasting blood glucose >7.0 mmol/l. Individuals who had smoked ≥10 cigarettes per day for at least 2 years were defined as smokers and those who had drunk ≥210 g alcohol per week for more than 3 years were defined as drinkers.
This study protocol was approved by the Ethics Committee of Guangzhou General Hospital of Guangzhou Military Command. All individuals in this manuscript gave written informed consent for the publication of their case details.
Peripheral venous blood was drawn from each individual. Genomic DNA was extracted from whole blood using the Tiangen DNA blood kit (Pangenetic Biotech Co., Ltd, Beijing, China). The
Statistical analysis was performed using the SPSS 13.0 software package (SPSS, Chicago, IL, USA). The genotype frequency distribution for each variant was separately tested for Hardy-Weinberg equilibrium (HWE) with a chi-square test in the case and control groups. Differences of continuous variables with a normal distribution (presented as mean ± SD) between the two groups were calculated using the independent-sample
To explore the association between the T8590C polymorphism of
The inclusion criteria were: (a) evaluation of the
Two investigators reviewed and extracted data from all of the eligible publications independently, according to the inclusion and exclusion criteria listed above. All data were collected according to a standard protocol. Studies that were repeated, of poor research quality, did not meet the inclusion criteria or provided little information or insufficient data were excluded. Study quality was assessed using the 9-star Newcastle-Ottawa Scale
Cases (n) | Controls (n) | ||||||||||||||
Author | Country | Ethnicity | StudyQuality |
Year | TT | TC | CC | T | C | TT | TC | CC | T | C | HWE( |
Sugimoto K | Japan | Asian | 8 | 2008 | 325 | 157 | 3 | 807 | 183 | 326 | 153 | 15 | 805 | 183 | 0.22 |
Ward NC | Australian | Caucasian | 6 | 2008 | 115 | 41 | 5 | 271 | 51 | 54 | 19 | 1 | 127 | 21 | 0.81 |
Gainer JV(1) | America | Caucasian | 7 | 2005 | 126 | 64 | 5 | 316 | 74 | 152 | 41 | 4 | 345 | 49 | 0.80 |
Gainer JV(2) | America | Caucasian | 7 | 2005 | 494 | 166 | 10 | 1154 | 186 | 678 | 180 | 10 | 1536 | 200 | 0.33 |
Mayer B | Germany | Caucasian | 7 | 2005 | 481 | 149 | 19 | 1111 | 187 | 574 | 164 | 10 | 1312 | 184 | 0.31 |
Mayer B | Germany | Caucasian | 7 | 2006 | 152 | 68 | 8 | 372 | 84 | 250 | 79 | 3 | 579 | 85 | 0.56 |
Fava C | Sweden | Caucasian | 7 | 2008 | 2924 | 800 | 81 | 6648 | 962 | 1665 | 475 | 30 | 3805 | 535 | 0.04 |
Williams JS | America | white/black/Asian/other | 6 | 2011 | 227 | 94 | 11 | 548 | 116 | 109 | 34 | 4 | 252 | 42 | 0.51 |
Current | China | Asian | 7 | 2012 | 175 | 132 | 21 | 482 | 174 | 150 | 123 | 24 | 423 | 171 | 0.60 |
Study quality was based on the Newcastle-Ottawa Scale (range: 1–9 stars).
The association between the
The heterogeneity of the studies was tested using the chi-square-based
Baseline characteristics of the study population are shown in
Characteristic | Patients( |
Controls( |
|
Age (years) | 62.66±11.16 | 63.15±8.41 | 0.786 |
Sex (male), n (%) | 188 (57.3) | 146 (49.2) | 0.041 |
BMI (kg/m2) | 23.55±2.76 | 23.47±3.02 | 0.741 |
Smoking, n (%) | 113 (34.5) | 44 (14.8) | 0.000 |
Drinking, n (%) | 108 (32.9) | 82 (27.6) | 0.149 |
SBP (mmHg) | 137.38±14.6 | 110.87±9.96 | 0.000 |
DBP (mmHg) | 78.17±9.96 | 67.30±7.16 | 0.000 |
TC (mmol/l) | 4.51±1.09 | 4.06±1.51 | 0.000 |
TG (mmol/l) | 1.57±1.08 | 1.66±0.82 | 0.215 |
HDL-C (mmol/l) | 1.15±0.29 | 1.18±0.31 | 0.121 |
LDL-C (mmol/l) | 2.78±0.86 | 2.58±0.92 | 0.005 |
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride. Age, SBP, DBP, TC, TG, LDL-C and HDL-C (expressed as mean ± standard deviation) were not normally distributed and were analyzed by the Mann-Whitney
For the total population, the frequencies of the 8590TT, 8590TC and 8590CC genotypes were 52.0%, 40.8% and 7.2%, respectively. These frequencies did not deviate from those predicted by HWE. The allele frequencies of the 8590C allele in cases and controls were 26.5% and 28.8%, respectively. No significant difference in the genotype frequency was observed between the cases and controls (
Cases ( |
Controls ( |
||||
Genotype | T/T | 175 (53.4) | 150 (50.5) | 0.905 | 0.636 |
T/C | 132 (40.2) | 123 (41.4) | |||
C/C | 21 (6.4) | 24 (8.1) | |||
Dominantmodel | TT | 175 (53.4) | 150 (50.5) | 0.507 | 0.477 |
TC+CC | 153 (46.6) | 147 (49.5) | |||
Recessivemodel | CC | 21 (6.4) | 24 (8.1) | 0.657 | 0.418 |
TC+TT | 307 (93.6) | 273 (91.2) | |||
Additivemodel | T | 482 (73.5) | 423 (71.2) | 0.799 | 0.371 |
C | 174 (26.5) | 171 (28.8) |
Eighteen papers were gathered from the literature research, among which seven papers were eligible based on the study selection criteria. Of the eleven excluded studies, one paper was a repeat publication
The main characteristics of the studies included in our meta-analysis are summarized in
We conducted subgroup analysis classified by ethnicity, gender and HWE population. Five of the studies assessed Caucasian populations, including one from Australia
Four of the eight eligible studies provided data on male and female subjects. The distribution of genotypes and alleles in males versus females is shown in
Cases (n) | Controls (n) | |||||||||||
Author | Gender | TT | TC | CC | T | C | TT | TC | CC | T | C | HWE ( |
Gainer JV (1) | Male | 66 | 31 | 2 | 163 | 35 | 79 | 18 | 2 | 176 | 22 | 0.95 |
Female | 60 | 33 | 3 | 153 | 39 | 73 | 23 | 2 | 169 | 27 | 0.76 | |
Gainer JV (2) | Male | 266 | 94 | 7 | 626 | 108 | 316 | 83 | 3 | 715 | 89 | 0.40 |
Female | 228 | 72 | 3 | 528 | 78 | 362 | 97 | 7 | 821 | 111 | 0.59 | |
Mayer B | Male | 274 | 83 | 10 | 631 | 103 | 258 | 85 | 3 | 601 | 91 | 0.95 |
Female | 207 | 66 | 9 | 480 | 84 | 316 | 79 | 7 | 711 | 93 | 0.12 | |
Fava C | Male | 1354 | 356 | 35 | 3064 | 426 | 604 | 174 | 12 | 1382 | 198 | 0.11 |
Female | 1570 | 444 | 46 | 3584 | 536 | 1064 | 301 | 18 | 2429 | 337 | 0.18 | |
Current | Male | 90 | 83 | 15 | 263 | 113 | 80 | 55 | 11 | 215 | 77 | 0.78 |
Female | 85 | 49 | 6 | 219 | 61 | 70 | 68 | 13 | 208 | 94 | 0.62 |
The findings for heterogeneity and the combined association between the
Allele and genotype | Populations | OR (95%CI) | I2 | Analysis model | ||
C allele vs. T allele | All populations | 1.15 (1.02, 1.29) | 47% | 0.06 | Random | 0.02 |
Caucasians | 1.23 (1.06,1.43) | 53% | 0.06 | Random | 0.007 | |
Asians | 0.95 (0.80, 1.12) | 0 | 0.52 | Fixed | 0.54 | |
CC vs. TT | All populations | 1.38 (1.07, 1.78) | 20% | 0.26 | Fixed | 0.01 |
Caucasians | 1.74 (1.27, 2.39) | 0 | 0.70 | Fixed | 0.0006 | |
Asians | 0.80 (0.49, 1.29) | 0 | 0.77 | Fixed | 0.35 | |
CC+TC vs. TT | All populations | 1.06 (1.01, 1.32) | 47% | 0.06 | Random | 0.03 |
Caucasians | 1.23 (1.03, 1.47) | 59% | 0.03 | Random | 0.03 | |
Asians | 0.96 (0.79, 1.18) | 0 | 0.54 | Fixed | 0.71 | |
CC vs. TC+TT | All populations | 1.52 (1.15, 2.02) | 0 | 0.59 | Fixed | 0.003 |
Caucasians | 1.71 (1.24, 2.34) | 0 | 0.73 | Fixed | 0.001 | |
Asians | 0.81 (0.50, 1.30) | 0 | 0.84 | Fixed | 0.38 |
Allele and genotype | Gender | OR (95% CI) | Analysis model | |||
C allele vs. T allele | Male | 1.11 (0.98, 1.26) | 40% | 0.15 | Fixed | 0.10 |
Female | 1.07 (0.84, 1.36) | 68% | 0.01 | Random | 0.57 | |
CC vs. TT | Male | 1.55 (1.00, 2.41) | 0 | 0.65 | Fixed | 0.05 |
Female | 1.33 (0.90, 1.97) | 46% | 0.11 | Fixed | 0.16 | |
CC+TC vs. TT | Male | 1.18 (0.94, 1.48) | 54% | 0.07 | Random | 0.16 |
Female | 1.07 (0.82, 1.40) | 66% | 0.02 | Random | 0.59 | |
CC vs. TC+TT | Male | 1.05 (0.40, 2.73) | 76% | 0.002 | Random | 0.92 |
Female | 1.29 (0.87, 1.89) | 38% | 0.17 | Fixed | 0.20 |
Significant heterogeneity between studies was observed in some comparisons; detailed data are shown in
For the total population, sensitivity analyses indicated that the present study was the main source of heterogeneity. In addition, among male subjects, the combined ORs of the additive model and the dominant model were influenced by one study in HWE. The
A funnel plot and Egger’s test were performed to assess publication bias in this meta-analysis. The funnel plot showed no apparent evidence of publication bias (
The vertical and horizontal axes correspond to the odds ratios and confidence limits. OR, odds ratio; s.e., standard error.
The product 20-HETE, the monooxygenase derivative of arachidonic acid synthesized by CYP450 enzymes, is a candidate for the regulation of BP and hypertension. In humans, two members of the CYP4A subfamily have been detected in the kidney.
In the present case-control study, no significant difference in the genotype frequency was observed between the cases and controls (
In this meta-analysis, we analyzed the data from eight available case-control studies (including the present study)
It is well established that the prevalence of hypertension and cardiovascular disease differs between men and women, the latter being protected from cardiovascular events until menopause; there is a rapid increase in the risk profile after menopause. Gene-specific effects have been indicated as responsible, but most genetic studies do not include sex as a variable in data analysis, and a recent meta-analysis pooling thousands of subjects of previous GWASs did not identify any sex-specific effect of genes associated with BP/hypertension. Experimental models suggest that enzymes involved in 20-HETE biosynthesis and metabolism have a role in the control of BP with a sex-specific effect
When interpreting these results, caution should be applied. Relatively large heterogeneity was present in the meta-analysis, perhaps due to the limited study sample size. A relatively limited number of studies and samples were analyzed, partly because the original studies had rather limited sample sets. Moreover, differences in the ethnicity and selection of controls, age distribution and lifestyle factors may have contributed to heterogeneity. Further large scale studies are needed to clarify whether the
In summary, our meta-analysis suggests that the
(DOC)
(DOC)