Sage Journals: Discover world-class research

Abstract

Background:

CYP4A11 (cytochrome P450, family 4, subfamily A, polypeptide 11) converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), which plays a crucial role in the modulation of cardiovascular homeostasis. The aim of the present study was to assess the association between the human CYP4A11 gene and coronary artery disease (CAD).

Methods:

A total of 361 patients with CAD and 315 controls were genotyped for 4 single-nucleotide polymorphisms (SNPs) of the human CYP4A11 gene (rs9332978, rs4660980, rs3890011, and rs1126742). The data were assessed for 3 groups: total participants, men, and women via case–control studies.

Results:

For total participants and men, the distribution of SNP3 (rs3890011) genotypes showed a significant difference between CAD and control participants (P = .030 and P = .013, respectively), the distribution of the recessive model of SNP3 (GG vs CC + GC) was significantly higher in CAD patients than in control participants (P = .011 and P = .014, respectively), the significant difference was retained after adjustment for covariates (for total participants, 95% confidence interval [CI]: 1.137-2.423, P = .009; and for males, 95% CI: 1.173-3.013, P = .009).

Conclusions:

rs3890011 maybe a novel polymorphism of the CYP4A11 gene associated with CAD in a Han Chinese population.

Keywords

CYP4A11 single-nucleotide polymorphism case–control study

Introduction

Coronary artery disease (CAD) is a complex multifactorial and polygenic disorder thought to result from an interaction between an individual’s genetic makeup and various environments.¹ Various gene variants have been shown to be associated with CAD.^2,3 Cytochrome p450 (CYP), a superfamily of cysteinato-heme enzymes, is responsible for not only the metabolism of xenobiotics but also a host of endobiotics whose metabolites have critical roles in the maintenance of cardiovascular health.^4,5 Mounting evidence has demonstrated that CYP enzymes are involved in the pathogenesis of CAD. Polymorphisms of CYP genes, for example, CYP1A1, CYP1A2 (which metabolizes polycyclic aromatic hydrocarbons and aromatic amines during smoking),^6,7 CYP2C8, CYP2C9, CYP2J2 (epoxyeicosatrienoic acid [EET] synthesis),^8–10 CYP8A (prostacyclin synthesis),¹¹ CYP11B2 (aldosterone synthesis),¹² CYP17, and CYP19 (synthesis of sex hormones), have been demonstrated to have a relationship with CAD.¹³ The CYP4A enzymes mainly metabolize arachidonic acid to hydroxyeicosatetraenoic acid (HETE) which has critical roles in the regulation of renal, pulmonary, and cardiac function as well as vascular tone.⁵ In humans, CYP4A11 (cytochrome P450, family 4, subfamily A, polypeptide 11) converts arachidonic acid to 20-HETE, which plays a crucial role in the modulation of cardiovascular homeostasis.⁴ The relationship between the polymorphisms of the CYP4A11 gene and hypertension as well as cerebral infarction has been established.^14–16 The aim of the present case–control study was to assess the association between the human CYP4A11 gene and CAD.

Participants and Methods

All patients gave written informed consent and explicitly provided permission for DNA analyses as well as collection of relevant clinical data. The study protocols were approved by the Ethics Committees of the participating institutes.

Participants

All patients and controls were Han Chinese who had a differential diagnosis for chest pain encountered in the Cardiac Catheterization Laboratory of First Affiliated Hospital of Xinjiang Medical University (Urumqi, China) from 2007 to 2009. The study population involved 361 patients with CAD defined by angiographic means (main coronary artery stenosis of >50%). Control participants (n = 315) did not have coronary vessel stenosis and did not show clinical or electrocardiographic evidence of myocardial infarction (MI) or CAD. Data and information about traditional coronary risk factors (including hypertension, diabetes mellitus [DM], and smoking) were collected from all study participants. The diagnosis of hypertension was established if patients were on antihypertensive medication or if the mean of 3 measurements of systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) >90 mm Hg, respectively. Diabetes mellitus was defined by patient recall and also if patients were taking antidiabetic medication or insulin therapy. “Smoking” was classified as smokers (including current or ex-smokers) or nonsmokers. All patients with impaired renal function, malignancy, connective tissue disease, or chronic inflammatory disease were excluded.

Genotyping

We selected 4 single-nucleotide polymorphisms (SNPs) in the human CYP4A11 gene as markers for assessment of genetic association. We designated these SNPs as SNP1, SNP2, SNP3, and SNP4 (rs9332978, rs4660980, rs3890011, and rs1126742) in order of increasing distance from the 5’ end of the gene (Figure 1 ). The minor allele frequency of each SNP was >10%, which indicated that they should be effective genetic markers. All 4 SNPs were confirmed using database single nucleotide polymorphisms (dbSNP) at the national center for biotechnology information (NCBI) Web site and the Applied Biosystems-Celera Discovery System. SNP4 (rs1126742) is located in exon 11. Thymidine substitutes cytosine at the locus (T8590C) that results in a nonsynonymous phenylalanine→serine (F-to-S) substitution at amino acid residue 434 of CYP4A11.¹⁴ SNP1, SNP2, SNP3 are located in introns.

Figure 1.

Structure of the human CYP4A11 gene. This gene consists of 12 exons separated by 11 introns. Boxes indicate exons, and lines indicate introns and intergenic regions. Filled boxes indicate coding regions. Arrows mark the locations of polymorphisms.

Blood samples were collected from all participants. Genomic DNA was extracted from peripheral blood leukocytes using phenol and chloroform. Genotyping was undertaken using the TaqMan SNP Genotyping Assay (Applied Biosystems [ABI], Foster City, California). TaqMan SNP Genotyping Assays were carried out using Taq amplification. The primers and probes used in the TaqMan SNP Genotyping Assays were chosen based on information available at the ABI Web site (http://myscience.appliedbiosystems.com). Thermal cycling was done using the Applied Biosystems 7900HT Fast Real-Time PCR System. Plates were read on the sequence detection systems (SDS) automation controller software v2.3 (ABI).

Biochemical Analyses

We measured the plasma concentration of blood urea nitrogen, creatinine (Cr), glucose (Glu), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL), using standard methods in the Clinical Laboratory Department of First Affiliated Hospital, Xinjiang Medical University.

Statistical Analyses

All continuous variables were expressed as mean ± standard deviation (SD). Differences in continuous variables between patients with CAD and control participants were analyzed using the Mann-Whitney U test. Differences in categorical variables were analyzed using Fisher’s exact test. Differences in distributions of genotypes and alleles between patients with CAD and control participants were analyzed using Fisher exact test. Based on the genotype data of the genetic variations, we undertook linkage disequilibrium (LD) analyses using the expectation maximization (EM) algorithm. Multivariate analyses were conducted with multiple logistic regression methods, and adjusted estimations of conditioned relative risk and 95% confidence intervals (CIs) were calculated. P value <.05 was considered significant. Statistical analyses were carried out using SPSS software for Windows, version 12 (SPSS Inc, Chicago, Illinois).

Results

Table 1 shows the clinical characteristics of the study participants. For total, male, and female participants, there was no significant difference in age between patients with CAD and control participants. That is, the study was an age-matched case–control study. For total participants, the plasma concentration of Cr, Glu, and TC was significantly higher for patients with CAD than for control participants, the prevalence of essential hypertension (EH), DM, and smoking was significantly higher for patients with CAD than for control participants, and the plasma concentration of HDL was significantly lower for patients with CAD than for control participants. For males, the plasma concentration of Cr and TC was significantly higher for patients with CAD than for control participants, the prevalence of EH and DM was significantly higher for patients with CAD than for control participants. For females, the plasma concentration of Cr and Glu was significantly higher for patients with CAD than for control participants, the prevalence of DM was significantly higher for patients with CAD than for control participants, and the plasma concentration of HDL was significantly lower for patients with CAD than for control participants.

Table 1.

Characteristics of Study Participantsa

	Total			Men			Women
	CAD Patients	Control Participants	P Value	CAD Patients	Control Participants	P Value	CAD Patients	Control Participants	P Value
Number (n)	361	315		276	180		85	135
Age (years)	61.31 ± 10.45	56.00 ± 10.46	.910	60.87 ± 11.05	54.16 ± 11.40	.461	62.75 ± 8.02	58.45 ± 8.50	.566
BMI (kg/m²)	25.39 ± 3.07	25.76 ± 3.05	.860	25.40 ± 2.93	25.84 ± 2.99	.828	25.36 ± 3.51	25.66 ± 3.14	.289
Pulse (beats/min)	73.50 ± 11.30	74.01 ± 10.34	.366	73.46 ± 11.31	74.74 ± 10.87	.493	73.77 ± 11.33	73.06 ± 9.57	.471
BUN (mmol/L)	4.93 ± 1.66	5.16 ± 1.77	.086	5.17 ± 1.73	5.13 ± 1.56	.086	5.14 ± 1.90	4.65 ± 1.75	.221
Cr (umol/L)	80.37 ± 23.06	75.44 ± 16.78	.009^b	83.28 ± 22.66	81.11 ± 16.64	.025^b	70.71 ± 21.8	67.69 ± 13.6	.003^b
Glu (mmol/L)	6.10 ± 2.30	5.49 ± 1.44	.000^b	5.89 ± 1.84	5.60 ± 1.64	.113	6.95 ± 3.37	5.33 ± 1.10	.000^b
TG (mmol/L)	1.8 ± 1.26	2.0 ± 1.76	.147	1.85 ± 1.26	2.03 ± 1.75	.061	1.92 ± 1.26	1.97 ± 1.79	.847
TC (mmol/L)	4.35 ± 0.96	4.24 ± 1.12	.038^b	4.19 ± 0.90	4.11 ± 1.06	.023^b	4.69 ± 1.18	4.58 ± 0.99	.258
HDL (mmol/L)	1.11 ± 0.33	1.13 ± 0.29	.044^b	1.07 ± 0.30	1.08 ± 0.30	.654	1.19 ± 0.24	1.24 ± 0.39	.000^b
LDL (mmol/L)	2.44 ± 0.87	2.46 ± 0.87	.652	2.38 ± 0.85	2.39 ± 0.81	.494	2.64 ± 0.92	2.55 ± 0.93	.576
EH (n)	182	126	.000^b	134	66	.027^b	48	60	.876
DM (n)	79	23	.007^b	58	16	.001^b	21	7	.000^b
Smoke (n)	198	126	.000^b	193	117	.303	5	9	1.000

Abbreviations: BMI, body mass index; BUN, blood urea nitrogen; Cr, creatinine; Glu, glucose; TG, triglyceride; TC, total cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; EH, essential hypertension; DM, diabetes mellitus.

^a Continuous variable were expressed as mean ± standard deviation. P value of continuous variables was calculated by Mann-Whitney U test. The P value of categorical variable was calculated by Fisher exact test.

^b P < .05.

Table 2 shows the distribution of genotypes and alleles of SNP1, SNP2, SNP3, and SNP4 for CYP4A11 gene. For total participants and males, the distribution of SNP3 (rs3890011) genotypes showed a significant difference between patients with CAD and control participants (P = .030 and P = .013, respectively), and the distribution of the recessive model of SNP3 (GG vs CC + GC) was significantly higher in patients with CAD than in control participants (P = .011 and P = .014, respectively). Dominant and recessive models were defined by their frequency among total participants. The distribution of the genotype of SNP1, SNP2, SNP3, and SNP4 in patients with CAD and controls was compatible with the Hardy-Weinberg equilibrium.

Table 2.

Genotype and Allele Distributions in Patients With CAD and Control Participantsa

				Total			Men			Women
				CAD	Control	P Value	CAD	Control	P Value	CAD	Control	P value
rs9332978	genotype		A/A	223	214	.107	172	120	.520	51	94	.128
(SNP1)			A/G	118	92		90	54		28	38
			G/G	20	9		14	6		6	3
		dominant model	AA	223	214	.107	171	120	.370	51	94	.148
			AG+GG	138	101	.107	104	60	.370	34	41	.148
		recessive model	GG	20	9	.091	14	6	.458	6	3	.092
			AG+AA	341	306	.091	262	174	.458	79	132	.092
	allele		A	564	520	.050	434	294	.274	130	226	.063
			G	158	110	.050	118	66	.274	40	44	.063
rs4660980	genotype		T/T	243	202	.138	184	118	.243	59	84	.288
(SNP2)			T/C	93	99		74	56		19	43
			C/C	25	14		18	6		7	8
		dominant model	TT	243	202	.416	184	118	.840	59	84	.311
			TC+CC	118	113	.416	92	62	.840	26	51	.311
		recessive model	CC	25	14	.188	18	6	.197	7	8	.586
			TT+TC	336	301	.188	258	174	.197	78	127	.586
	allele		T	579	503	.892	442	292	.733	137	211	.630
			C	143	127	.892	110	68	.733	33	59	.630
rs3890011	genotype		C/C	97	88	.030^b	78	46	.013^b	19	42	.343
(SNP3)			C/G	166	168		121	102		45	66
			G/G	98	59		77	32		21	27
		dominant model	CC	97	88	.795	78	46	.591	19	42	.168
			GC+GG	264	227	.795	198	134	.591	66	93	.168
		recessive model	GG	98	59	.011^b	77	32	.014^b	21	27	.409
			CC+GC	263	256	.011^b	199	148	.014^b	64	108	.409
	allele		C	360	344	.091	277	194	.279	83	150	.171
			G	362	286	.091	275	166	.279	87	120	.171
rs1126742	genotype		T/T	245	202	.107	186	118	.208	59	84	.288
(SNP4)			T/C	91	99		72	56		19	43
			C/C	25	14		18	6		7	8
		dominant model	TT	245	202	.329	186	118	.686	59	84	.311
			TC+CC	116	113	.329	90	62	.686	26	51	.311
		recessive model	CC	25	14	.188	18	6	.197	7	8	.586
			TC+TT	336	301	.188	258	174	.197	78	127	.586
	allele		T	581	503	.785	444	292	.864	137	211	.630
			C	141	127	.785	108	68	.864	33	59	.630

Abbreviations: SNP, single-nucleotide polypeptide; CAD, coronary artery disease.

^a The P value of genotype was calculated by Fisher exact test.

^b P <.05.

Table 3 shows that multiple logistic regression analysis done with or without EH, DM, and smoking because these 3 variables were the major confounding factors for CAD (Table 1). The significance of the recessive model of SNP3 (GG vs CC + GC) between patients with CAD and control participants was retained after adjustment for EH, DM, and smoking (for total participants, 95% CI: 1.137-2.423, P = .009; for males, 95% CI: 1.173-3.013, P = .009).

Table 3.

Multiple Logistic Regression Analysis of Patients With CAD and Control Participants

	Total				Men				Women
	CAD	Control	OR (95% CI)	P Value	CAD	Control	OR (95% CI)	P Value	CAD	Control	OR (95% CI)	P Value
	(n = 361)	(n = 315)	OR (95% CI)	P Value	(n = 276)	(n = 180)	OR (95% CI)	P Value	(n = 85)	(n = 135)	OR (95% CI)	P Value
G/G	98 (27.15%)	59 (18.73%)	1.137-2.423	.009^a	77 (27.90%)	32 (17.78%)	1.173-3.013	.009^a	21 (24.71%)	27 (20.00%)	0.573-2.284	.704
EH	182 (50.42%)	126 (40.00%)	0.386-0.728	.000^a	134 (48.55%)	66 (36.67%)	0.514-1.172	.229	48 (56.47%)	60 (44.44%)	0.321-3.391	.943
DM	79 (21.88%)	23 (7.30%)	0.480-0.908	.011^a	58 (21.01%)	16 (8.89%)	0.420-0.923	.018^a	21 (24.71%)	7 (5.19%)	0.388-1.215	.196
Smoke	198 (54.85%)	126 (40.00%)	0.177-0.480	.000^a	193 (69.93%)	117 (65.00%)	0.203-0.670	.001^a	5 (5.88%)	9 (6.67%)	0.071-0.444	.000^a

Abbreviations: EH, essential hypertension; DM, diabetes mellitus; CAD, coronary artery disease; OR, odds ratio; CI, confidence interval. ^a P < .05.

Discussion

Several CYP enzyme families have been identified in the heart, endothelium, and smooth muscle of blood vessels. Increasing evidence points to the role of endogenous CYP metabolites such as EETs, HETEs, prostacyclin (PGI2), aldosterone, and sex hormones indicate the maintenance of cardiovascular health. A link between the expression and activity of CYP and cardiovascular disease (CVD) such as hypertension, CAD, heart failure, stroke, and cardiomyopathy and arrhythmias has been established.⁵ In humans, CYP4A11 acts mainly by converting arachidonic acid to 20-HETE. The latter has been shown to have 5 physiological functions. First, 20-HETE increases thymidine incorporation in cells and mediates growth responses in vascular smooth muscle cells (VSMCs) in response to norepinephrine and angiotensin II.^17–19 Second, 20-HETE increases the intracellular calcium concentration and mediates the vasoconstrictor responses of angiotensin II, vasopressin, and norepinephrine.^20–22 Third, 20-HETE inhibits Na⁺-K⁺-ATPase activity and sodium transport in the proximal tubule and is a key mediator of long-term control of arterial pressure.^23–25 Fourth, 20-HETE inhibits platelet aggregation and formation of thromboxaneA2 (TxA2) during platelet activation.²⁶ Fifth, 20-HETE is a significant contributor to ischemia–reperfusion injury, and exogenous administration of 20-HETE significantly increases the infarct size.^27,28 Polymorphisms of the CYP4A11 gene can affect the metabolism of arachidonic acid, resulting in an altered generating capacity of 20-HETE. We hypothesized that variability in the gene might also affect the risk of CAD. We genotyped 4 SNPs of the CYP4A11 gene in a Han Chinese population and assessed the association between the CYP4A11 gene and CAD using case–control analyses. For the total participants and the male group, there was a significant difference in the genotypic distribution of SNP3 (rs3890011) between patients with CAD and control participants, and the distribution of the recessive model of SNP3 (GG vs CC + GC) was significantly higher in patients with CAD than in control participants. The significant difference in the recessive model of SNP3 (GG vs CC + GC) between patients with CAD and control participants was retained after adjustment for covariates such as EH, DM, and smoking. This indicated that the risk of CAD may be increased in men with the GG genotype of rs3890011. Although rs3890011 is located in the introns and has no function, it is tightly linked to neighboring functional SNPs and constructs different haplotypes, potentially affecting the structure and/or catalytic activity of the enzyme,²⁹ we speculated that participants with the GG genotype of rs3890011 may have a high ability of synthesizing 20-HETE. 20-HETE increases the intracellular concentration of calcium and mediates the action of vasoconstrictors. Coronary artery disease is a multifactorial disorder, and this SNP could be a genetic marker for CAD risk.

SNP4 (rs1126742) is one of the most important genetic variants of CYP4A11. The thymidine→cytosine substitution at nucleotide 8590 in the CYP4A11 gene results in a phenylalanine→serine substitution at amino acid 434 which significantly reduces the catalytic activity of the CYP4A11 enzyme through a loss-of-function mechanism in vitro.¹⁴ Several studies recently focused on the association between rs1126742 and hypertension. Gainer et al,¹⁴ Mayer et al,¹⁵ Laffer at al,³⁰ Fava et al,³¹ and Williams et al³² showed a clear association between the 8590C allele and hypertension, whereas Ward et al³³ and Sugimoto et al³⁴ showed no association between the 8590C allele and hypertension. These contradictory results may arise from the difference in ethnic background. Few studies focus on the association between rs1126742 and CAD. Although Hermann et al demonstrated that the 8590C allele increased coronary vasoconstriction,³⁵ Mayer et al did not show an association between the 8590C allele and MI.³⁶ Fava et al did not show an association between the 8590C allele and CAD or stroke either.³¹ We also did not find an association between the 8590C allele and CAD in the present study. Sugimoto et al demonstrated that rs9332978 is associated with hypertension,³⁴ whereas we found that it was not associated with CAD. Zhang et al showed SNP3 (rs3890011) not to be associated with hypertension,³⁷ whereas we demonstrated that it is associated with CAD. The different results can be explained by the different pathogenesis of hypertension and CAD, both of which are complex multifactorial and polygenic disorders, so it is hard to interpret them clearly only with respect to genetic makeup.

In conclusion, rs3890011 maybe a novel polymorphism of the CYP4A11 gene associated with CAD. The GG genotype of rs3890011 appears to be a genetic marker of CAD for men in a Han Chinese population. Further studies are needed to isolate functional mutations in the CYP4A11 gene related to CAD.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (grant number: 81060020).

References

Frazier

Johnson

Sparks

. Genomics and cardiovascular disease. J Nurs Scholarsh. 2005;37(4):315–321.

Nordlie

Wold

Kloner

. Genetic contributors toward increased risk for ischemic heart disease. J Mol Cell Cardiol. 2005;39(4):667–679.

Winkelmann

Hager

. Genetic variation in coronary heart disease and myocardial infarction: methodological overview and clinical evidence. Pharmacogenomics. 2000;1(1):73–94.

Zordoky

El-Kadi

. Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases. Pharmacol Ther. 2010;125(3):446–463.

Elbekai

El-Kadi

. Cytochrome P450 enzymes: central players in cardiovascular health and disease. Pharmacol Ther. 2006;112(2):564–587.

Wang

Greco

Sim

Duarte

Wang

Wilcken

. Effect of CYP1A1 MspI polymorphism on cigarette smoking related coronary artery disease and diabetes. Atherosclerosis. 2002;162(2):391–397.

Cornelis

El-Sohemy

Campos

. Genetic polymorphism of CYP1A2 increases the risk of myocardial infarction. J Med Genet. 2004;41(10):758–762.

Yasar

Bennet

Eliasson

. Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction. Pharmacogenetics. 2003;13(12):715–720.

Funk

Endler

Freitag

. CYP2C9*2 and CYP2C9*3 alleles confer a lower risk for myocardial infarction. Clin Chem. 2004;50(12):2395–2398.

10.

Spiecker

Darius

Hankeln

. Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2. Circulation. 2004;110(15):2132–2136.

11.

Nakayama

Soma

Saito

. Association of a novel single nucleotide polymorphism of the prostacyclin synthase gene with myocardial infarction. Am Heart J. 2002;143(5):797–801.

12.

Hengstenberg

Holmer

Mayer

. Evaluation of the aldosterone synthase (CYP11B2) gene polymorphism in patients with myocardial infarction. Hypertension. 2000;35(3):704–709.

13.

Letonja

Peterlin

Bregar

. Are the T/C polymorphism of the CYP17 gene and the tetranucleotide repeat (TTTA) polymorphism of the CYP19 gene genetic markers for premature coronary artery disease in Caucasians?. Folia Biol (Praha). 2005;51(3):76–81.

14.

Gainer

Bellamine

Dawson

. Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension. Circulation. 2005;111(1):63–69.

15.

Mayer

Lieb

Götz

. Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy. Hypertension. 2005;46(4):766–771.

16.

Muthalif

Benter

Karzoun

. 20-Hydroxyeicosatetraenoic acid mediates calcium/calmodulin-dependent protein kinase II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. Proc Natl Acad Sci U.S.A. 1998;95(21):12701–12706.

17.

Nakayama

Sato

. Haplotype-based case study of human CYP4A11 gene and cerebral infarction in Japanese subject. Endocrine. 2008;33(2):215–222.

18.

Uddin

Muthalif

Karzoun

. Cytochrome P-450 metabolites mediate norepinephrine-induced mitogenic signaling. Hypertension. 1998;31(2):242–247.

19.

Muthalif

Karzoun

Gaber

. Angiotensin II-induced hypertension: contribution of Ras GTPase/Mitogen-activated protein kinase and cytochrome P450 metabolites. Hypertension. 2000;36(4):604–609.

20.

Vazquez

Rios

Escalante

. Arachidonic acid metabolism modulates vasopressin-induced renal vasoconstriction. Life Sci. 1995;56(18):1455–1466.

21.

Chu

Croft

Kingsbury

Falck

Reddy

Beilin

. Cytochrome P450 metabolites of arachidonic acid may be important mediators in angiotensin II-induced vasoconstriction in the rat mesentery in vivo. Clin Sci (Lond). 2000;98(3):277–282.

22.

Imig

Pham

LeBlanc

Reddy

Falck

Inscho

. Cytochrome P450 and cyclooxygenase metabolites contribute to the endothelin-1 afferent arteriolar vasoconstrictor and calcium responses. Hypertension. 2000;35(1 pt 2):307–312.

23.

Schwartzman

Abraham

Masferrer

. Cytochrome P450 dependent metabolism of arachidonic acid in bovine corneal epithelium. Biochem Biophys Res Commun. 1985;132(1):343–351.

24.

Quigley

Baum

Reddy

. Effects of 20-HETE and 19(S)-HETE on rabbit proximal straight tubule volume transport. Am J Physiol Renal Physiol. 2000;278(6):949–953.

25.

McGiff

Quilley

. 20-Hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids and blood pressure. Curr Opin Nephrol Hypertens. 2001;10(2):231–237.

26.

Hill

Fitzpatrick

Murphy

. Biological activity and metabolism of 20-hydroxyeicosatetraenoic acid in the human platelet. Br J Pharmacol. 1992;106(2):267–274.

27.

Gross

Falck

Gross

. Cytochrome P450 and arachidonic acid metabolites: role in myocardial ischemia/reperfusion injury revisited. Cardiovasc Res. 2005;68(1):18–25.

28.

Nithipatikom

Gross

Endsley

. Inhibition of cytochrome P450omega-hydroxylase: a novel endogenous cardioprotective pathway. Circ Res. 2004;95(8):e65–e71.

29.

Lino Cardenas

Renault

Farce

. Genetic polymorphism of CYP4A11 and CYP4A22 genes and in silico insights from comparative 3D modelling in a French population. Gene. 2011;487(1):10–20.

30.

Laffer

Gainer

Waterman

. The T8590C polymorphism of CYP4A11 and 20-hydroxyeicosatetraenoic acid in essential hypertension. Hypertension. 2008;51(3):767–772.

31.

Fava

Montagnana

Almgren

. The V433 M variant of the CYP4F2 is associated with ischemic stroke in male Swedes beyond its effect on blood pressure. Hypertension. 2008;52(2):373–380.

32.

Williams

Hopkins

Jeunemaitre

Brown

. CYP4A11 T8590C polymorphism, salt-sensitive hypertension, and renal blood flow. J Hypertens. 2011;29(10):1913–1918.

33.

Ward

Tsai

Barden

. A single nucleotide polymorphism in the CYP4F2 but not CYP4A11 gene is associated with increased 20-HETE excretion and blood pressure. Hypertension. 2008;51(5):1393–1398.

34.

Sugimoto

Akasaka

Katsuya

. A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population. Hypertension. 2008;52(6):1142–1148.

35.

Hermann

Hellermann

Quitzau

. CYP4A11 polymorphism correlates with coronary endothelial dysfunction in patients with coronary artery disease--the ENCORE trials. Atherosclerosis. 2009;207(2):476–479.

36.

Mayer

Lieb

Götz

. Association of a functional polymorphism in the CYP4A11 gene with systolic blood pressure in survivors of myocardial infarction. J Hypertens. 2006;24(10):1965–1970.

37.

Zhang

. A common polymorphism of CYP4A11 is associated with blood pressure in a Chinese population. Hypertens Res. 2011;34(5):645–648.

A Novel Polymorphism of the CYP4A11 Gene is Associated With Coronary Artery Disease

Abstract

Background:

Methods:

Results:

Conclusions:

Keywords

Introduction

Participants and Methods

Participants

Genotyping

Biochemical Analyses

Statistical Analyses

Results

Discussion

Footnotes

Declaration of Conflicting Interests

Funding

References