Original Article Association of CYP4A11 Gene Polymorphism with Diabetic Retinopathy in Chinese Patients

Int J Clin Exp Med 2016;9(9):18346-18352 www.ijcem.com /ISSN:1940-5901/IJCEM0025657

Original Article Association of CYP4A11 gene polymorphism with diabetic retinopathy in Chinese patients

Xue-Feng Sun, Xian-Jiang Wang, Yu-Yong Yang

Department of Ophthalmology, Yantai Yeda Hospital, Yantai 264006, China Received February 5, 2016; Accepted June 8, 2016; Epub September 15, 2016; Published September 30, 2016

Abstract: Hypertension is an important risk factor to diabetic retinopathy (DR). CYP4A11 is a member of the cytochrome P450 enzymes, which is involved in the regulation of blood pressure by metabolism of arachidonic acid. It is unknown whether CYP4A11 gene polymorphism T8590C may be associated with DR in China. Here, in a case- control study, we included 395 type 2 diabetes (T2DM) participants with DR and 415 T2DM participants without DR. A single nucleotide polymorphism (SNP) of CYP4A11 was genotyped, and its association with DR was explored using a dominant genetic model. IPLEX technology was performed to analyze the T8590C polymorphism of the CYP4A11 gene. Multivariate logistic regression analysis was conducted to evaluate the association between SNP (rs1126742) and DR. We found that the C allele frequency of T8590C was significantly higher in subjects with DR than the subjects without DR. The variable of SBP level and the duration of T2DM were significantly higher in cases with DR than those without DR. However, the level of HDL-C was significantly higher in individuals without DR than those with DR. Moreover, C allele appeared to increase the risk of development of DR. Thus, we conclude that the CC genotype and C allele may be associated with DR in China. CYP4A11 8590C allele may predispose DR.

Keywords: CPY4A11, diabetic retinopathy (DR), polymorphism, type 2 diabetes (T2DM)

Introduction Blindness primarily develops from either progression of diabetic macular edema (DME) or Diabetes mellitus is a disordered metabolism increases in new retinal vessels [6]. Prolonged with abnormally high blood glucose levels. The duration diabetes, poor control of high blood two most common forms of diabetes are type 1 pressure and blood glucose have been consid- diabetes (impaired production of insulin) and ered as responsible factors for triggering the type 2 diabetes (T2DM; β-cell dysfunction and onset and progression of DR [7]. Hypertension diminished response to insulin) [1]. T2DM is could induce the abnormal balance between considered as a complex heterogeneous group diabetes-associated coagulation and fibrinoly- of metabolic disorders including hyperglycemia sis, and contribute to endothelial dysfunction and impaired insulin action and insulin secre- [8]. In addition, hypertension could induce insu- tion [2]. T2DM causes various dysfunctions in lin resistance, by overexpression of AT1 recep- multiple organs or tissues. Diabetic retinopathy tors and angiotensin II [8]. (DR) is one of the most important complications of T2DM. DR is responsible for blindness CYP4A11, as a member of Cytochrome P450 in as many as 2.5% of the population worldwide superfamily, is responsible for the formation of [3]. DR is also the leading cause of vision loss 20-hydroxyeicosatetraenoic acid (20-HETE), in individuals at the age from 20 to 75 [4]. which forms potent biological effects on vascular functions and controls arterial pressure [9, Clinically, DR is classified into non-proliferative 10]. The alteration of 20-HETE productions, diabetic retinopathy (NPDR) and proliferative which contributes to the development of hyper- diabetic retinopathy (PDR). NPDR inflicts dam- tension, has been reported in both rodents and age to retinal vasculature and leaky blood ves- humans [11]. One of the most meaningful sels. PDR is associated with growth of blood genetic variants of CYP4A11 is the T8590C vessels on the surface of the retina [5]. variant, which is registered as rs1126742 in the CYP4A11 polymorphism with DR

Table 1. Characteristics of study participants DR risk, including serum cholesterol, fast- T2DM T2DM ing blood sugar, blood pressure, HbA1c, with DR without DR P value etc. was collected from all participants. N = 395 N = 415 Local institutional review boards approved Age (years) 63±5.3 61±5.6 0.15 this study, and written informed consents were obtained from all patients before BMI (kg/m2) 28.8±3.8 29.5±4.1 0.16 enrollment. SBP (mmHg) 145±21 134±18 0.016* DBP (mmHg) 88±13 85±15 0.87 Diabetes was defined as according to TC (mmol/L) 5.4±0.6 5.3±0.8 0.22 1999 WHO criteria [16], which met one of TG (mmol/L) 1.95±1.6 1.85±1.5 0.68 the following: fasting plasma glucose FPG HbAlc (mmol/L) 7.3±1.5 7.1±1.2 0.35 ≥ 7.0 mmol/l, random plasma glucose ≥ HDL-C (mmol/L) 1.1±0.2 1.2±0.1 0.01* 11.1 mmol/l or plasma glucose ≥ 11.1 mmol/l 2 hours after an oral glucose tol- LDL-C (mmol/L) 2.6±0.5 2.5±0.6 0.79 2 erance test (OGTT). Patients with diabetic RPF (ml/min per 1.73 m ) 525±95 509±105 0.49 ketoacidosis or ketonuria also were Duration (years) 7.8±4.7 6.7±2.5 0.02* excluded. All the patients underwent digi- BMI = body mass index; SBP = systolic blood; DBP = diastolic blood tal non-mydriatic fundus photography and pressure; HDL-C = high density lipoprotein cholesterol; LDL-C = low- were determined by two independent reti- density lipoprotein cholesterol; TC = total cholesterol; TG = triglyceride; RPF = renal plasma flow. *P < 0.05. The P value of genotype nal specialists without knowledge of was calculated by independent sample t test. patient clinical details. The patients were classified according to the presence or absence of DR. The duration was defined NCBI online database. The substitution of thy- as the interval between the first diagnosis of midine by cytosine at the site of 8590 in diabetes and the time of enrollment in the pres- CYP4A11 gene results in a phenylalanine-to- ent study. Individuals with known or suspected serine transformation at amino acid 434 [12, primary or secondary hypertension, stroke, 13]. This gene mutation significantly reduces coronary artery disease, retinal diseases the catalytic activity of CYP4A11 enzyme in (except DR), overt renal insufficiency (serum vitro [14]. A 24 h urinary 20-HETE excretion is creatinine > 1.5 mg/dl), or other significant lower in homozygotes for the CYP4A11 8590C medical or psychiatric illnesses were excluded. allele compared to heterozygotes and homozy- Besides, Individuals with abnormal electrolytes gotes for the T allele [15]. Moreover, CYP4A11 or thyroid/liver function tests were also 8590C allele is more potent at presence of excluded. load of salt [11]. Since high salt-diet has been a Biochemical analysis custom in China, we hypothesize that CYP4A11 8590C allele may influence the DM in China The plasma concentration of fasting blood and promote the progression of DR. sugar (FBS), glycosylated hemoglobin (HbA1C), high-density lipoprotein (HDL), Total choles- Therefore, the purpose of this study was to terol (TC); Triglyceride (TG) and low-density lipo- examine whether the T-to-C polymorphism of protein (LDL) was measured by standard the CYP4A11 gene plays a role in onset and methods. progression of DR in individuals with T2DM in China. Sample DNA extraction

Materials and methods Blood samples were collected with a standard venipuncture technique and EDTA-containing Individuals and protocol tubes. DNA was extracted from peripheral vein blood leukocytes by the conventional phenol/ Here, 395 patients diagnosed as T2DM with chloroform method. DR and 415 age-matched individuals with T2DM without DR (as control subjects) were SNP genotyping recruited at Yantai Yeda Hospital from 2010 to 2014. All patients and controls involved in this There are 121 SNPs for the human CYP4A11 study were from China. Information related to gene listed in the National Center for Bio-

18347 Int J Clin Exp Med 2016;9(9):18346-18352 CYP4A11 polymorphism with DR

Table 2. Genotype and allele distributions in patients with DR and con- Statistical analysis trol subjects Data are presented as T2DM Total T2DM with DP means ± SD unless without DP P value N = 810 N = 395 N = 415 otherwise stated. Fre- quencies were com- Genotype T/T 466 (57.5%) 192 (48.6%) 274 (66.0%) 0.08 pared among genotype T/C 268 (33.1%) 132 (33.4%) 136 (32.8%) groups using χ2-test or C/C 65 (8.0%) 32 (8.1%) 33 (8.0%) Fisher’s exact test. The Dominant model TT 475 (58.6%) 200 (50.6%) 275 (66.3%) 0.02* differences between the TC+CC 325 (40.1%) 165 (451.8%) 160 (38.6%) patients with DR and Recessive model CC 63 (7.8%) 33 (8.4%) 30 (7.2%) 0.25 the control subjects TC+TT 751 (92.7%) 343 (86.8%) 408 (98.3%) were assessed by inde- Allele T 687 (84.8%) 320 (81.0%) 367 (88.4%) 0.011* pendent sample t te- C 390 (48.1%) 195 (49.4%) 195 (47.0%) st. Continuous variables *P < 0.05. The P value of genotype was calculated by Fisher’s exact test. were compared among genotype groups using one-way analysis of vari- ance or Kruskal-Wallis test. Multiple logistic regression analysis was used to estimate the odds ratio (OR) and its 95% confidence interval (CI) as a measure of the CYP4A11 polymorphism with DR. All statistical analyses were performed using SPSS version 18.0 software (SPSS Inc., Chicago, IL, USA). A p value less than 0.05 was considered significant.

Results

Baseline clinical characteristics of subjects

The baseline characteristics of the 810 participants were listed (Table 1). The variable of SBP Figure 1. Distributions of the C allele. The signifi- level was significantly higher in cases than that cance of the distribution of the C allele was detected in controls (P < 0.05). However, the level of in these two groups. NS: non-significant. HDL-C was significantly higher in controls than in cases (P < 0.05). In addition, there was a significantly longer duration of T2DM in with-DR technology Information SNP database (http:// group as compared with the without-DR group www.ncbi.nlm.nih.gov/SNP). CYP4A11 T8590C (P < 0.05). Other variables of sex, age, height, (rs1126742) is located in exon 11 of CYP4A11, DBP, HbAlc, BMI, TC and TG were no difference and involves in a thymidine cytosine (T8590C) between two groups (P > 0.05 for all). More substitution that results in a non-synonymous importantly, no significance of the amount of phenylalanine serine (F-to-S) substitution at renal plasma flow was detected in these two amino acid residue 434 of CYP4A11. The groups. genetic variant of CYP4A11 T8590C was genotyped using iPLEX (Sequenom, San Diego, Genotype and allele distributions in patients CA, USA) with detection by the matrix-assisted with DR and control subjects laser desorption/ionization time-of-flight mass spectrometry platform. The with-DR and with- The distribution of genotypes and alleles of out-DR groups were mixed for genotyping. T8590C in the CYP4A11 gene was analyzed There was a 99.9% genotype concordance (Table 2). The genotype distributions were in when duplicated samples were compared agreement with the predicted Hardy-Weinberg across plates. equilibrium values. The distribution of CYP4A11

18348 Int J Clin Exp Med 2016;9(9):18346-18352 CYP4A11 polymorphism with DR

Table 3. Variables in different genotypes of patients with DR analyses showed that SNP Variables TT TC CC P value (rs1126742) was associated with DR (P < 0.05, Table 4). Age (years) 59.7±4.5 61.5±4.2 60.7±3.57 0.35 2 BMI (kg/m ) 28.5±3.2 27.8±3.7 28.2±3.1 0.51 Discussion SBP (mmHg) 132±21 148±24.3 143±21 0.015* DBP (mmHg) 88.1±13 84.4±11 86.5±12 0.015* The polymorphism of CYP4A11 TC (mmol/L) 5.4±1.1 5.3±0.9 5.35±0.6 0.53 8590C allele is thought to be TG (mmol/L) 1.90±1.5 1.92±1.2 1.91±1.4 0.8 related with high BP or a diag- HbAlc (mmol/L) 7.1±1.3 7.2±1.6 7.2±1.2 0.375 nosis of hypertension in popu- HDL-C (mmol/L) 1.1±0.3 1.0±0.2 1.06±0.2 0.035* lation studies [17-19]. To the LDL-C (mmol/L) 2.6±0.8 2.5±0.7 2.5±0.6 0.76 best of our knowledge, it is the first study to show that the RPF (ml/min per 1.73 m2) 542±110 506±98 515±100 0.28 genotypic and allelic frequen- Duration (years) 7.6±5.2 6.8±2.4 7.1±2.7 0.12 cies of the T8590C gene BMI = body mass index; SBP = systolic blood; DBP = diastolic blood pressure; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein polymorphism on exon 11 of cholesterol; TC = total cholesterol; TG = triglyceride; RPF = renal plasma flow.* P < CYP4A11 were associated with 0.05. The P value of genotype was calculated by Fisher’s exact test. the occurrence and development of DR in China.

Table 4. Multiple logistic regression analysis for DR DM is a multifactorial and com- Variables B S.E. P value OR 95% CI plex disease resulting from a CYP4A11 (rs1126742 A/G)a 0.45 0.08 0.015 1.3 1.1-2.2 subtle interaction between genes and environmental fac- CYP4A11 (T8590C) 0.51 0.09 0.002 1.6 1.4-2.1 tors, with which microvascular aadjusted for variables of BMI; SBP; DBP; HDL-C; LDL-C; TC; TG; RPF. and macrovascular complications are highly prevalent 8590TT genotype showed a significant differ- among DM individuals. DR is supposed to be ence between patients with DR and controls. one of the most common and specific micro- The significance of the distribution of the C vascular complications, and is influenced by allele in two groups was also detected (Figure environmental factors and hereditary [20]. 1). Given that DR is one of the leading causes of blindness worldwide, the identification of the Variables in different genotypes of patients associated genes for DR may result in a with DR decrease in vision loss associated with DM [3]. Numerous studies have been conducted over Table 3 showed that the levels of SBP and LBP the past few decades for identification of the were significantly higher in homozygotes for the associated genes for DR. The genes of vascular CYP4A11 8590C allele than the other two endothelial growth factor (VEGF), aldose reduc- groups (P < 0.05, Table 3). Similar to Table 1, tase (ALR) and the receptor for advanced glyca- the level of HDL-C was significantly higher in tion end products (RAGE) have been extensive- homozygotes for the CYP4A11 8590T allele ly studied [6, 21, 22]. Moreover, the polymor- than heterozygotes and homozygotes for the C allele (P < 0.05). Other variables of sex, age, phism of function genes such as KCNJ11 height, DBP, HbAlc, BMI, TC, TG and duration of (rs5219), which controls the regulation of insu- T2DM were no difference between these two lin secretion, is also identified as a genetic risk groups (P > 0.05 for all). factor for DR [22].

Multiple logistic regression analysis for DR In our study, we found that the frequency of the CC genotype and C allele was higher in DR To estimate the association of various clinical than in controls in China. Based on logistic factors and DR, multiple logistic regression regression analyses, we hypothesize that the was developed to include BMI, SBP, DBP, HDL- CC genotype and C allele of CYP4A11 could be C, LDL-C, TC, TG, RPF and genetic variant risk factors for DR. Previous studies have of CYP4A11 T8590C. The multiple logistic reported that the polymorphisms of CYP4A11

18349 Int J Clin Exp Med 2016;9(9):18346-18352 CYP4A11 polymorphism with DR

T8590C have an influence on the production of these findings may be that carriers of the of 20-HETE [11, 15, 23]. Wang et al. showed CYP4A11 8590C allele were significantly young- that inhibition of 20-HETE attenuates DM- er than subjects in the CYP4A11 8590TT geno- induced decreases in retinal hemodynamics type group between the two populations [24]. In the vasculature, 20-HETE is a potent studied. oxygen-dependent vasoconstrictor and up-regulation of the production of this compound 20-HETE inactivates calcium-sensitive potassi- contributes to the elevation in oxidative stress um channels in vascular smooth muscle to [25]. Thus, it may be a link between hypoxia cause renal vasoconstriction, and to increase and vasoconstriction in the DR. 20-HETE vascular reactivity to constrictors such as Ang also lead to endothelial dysfunction and the II, endothelin, and norepinephrine [34, 35]. increase in peripheral vascular resistance However, we didn’t detect the increases in renal associated with some forms of hypertension plasma flow in cases homozygous for the C [26]. In addition, the decrease of 20-HETE is allele. A possible explanation is that although associated with other constriction pathways, 20-HETE is a vasoconstrictor, metabolites of including vasopressin, serotonin, angiotensin CYP4A may induce CYP2C and the renal forma- II and thromboxane [27]. More case studies tion of vasodilator EETs. Wang et al. showed and theoretical analysis are needed to investi- that it is the decreases in retinal blood flow and gate the frequency of this polymorphism in shear force that are responsible for DM-induced Chinese ethnicities. retinal capillary occlusion [24]. Thangaraju et al. and Sen et al. reported that the flow from Blood pressure levels and hypertension preva- both of retina and kidney were attenuated by lence detected in our study are similar to the renin angiotensin system (RAS) and endothelin previous studies. The group of Gainer et al. (ET), but they responded differently under the identified the T8590C variants of CYP4A11 function of same molecule [36, 37]. gene, which affects the catalytic activity of the 20-HETE synthase and influences the There are several limitations of this study. First, link between hypertension and the T8590C all participants in the study were recruited from polymorphism in White and African American China. The high-salt diet habits of the partici- [13, 23]. Mayer et al. further showed that pants may influence BP levels of the individuals the CYP4A11 T8590C polymorphism adjusts with the CC genotype and C allele of CYP4A1l blood pressure levels and hypertension preva- [15, 38]. Second, our report focused primary lence by affecting the systolic and diastolic analyses on a comparison of patients with DR blood pressure [28]. However, Akasaka et al. to participants without DR rather than compar- showed that rather than CYP4A11 T8590C ing those with proliferative DR to those without polymorphism, haplotype was significantly advanced DR. The possibility of an overlap with associated with hypertension [29]. These dif- other causes of retinopathy may limit the iden- ferent results may result from various factors, tification of DR genes. such as ethnic differences, sample size and patient selection. In conclusion, we identified the CC genotype and C allele of CYP4A1l as a genetic risk factor Here, we detected the lower HDL-C in individu- for DR in DM patients. Further studies on the als with CYP4A11 8590C allele. Previous stud- functional effects of CYP4A11 gene T8590C ies have shown that CYP4A11 could catalyze polymorphisms should be conducted to reveal the metabolism of EETs to generate o-hydroxyl- their contribution to DR. ated-EETs [30], the potent endogenous PPARa agonists, which decrease HDL-C by reducing Disclosure of conflict of interest apolipoprotein (apo) A-I and A-II and by down- regulating the reverse cholesterol transport None. pathway [31]. Our findings are consistent with a previous study [32]. However, Hermann et al. Address correspondence to: Xue-Feng Sun, Depart- reported high concentration of HDL-C in homo- ment of Ophthalmology, Yantai Yeda Hospital, zygotes for the CYP4A11 8590C allele com- 11 Taishan Road, Yantai 264006, China. Tel: pared with heterozygotes and homozygotes for +865356375764; Fax: +865356375764; E-mail: the T allele [33]. The reason for the divergence [email protected]

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