Angiotensin converting enzyme (ACE) and angiotensin II type I receptor (ATIR) polymorphisms in Egyptian patients with preeclampsia
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https://www.eduzhai.net Clinical M edicine and Diagnostics 2013, 3(5): 123-128 DOI: 10.5923/j.cmd.20130305.06 Angiotensin Converting Enzyme (ACE) and Angiotensin II Type I Receptor (ATIR) Polymorphisms in Egyptian Preeclamptic Patients Eman S Kamha1, Doaa A Abdelmonsif1,*, Tamer M H Abdeldaim2 1Dep artment of medical bioch emistry, Faculty of medicine, Alexandria Univ ersity, 21511, Egypt 2Department of obstetric and gynecology, Faculty of medicine, Alexandria University, 21526, Egypt Abstract The aim of the present study was to investigate the possible associations of ACE I/D and AT1R A1166C genotypes and alleles with the risk of preeclampsia in Egypt. The study was conducted on 65 wo men with severe preeclampsia and 25 age and parity-matched controls. They were selected fro m the obstetric clin ic of Elshatby Hospital, faculty of medicine, Alexandria University, Egypt. All patients were subjected to full history taking, clinical examination, serum uric acid, liver function tests (ALT &AST), and determination of fetal outcome (fetal distress state). Patients and controls were subjected to ACE I/ D gene polymorphis m analysis by polymerase chain reaction (PCR) and AT1R A1166C gene polymorphism analysis by PCR-restriction frag ment length polymorphism (RFLP). Both DD and ID genotypes of the ACEgene showed a significant relat ion to the occurrence of preeclampsia. Additionally, ACE DD genotype was significantly related to early onset preeclampsia. D allele showed a significant relation to the occurrence of early preeclampsia as well. Furthermore, the risk of early preeclampsia was 5.44 fo ld with D allele. The distribution of the AT1R A1166C poly morphis m was similar in the preeclamptic patients and control group. Consequently, ACE gene I/D poly morphis m, but not AT1R gene A1166C, poly morphis m could be related to the occurrence and onset of preeclampsia in Egyptian wo men. When proved by large-scale studies, we might be able to assess patients’ risk of developing preeclampsia especially early-onset preeclampsia. Consequently, preventative or early therapeutic interventions could be considered in order to reduce preeclampsia-associated morb idity and mortality. Keywords Preeclampsia, Angiotensin Converting Enzy me (A CE), Angiotensin II Type I Receptor (ATIR) 1. Introduction Preeclampsia is a pregnancy-specific d isorder in 6-8% of all pregnancies, mostly in primigravida. Preeclampsia is characterized by new-onset hypertension, proteinuria and vascular dysfunction presenting after the 20th week of gestation.[1,2] It remains a leading cause of maternal and fetal mo rbid ity and mortality worldwide. Preeclampsia is mu ltifactorial d isorder that results fro m co mplex interaction between genetic and environmental factors. During normal pregnancy, because of the stimu lation of the ren in -ang iotens in -aldosteron e system (RAA S), the plasma levels of renin and aldosterone are increased. In contrast, preeclamptic wo men suffer fro m suppression of the RAAS system and are h ighly sensitive to the pressor effects of angiotensin II together with increased vascular res is tance and failure to develop the phys iologic * Corresponding author: firstname.lastname@example.org (Doaa A Abdelmonsif) Published online at https://www.eduzhai.net Copyright © 2013 Scientific & Academic Publishing. All Rights Reserved hypervolemia of pregnancy.[4,6] Genes coding for components of the renin–angiotensin system (RAS) are considered to be candidates that may affect the risk o f gestational hypertension and preecla mpsia. Angiotensin-converting enzyme (ACE) is an important circulating enzy me in the RAS, wh ich catalyzes the conversion of angiotensin I to angiotensin II and degrades bradykinin. As a result, it p lays an important ro le in blood pressure homeostasis. A co mmon insertion/deletion (I/D) polymorphis m in intron 16 within the ACE gene was previously reported to be associated with different plas ma ACE levels, and indiv iduals carry ing the D allele had higher ACE activit ies. Furthermo re, several studies, have reported that wo men carrying the D allele of the ACE-I/D polymorphis m had higher ACE act ivity and higher measures of uterine artery resistance, which is a marker for development of intrauterine g rowth retardation and preecla mp s ia. [8 ,9 ] Angiotensin II, wh ich results fro m enzy mat ic reaction of ACE on angiotensin I, binds to angiotensin II type-1 receptor (AT1R). Angiotensin II-AT1R axis might explain vascular maladaptation in preeclampsia with 124 Eman S Kamha et al.: Angiotensin Converting Enzyme (ACE) and Angiotensin II Type I Receptor (ATIR) Polymorphisms in Egyptian Preeclamptic Patients increased vasomotor tone, endothelial dysfunction, and increased sensitivity to angiotensin II and norepinephrine in man ifest preeclampsia. As a result, enhanced activity of the angiotensin II-AT1R axis was hypothesized to contribute to the complications of preeclampsia. Although ACE and AT1R gene poly morph isms have been studied in other preeclamptic population, their possible role in Egyptian preeclamptic patients hasn’t been settled yet. The aim of the present study is to investigate the frequency of A CE I/D and AT1R A 1166C alleles and genotypes in Egyptian preeclampt ic patients. Moreover, to investigate their possible association with the risk of preeclampsia among Egyptian pregnant women as well as their possible relation to maternal outcome. 2. Material and Methods The study was conducted on 65 wo men with severe form of preeclampsia and 25 age and parity-matched controls. They were selected fro m the obstetric clinic of Elshatby Hospital, faculty of med icine, Alexandria University, Egypt. An informed written consent was obtained fro m each individual before part icipation in the study. Moreover, the study was approved by the institutional Ethics Co mmittee. Preeclampsia was defined as blood pressure≥140/90 mmHg and proteinuria ≥300 mg/24hr. Severe preeclampsia was defined as blood pressure≥160/ 110mmHg, proteinuria ≥2g/24hr, platelet count of<100,000/ mm3, or elevated hepatic enzymes. All patients were subjected to full history taking, clinical examination, seru m uric acid, liver function tests (ALT &AST), and determination of fetal outcome (fetal distress state) using umbilical artery systolic/diastolic (S/D) ratio and middle cerebral artery resistance index (M CA RI). Besides, DNA was extracted fro m blood for analysis of ACE I/D gene polymo rphism by polymerase chain reaction (PCR). Moreover, AT1R A1166C gene poly mo rphis m was detected using PCR-restr iction frag ment length polymorphis m (RFLP). DNA extraction and genotyping; Leukocytes pellet was separated from peripheral blood anticoagulated with Ethylenediaminetetraacetic acid (EDTA). All leukocytes samples were stored at –20ºC until DNA isolation. Geno mic DNA was ext racted using a spin co lu mn protocol [GeneJET™ Whole Blood Geno mic DNA Purification Mini Kit (Thermo Fisher Scient ific Inc. http://www.thermoscient ific.co m/fermentas)]. Poly merase chain reaction (PCR) was performed to determine the different genotypes of ACE I/D polymorphis m. The specific primers were 5′- CTG GA G ACC A CT CCC ATC CTT TCT- 3′ (forward) and 5′- GAT GTG GCC ATC A CA TTC GTC A GA T- 3′ (reverse). A total of ≈100 ng of genomic DNA was used in the PCR amp lification which was performed in a total volu me of 25 μl using optimized primer vo lu mes. The PCR protocol consisted of 5 min at 94ºC, 40 cycles of 30 s at 94ºC, 30 s at 60ºC and 1 min at 72ºC and then, 10 min at 72ºC fo r final extension (What man , Bio met ra, T personal. http://www.bio metra.co m). PCR products were electrophoresed on a 1.5% agarose gel and visualized by UV illu mination[Bio metra. http://www.bio met ra.co m]. A CE II genotype produced a 490-bp frag ment, DD genotype produced a 190-bp frag ment, and ID genotype produced two frag ments of 490 and 190-bp. The AT1R A1166C poly morph ism was detected using RFLP. The PCR react ion included the forward primer of 5’-GCA CCATGTTTTGA GGTTG-3’ and the reverse primer of 5′-CGA CTA CTGCTTA GCATA -3′. A total of ≈100 ng of genomic DNA was used in PCR amp lification which was performed in a total volume o f 25 μl using optimized primer volu mes. The PCR conditions were as follows: initial denaturation at 96ºC for 5 min, followed by 35 cycles of denaturation (96ºC fo r 30 s), annealing (55ºC for 30s), and extension (72ºC for 60s). The terminal extension was performed at 72ºC for 10 min. (What man, Bio metra, T personal. http://www.bio metra.com). To illustrate the AT1R A1166C poly morphis m, PCR products (540 bp) were processed with the restriction endonuclease Dde I (Thermo Fisher Scientific Inc. http://www.thermoscientific.co m/fermentas) at 37ºC, which cuts the product into two pieces, 430 bp and 110 bp long. Dde I detection site was created in the C-type variant at nucleotide 1166. Thus, the homozygote CC created two bands (430 and 110 bp long), the homo zygote AA produced one band (540 bp long), and the heterozygote AC produced all three bands (540,110 and 430 bp long). Digested products were detected on 3% agarose gel containing ethidium bro mide and visualized by UV illu mination [Bio metra. http://www.bio metra.co m]. 3. Results The present case-control study included 65 severe preeclamptic wo men with a mean age of 29±4.5 years. In addition, 25 age and parity-matched pregnant controls were enrolled in the study with a mean age of 28.25±3.9 years. Early onset preeclampsia (before 34 weeks’ gestation) was diagnosed in 15 preeclampt ic wo men wh ile 50 cases were diagnosed as late-onset preeclampsia (after 34 weeks’ gestation). The clinico-laboratory characteristics of the studied groups are shown in table 1. The results showed a significant difference between preeclampt ic patients and control group as regards gestational age, systolic and diastolic blood pressure, serum uric acid, serum ALT&AST, umbilical artery S/D ratio and MCA RI. Clinical M edicine and Diagnostics 2013, 3(5): 123-128 125 Table 1. Clinico-laboratory characteristics of preeclamptic patients and controls MCARI Umbilical artery S/D Gestational age(weeks) Systolic BP(mmHg) Diastolic BP(mmHg) Uric acid(mg/dl) SGPT (U/L) SGO T (U/L) Preecl ampsia (n = 65) 0.64 ± 0.05 6.16 ± 0.81 34.26 ± 1.53 163.0 ± 12.68 115.15 ± 7.65 6.67 ± 0.95 59.0 (41.0 – 920.0) 57.0 (34.0 – 894.0) Con trols (n = 25) 0.76 ± 0.04 2.51 ± 0.27 36.04 ± 1.02 127.0 ± 10.99 82.80 ± 9.02 5.30 ± 0.49 27.0 (20.0 – 30.0) 32.0 (22.0 – 42.0) P value <0.001* t <0.001* t <0.001* t <0.001* t <0.001* t <0.001* t <0.001*MW <0.001*MW Data are express ed in mean ± SD or median (min.–max.). *: Statistically significant at p ≤ 0.05, MW: Mann Whitney test, t: Student t-test. MCARI: middle cerebral artery resistance index, umbilical artery S/D: umbilical artery systolic/diastolic ratio After gel electrophoresis, ACE II genotype produced a 490-bp frag ment, DD genotype produced a 190-bp frag ment, and ID genotype produced two frag ments of 490 and 190-bp (Figure 1A). Furthermo re, after digestion of the amp lified DNA frag ment with DdeI restrict ion enzy me, The AT1R 1166A allele resulted in a 540 bp frag ment, while the 1166C allele resulted in 110 and 430 bp frag ments (Figure 1B). Figure 1. A. PCR analysis for ACE gene. Lane 7 shows the negative control for PCR and Lane 6 shows the 100bp DNA ladder. DD genotype is shown in lanes 3 and 4, ID genotype is shown in lanes 1 and 2, and II genotype is shown in lane 5. B. RFLP analysis for AT1R gene. Lane 2 shows the negative control for PCR and Lane 3 shows the 100bp DNA ladder. AA genotype is shown in lanes 5 and 6, AC genotype is shown in lane 1 and CC genotype is shown in lane 4 The genotype frequencies of A CE and AT1R genes in all groups were in Hardy-Weinberg equilibriu m (p=0.355 and 0.054, respectively). The frequencies of DD, ID, and II genotypes were 63.1, 27.7, and 9.2%% in preeclampt ic patients and 40, 56, and 4% in healthy pregnant wo men, respectively. The frequency of D allele was 76.9% in preeclamptic patients and 68% in controls. There was a significant relation between ACE I/ D genotypes and the occurrence of preeclampsia (p= 0.041). Additionally, each of DD and ID genotypes showed a significant relation to the occurrence of preeclampsia (p=0.048 and 0.012, respectively). The distribution of the AT1R A 1166C polymorphis m was similar in the preeclamptic and control groups. The AA, AC, and CC genotypes frequencies for preeclamptic wo men were 55.4, 41.5, and 3.1% and were 48, 52, and 0% for the controls, respectively. Only two subjects with the CC genotype were identified in the subject with preeclampsia. The C allele frequencies of the AT1R gene were 26 and 23.8% in control subjects and preeclampt ic wo men, respectively (Tab le 2). Regarding the maternal outcome, 96.9% of preeclamptic patients had preterm caesarean section (CS), 1.5% had renal failure and died while 1.5% of patients had HELLP syndrome and died. 61.9% of preterm patients had DD genotype of ACE gene, 28.57% had ID genotype and 9.52% had II genotype. As for AT1R gene, 53.96% of preterm cases had AA genotype, 42.85% had AC genotype and 3.17% had CC genotype. The 2 reported cases for renal failure and HELLP syndrome had ACE DD and AT1R AA genotypes. With respect to the onset of preeclampsia, the present study showed a significant relation between A CE DD genotype and the onset of preeclampsia (p=0.031). D allele showed a significant relation to the occurrence of early preeclampsia as well (p = 0.015). Furthermore, the risk of early preeclampsia was 5.44 fo ld with D allele[OR 5.44 (1.14 - 35.43)]. As for AT1R gene, AA genotype was weakly related to the late onset of preeclampsia (p=0.049). On the other hand, in spite of the higher frequency of the risky AT1R genotypes (AC + CC) co mpared to AA genotype in early preeclampsia, it showed no significant relation with the onset of preeclampsia (p=0.051). Moreover, neither AT1R genotype nor allele had a significant relat ion to the onset of preeclampsia (p=0.117 and 0.060, respectively) (Table 3). 126 Eman S Kamha et al.: Angiotensin Converting Enzyme (ACE) and Angiotensin II Type I Receptor (ATIR) Polymorphisms in Egyptian Preeclamptic Patients Table 2. Genotype and allelic frequencies of ACE and AT1R genes in the studied groups Cases Con trols P value N (%) N (%) ACE Genotype DD ID II O verall p value for Genotype ACE Allele D n = 65 41 (63.1) 18 (27.7) 6 (9.2) n = 130 100 (76.9) n = 25 10 (40) 14 (56) 1 (4) χ2p = 0.041* n = 50 34 (68) χ2p = 0.048* χ2p = 0.012* FEp = 0.668 χ2p = 0.219 I ACE Risky Genotypes DD+ID AT1R Genotype AA AC CC O verall p value for Genotype AT1R Allele A 30 (23.1) 59 (90.8) n = 65 36 (55.4) 27 (41.5) 2 (3.1) n = 130 99 (76.2) 16 (32) 44 (88) n = 25 12 (48) 13 (52) 0 (0) MCp = 0.648 n = 50 37 (74) χ2p = 0.406 χ2p = 0.529 χ2p = 0.371 FEp =1.000 χ2p = 0.763 C 31 (23.8) 13 (26) AT1R Risky Genotypes AC + CC 29 (44.6) 13(52) χ2p = 0.529 χ2: Chi square test, FE: Fisher’s Exact test, MC: Monte Carlo test, *: Statistically significant at p ≤ 0.05. Allele frequ encies were estimated by the gene counting method Table 3. Relation between ACE and AT1R genes and the onset of prepeclampsia Onset of preeclampsia Early N (%) Late N (%) P value OR (95% C I) AC EGenotype n = 15 DD 13 (86.7) ID 2 (13.3) II 0 (0.0) O verall p value for Genotype ACE Allele n = 30 D 28 (93.3) I 2 (6.7) n = 50 28 (56.0) 16 (32.0) 6 (12.0) MCp = 0.099 n = 100 72 (72.0) 28 (28.0) χ2p= 0.031* FEp = 0.201 FEp = 0.322 χ2p= 0.015* 5.44(1.14-35.43) ACE Risky Genotypes DD+ID AT1R Genotype 15(100) n = 15 AA 5 (33.3) AC 9 (60) CC 1 (6.7) O verall p value for Genotype AT1R Allele n = 30 A 19 (63.3) 44 (88) n = 50 31 (62) 18 (36) 1 (2) MCp = 0.117 n = 100 80 (80) χ2p= 0.159 χ2p= 0.049* χ2p= 0.098 FEp= 0.411 χ2p = 0.060 C 11 (36.7) 20 (20) AT1R Risky Genotypes AC + CC 10(66.7) 19(38) χ2p = 0.051 P: p value for comparing between the two studied group, FE: Fisher’s Exact test, MC: Monte Carlo test, χ2: Chi square test, OR: odds ratio, CI: confidence interval, *: Statistically significant at p ≤ 0.05. Allele frequenci es were estimated by the gene counting method Concerning ACE gene, both genotype and allele had a significant effect on the gestational age among the patients’ group (p = <0.001 and <0.001, respectively). On the other hand, neither AT1R genotype nor allele showed a significant effect on the studied parameters (Data not shown). 4. Discussion The understanding of the underlying factors that exp lain the pathogenesis of preeclampsia and the early identification of the patients at risk of the disease will help in the Clinical M edicine and Diagnostics 2013, 3(5): 123-128 127 development of preventative or early therapeutic interventions. These may reduce the long-term severe problems that preeclampsia may produce or is associated with. Angiotensin-converting enzyme is an important member of the RAS family that regulates blood pressure by catalyzing the conversion of angiotensin I into the potent vasoconstrictor angiotensin II. Its action causes vasoconstriction, and elevated ACE activity leads to hypertension. The ACE poly morphism is due to the insertion or deletion of an Alu 289 base pair (bp) sequence located at intron 16. The present study showed a significant difference in the frequency of DD and ID genotypes between the preeclampt ic patients and the control group. In addition, the overall difference between the patients and control subjects was statistically significant. Th is is consistent with a previous meta-analysis based on preeclampsia. Mello et al. exp lained the possible association between ACE poly morphism and preeclampsia, as higher ACE activity, in the presence of DD genotype, may result in an increased angiotensin II level that could cause an inflammatory response. Also, the ACE I/D poly mo rphism is involved in the modulation of maternal uteroplacental and fetal u mbilical flows. It has been suggested that in some populations the D allele, by elevating A CEact ivity and in the presence of various environmental variables, may be associated with hypertension. Furthermore, the study of Bereketoglu et al. suggested the association between the ACE DD genotype and preeclampsia in the analy zed Turkish population. On the other hand, other studies found no difference in the genotype distribution and allele frequency together with no association between DD genotype and occurrence of preeclampsia. [17,18] A possible explanation for the inconsistency among these reports might be genetically based causing different susceptibilit ies among different populations with the same genotype. With respect to the onset of preeclampsia, the current results showed the significant effect of A CE genotype and allele on the gestational age. Further; the study suggested that the DD genotype is significantly h igher in the early onset preeclamptic patients where the D allele was higher in early onset compared to late onset preeclampsia. Besides, the present results indicated that D allele was the risk allele for preeclampsia, where the study subjects carrying the D allele had a 5.44 fo ld higher risk for preeclampsia. Uma et al. suggested the association between the ACE gene DD genotype and early-onset preeclampsia. Additionally, Kaur et al. reported that the ACE DD genotype could be a potent risk factor for the develop ment of hypertension during pregnancy. Besides, a meta-analysis by Chen et al., which included 30 case-control studies, reported the relation between the ACE gene DD genotype and increased risk of pregnancy hypertensive disorders, especially among Asian and Caucasians. With respect to the AT1R A1166C poly morphis m, the present study found no significant difference between the studied groups. On the other hand, AA genotype showed a weak relation to late onset preeclampsia. A kbar et al. reported lack o f association between AT1R A 1166C polymorphis m and preeclampsia in Afro-Caribbean, Asian and Caucasian populations. Li et al. reported that the frequency of genotypes of the AT1R gene was similar in preecla mpsia and norma l p regnancy as well. In addit ion, it has been suggested that AT1R A1166C gene poly morphism had no effect on receptor function or density, although it might alter sensitivity to angiotensin. In contrary, Seremak-Mro zikiewicz et al. revealed that presence of A1166C poly morphis m could be a risk factor for the development of pregnancy-induced hypertension (PIH). Furthermore, Hu et al. reported that the frequency of variants (AC, CC) of AT1R gene A1166C poly morphis m in PIH (20.5%) was significantly h igher than that of control subjects (7.4%). We failed to investigate the combined effect of ACE I/D and AT1R A1166C po ly morphisms on the risk of preeclampsia because of the lack of association ATIR A1166C poly morphism with the risk of preeclampsia. Concerning the maternal outcome, due to limited nu mber of the complicated preeclamptic cases, we were unable to draw a conclusion wh ich necessitates large-scale studies for such patients to come up with a better solution for the preeclampsia-associated morbidity and mortality. 5. Conclusions In conclusion, ACE gene I/ D poly morphis m, but not AT1R gene A1166C poly morphis m, could be related to the risk o f preeclampsia in Egyptian wo men. Fu rther studies are required to validate the testing for ACE gene I/D polymorphis m in preeclampsia. Besides, large-scale studies are needed to elucidate/rule out the possible ru le of AT1R gene A1166C poly mo rphism in preeclampsia. 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