Mol. Hum. Reprod. Advance Access originally published online on November 5, 2004
Molecular Human Reproduction 2005 11(1):11-14; doi:10.1093/molehr/gah131
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Angiotensin I-converting enzyme ACE 2350*G and ACE-240*T-related genotypes and alleles are associated with higher susceptibility to endometriosis
1Department of Obstetrics and Gynecology, 2Department of Pediatrics and Medical Genetics, 3Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan, 4Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan and 5Taichung Health Care and Management University, Taichung, Taiwan, Republic of China
6 To whom correspondence should be addressed at: Department of Pediatrics and Medical Genetics, China Medical University Hospital, No.2 Yuh-Der Road, Taichung, Taiwan. Email: d0704{at}www.cmuh.org.tw
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Abstract |
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Endometriosis displays features similar to malignancy, ranging from neovascularization to local invasion and aggressive spread to distant organs. The altered vascular-related genes might be related to the development of endometriosis. This study investigates whether angiotensin I-converting enzyme (ACE) *A2350G and A-240T gene polymorphisms could be used as markers of susceptibility in endometriosis. Women were divided into two groups: (1) endometriosis group (n=150) and (2) non-endometriosis group (n=159). Genomic DNA was obtained from peripheral leukocytes. ACE A2350G and A-240T gene polymorphisms were amplified by PCR and detected after restriction enzyme digestion with BstUI and XbaI. Genotypes and allelic frequencies in both groups were compared. We observed that genotype distribution and allele frequency of ACE 2350 and ACE-240 gene polymorphisms in both groups were significantly different. Proportions of ACE 2350*A homozygote/heterozygote/G homozygote in both groups were: (1) 66.7/29.3/4% and (2) 96.2/3.1/0.7%. Proportions of ACE-240*A homozygote/heterozygote/T homozygote in both groups were: (1) 43.3/46/10.7% and (2) 62.9/35.8/1.3%. We concluded that ACE 2350*G and ACE-240*T-related genotypes and alleles are associated with higher susceptibility to endometriosis. ACE A2350G and A-240T gene polymorphisms might be associated with endometriosis development.
Key words: angiotensin I-converting enzyme/ACE/endometriosis/polymorphism/SNP
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Introduction |
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Endometriosis, a polygenic/multi-factorial disease, is associated with complex interactions between hormone and cytokine activation, immunoinflammatory processes and genetic factors (Vigano et al., 1998
). Endometriosis displays some features of malignancy, including local invasion and aggressive spread to distant organs. Similar to tumour metastases, endometriotic implants require neovascularization to become established, grow and invade tissues. Neovascular processes are prominent in the endometric tissue. Heritable genetic factors may contribute to the initiation and progression of endometriosis (Treloar et al., 1999).
Cardiovascular genes play a role in the regulation and growth of tumour and altered vascular-related genes might be related to the development of endometriosis. The renin–angiotensin system (RAS) regulates blood pressure through its effects on vascular tone, renal haemodynamics and fluid–electrolyte balance (Fornage et al., 1998). Angiotensin I-converting enzyme (ACE) regulates systemic circulation through angiotensin II formation and kinin metabolism. ACE cleaves angiotensin I to angiotensin II, which is the key component in RAS (Berge et al., 1994). The ACE and RAS genes are related to the regulatory pathway in cardiovascular disease (Zhu et al., 2001), while the ACE gene is implicated as a risk factor in coronary artery disease and myocardial infarction (Zhu et al., 2001).
Gene polymorphisms are useful tools in the study of multi-factorial disorders (Anderson et al., 1994). The analyses of single nucleotide polymorphism (SNP) can be implemented to determine the mechanisms of complex genetic disorders. Numerous chronic disorders, such as endometriosis, osteoporosis, hypertension, diabetes and asthma, have been attributed to genetic susceptibility. Most studies on ACE gene polymorphisms have been focused on their associations with cardiovascular diseases, serum ACE level and blood pressure (Zhu et al., 2001).
Angiogenesis and vascular remodelling play critical roles in the growth, invasion and regression of endometriosis (Donnez et al., 1998). The presence of angiotensin receptors has been demonstrated in the endometrial tissue. Angiotensin II in endometrial stromal cells was mediated via angiotensin I receptors (Braileanu et al., 2002). Angiotensin II could increase the intracellular calcium concentration by interaction with angiotensin receptor in endometrial stromal cells (Braileanu et al., 2001). Vasopressin also stimulates phospholipase C activity in endometrial explants (Braileanu et al., 2001). These findings suggest an underlying contribution of ACE for the development of endometrium and endometriosis. In this study, we aimed primarily to evaluate whether ACE A2350G and A-2240T gene polymorphisms are attractive markers for moderate/severe endometriosis susceptibility. To the best of our knowledge, this is the first survey in this field.
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Materials and methods |
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Premenopausal Taiwan Chinese women with surgically diagnosed endometriosis and non-endometriosis were included. All patients were divided into two groups: (1) endometriosis stage III/IV (n=150); (2) non-endometriosis group (n=159). All individuals with endometriosis accepted laparoscopy or laparotomy management and endometriosis was confirmed pathologically. The non-endometriosis status in the control group was confirmed by sonography and clinical evaluation. All patients had normal blood pressure without obvious cardiovascular disease. There were non-significant differences between both groups in age (34.5±4.2 versus 36.2±5.1 years), weight (51.4±3.5 versus 53.8±4.2 kg) and height (159.4±2.5 versus 157.4±3.8 cm). In clinical practice, most women with minimal/mild endometriosis accept conservative medication instead of invasive management. Therefore, we only recruited the moderate/severe endometriosis women for the survey. All women had consented to peripheral blood sampling for genotype analyses. The studies were approved by the ethical committee and institutional review board of the China Medical University Hospital. Informed consents were signed by all women who donated their blood.
The ACE A2350G genotypes (intron 17) were determined as previously described (Zhu et al., 2001). The genomic DNA was prepared from peripheral blood leukocytes by the use of a genomic DNA isolation kit (Blossom, Taipei, Taiwan). A total of 50 ng genomic DNA was mixed with 20 pmol of each PCR primer in a total volume of 25 µl containing 10 mM Tris–HCl pH 8.3, 50 mM potassium chloride, 2.0 mM magnesium chloride, 0.2 mM each deoxyribonucleotide triphosphate and 1 U DNA polymerase (Amplitag; Perkin–Elmer, Foster City, CA, USA). A total of two gene polymorphisms was surveyed, including ACE A2350G and ACE A-240T. The SNP information for the genes involved was obtained via the Internet (http://www.ncbi.nlm.nih.gov/LocusLink/).
The PCR primer sequences and conditions for each primer are listed in Table I. The PCR amplification was performed in a programmable thermal cycler GenAmp PCR system 2400 (Perkin–Elmer Applied Biosystems, Foster City, CA, USA). After PCR amplification, the individual gene polymorphisms were analysed by restriction digestion with restriction enzyme (New England Biolabs, Inc., Beverly, MA). The base pairs for their wild, heterozygote and SNP types are listed in Table I.
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The PCR products were mixed together and 10 µl of this solution was loaded into 3% agarose gel containing ethidium bromide for electrophoresis. Genotypes and allelic frequencies for ACE A2350G and A-240T gene polymorphisms in both groups were compared. Correlation between the ACE A2350G genotype and moderate/severe endometriosis was evaluated. Allelic frequencies are expressed as a percentage of the total number of alleles. The SAS system with
2 and Fisher's exact tests were utilized for statistical analyses. A P-value of <0.05 was considered statistically significant. |
Results |
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Genotype distribution and allele frequency of ACE 2350 and ACE-240 gene polymorphisms in both groups were significantly different (Tables II and III). Proportions of ACE 2350*A homozygote/heterozygote/G homozygote in endometriosis and non-endometriosis populations were (1) 66.7/29.3/4% and (2) 96.2/3.1/0.7%, respectively (P<0.0001; Table II). The percentage of ACE 2350*A/G alleles in both groups were (1) 81.3/18.7% and (2) 97.8/2.2%, respectively (P<0.0001; Table II). Proportions of ACE-240*A homozygote/heterozygote/T homozygote in both groups were (1) 43.3/46/10.7% and (2) 62.9/35.8/1.3%, respectively (P<0.0001; Table III). The percentage of ACE-240*A/T alleles in both groups were (1) 66.3/33.7% and (2) 81.8/18.2%, respectively (P<0.0001; Table III).
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The most common genotype and allele for ACE 2350 and ACE-240 gene polymorphisms in both groups were A homozygote and allele. However, the ACE 2350*G-related genotypes (A/G heterozygote, G homozygote, G allele) and ACE-240*T-related genotypes (A/T heterozygote, T homozygote, T allele) were strikingly higher among the endometriosis population (Tables II and III). These findings indicated that ACE 2350*G and ACE-240*T-related genotype and allele were associated with higher susceptibility to endometriosis.
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Discussion |
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The endometrium, which has prominent blood vessels and blood flow, is one of the few adult tissues that exhibits regular periods of rapid growth. Angiogenesis, therefore, is an important component for the growth and function of these tissues. Endometriosis is a disease of endometrial tissue shedding outside the uterus during menstruation. These explants require a rich blood supply which enables them to survive and grow. The activation of angiogenesis, therefore, might be a key factor in pathogenesis of endometriosis (Inan et al., 2003
).
ACE activity is associated with angiogenesis. ACE inhibition by perindopril improves myocardial angiogenesis (Toblli et al., 2004). Angiotensin II, a key regulator of blood pressure and body fluid homeostasis, exerts mitogenic effects on endothelial cells. Angiotensin II is also a humoral regulator of peripheral angiogenesis (Walther et al., 2003). ACE catalyses angiotensin II formation; therefore, the ACE activity is positively correlated with angiotensin II production.
Recently, ACE inhibitors were found to significantly inhibit tumour growth and angiogenesis along with suppression of the vascular endothelial growth factor (VEGF) level (Yasumatsu et al., 2004). Angiotensin II might have an important role in carcinogenesis and the anti-angiogenic activity is partly mediated by angiotensin II and ACE inhibition. ACE and angiotensin II inhibitors might be considered as useful anti-tumour agents. However, the mechanisms of suppression of the VEGF level are still unclear. Furthermore, in our previous survey, we also observed a correlation between VEGF and endometriosis (Hsieh et al., 2004). Considering all these observations ACE appears to have angiogenic and tumorigenic effects upon endometriosis.
The ACE gene, which is located on chromosome 17q23, contains some gene polymorphisms and candidate markers for hypertension and related diseases (Doria et al., 1994). The ACE gene polymorphism located on intron 17 of the ACE gene might be in linkage disequilibrium with other important gene variants. ACE gene polymorphisms are related to numerous diseases, including carotid artery wall thickness (Sayed-Tabatabaei et al., 2003), post-transplant erythrocytosis (Yildiz et al., 2003), diabetic nephropathy (Chang et al., 2003), Alzheimer's disease (Kehoe et al., 2003), ischwemic cerebrovascular disease (Um et al., 2003), dementia (Choi et al., 2003), segmental glomerulosclerosis (Dixit et al., 2002), cystic fibrosis (Arkwright et al., 2003), etc. ACE insertion/deletion (I/D) polymorphism affects the uteroplacental and umbilical flow as well as the recurrence of an adverse pregnancy outcome in women with pre-eclampsia (Mello et al., 2003). The ACE I/D and M235T polymorphisms are associated with an increased risk of developing coronary heart disease, hypertension and ventricular hypertrophy (Alvarez et al., 2000; Sethi et al., 2003). Three ACE gene polymorphisms [Alu insertion/deletion, 23949 (CT), 10698 (G)] might influence the development of systemic lupus erythematosus and nephritis (Parsa et al., 2002).
In contrast, some investigators have demonstrated the non-association between the ACE gene polymorphisms with individual diseases, including hypertension (Harrap et al., 1993), left ventricular hypertrophy (West et al., 1997), pregnancy outcomes, pregnancy-induced hypertension (Tamura et al., 1996) and nephronophthisis (Omran et al., 1999). ACE-5466C and 4656 gene polymorphisms are not directly related to the occurrence of sarcoidosis (Schurmann et al., 2001). However, the genotype frequencies of the insertion/deletion polymorphisms of the ACE gene and the M235T polymorphism for the angiotensin gene might not contribute to hypertension. This discrepancy might be due to different illness classifications, or racial and disease variations. In fact, different ethnic groups might influence the ACE gene distributions (McKenzie et al., 2001). Ethnic variation plays a major role in the genetic regulation of serum ACE activity and ACE gene polymorphism for cardiovascular disease (Bloem et al., 1996).
Zhu et al. (2001) demonstrated that ACE A2350G and A-240T polymorphisms are significantly associated with blood pressure and ACE concentration. The G allele for the ACE 2350 gene polymorphism is significantly associated with higher blood pressure and ACE concentration (Zhu et al., 2001). They suggested that allelic interaction of these gene polymorphisms might play an important role in the dissection of complex traits such as blood pressure. They also indicated that these associations were more obvious in female individuals than in male patients. Therefore, the gender-specific influence of these gene polymorphisms should be addressed in these studies.
In this study, we noted that the genotype distributions for ACE A2350G and A-240T gene polymorphisms were significantly different between the individuals with and without endometriosis. This finding is the first indicating that ACE gene polymorphisms might predispose to endometriosis development. We also observed that the ACE 2350*G-related genotypes and G allele appeared in a higher percentage among the moderate/severe endometriosis populations than the controls. This finding is compatible with the result of Zhu et al. (2001), who suggested that the ACE 2350*G allele might be associated with a higher risk of vascular lesion (higher systolic blood pressure) and higher ACE concentrations. Therefore, our data strongly suggest that the ACE gene polymorphisms might substantially contribute to the pathogenesis of endometriosis. The data also suggest that RAS might be involved in the pathogenesis of endometriosis.
The mechanisms of SNPs on individual disease remain uncertain. Despite SNPs not altering transcript levels, some investigators have demonstrated that the disequilibrium effects of certain genotypes might influence the related three-dimensional structure and efficiency of the transcripts (Shintani et al., 1999; Kennon et al., 2004; Shirasawa et al., 2004). Presumably, the distinct biological condition caused by ACE is among numerous contributions that influence endometriosis development. These contributions include genetic, dietary and environmental factors regulating hormonal and non-hormonal conditions. Furthermore, the ACE polymorphisms might be in linkage disequilibrium with other unidentified functional polymorphisms, which co-operatively influence the susceptibility to endometriosis.
In conclusion, associations of moderate/severe endometriosis with ACE*A2350G and A-240T gene polymorphisms exist. ACE 2350*G and ACE-240*T-related genotypes and alleles increase the susceptibility to endometriosis. The ACE gene polymorphisms likely contribute to the pathogenesis of endometriosis. Although the real role and mechanism of ACE gene polymorphisms has not yet been clarified, this polymorphism deserves more attention for realizing its importance to endometriosis development. Furthermore, this study could be extended to determine whether the RAS and its related gene polymorphism also affect the endometriosis formation. After the clarification of its role in endometriosis, ACE gene polymorphism may become a useful marker to predict the future development of endometriosis and to permit early therapeutic intervention in women at high risk of endometriosis.
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References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Alvarez R, Terrados N, Ortolano R, Iglesias-Cubero G, Reguero JR, Batalla A, Cortina A, Fernandez-Garcia B, Rodriguez C, Braga S et al (2000) Genetic variation in the renin–angiotensin system and athletic performance. Eur J Appl Physiol 82, 117–120.[CrossRef][ISI][Medline]
Anderson TI, Heimdal KR, Skrede M, Tveit K, Berg K and Borresen AL (1994) Oestrogen receptore (ESR) polymorphisms and breast cancer susceptibility. Hum Genet 94, 665–670.[ISI][Medline]
Arkwright PD, Pravica V, Geraghty PJ, Super M, Webb AK, Schwarz M and Hutchinson IV (2003) End-organ dysfunction in cystic fibrosis: association with angiotensin I converting enzyme and cytokine gene polymorphisms. Am J Respir Crit Care Med 167, 384–389.
Berge KE and Berg K (1994) No effect of insertion/deletion polymorphism at the ACE locus on normal blood pressure level or variability. Clin Genet 45, 169–174.[ISI][Medline]
Bloem LJ, Manatunga AK and Pratt JH (1996) Racial difference in the relationship of an angiotensin I-converting enzyme gene polymorphism to serum angiotensin I-converting enzyme activity. Hypertension 27, 62–66.
Braileanu GT, Simasko SM, Hu J, Assiri A and Mirando MA (2001) Effects of arginine- and lysine-vasopressin on phospholipase C activity, intracellular calcium concentration and prostaglandin F2alpha secretion in pig endometrial cells. Reproduction 121, 605–612.[Abstract]
Braileanu GT, Simasko SM, Speth RC, Daubert DC, Hu J and Mirando MA (2002) Angiotensin II increases intracellular calcium concentration in pig endometrial stromal cells through type 1 angiotensin receptors, but does not stimulate phospholipase C activity or prostaglandin F2alpha secretion. Reprod Fertil Dev 14, 199–205.[CrossRef][Medline]
Chang HR, Cheng CH, Shu KH, Chen CH, Lian JD and Wu MY (2003) Study of the polymorphism of angiotensinogen, anigiotensin-converting enzyme and angiotensin receptor in type II diabetes with end-stage renal disease in Taiwan. J Chin Med Assoc 66, 51–56.[Medline]
Choi YH, Kim JH, Kim DK, Kim JW, Kim DK, Lee MS, Kim CH and Park SC (2003) Distributions of ACE and APOE polymorphisms and their relations with dementia status in Korean centenarians. J Gerontol A Biol Sci Med Sci 58, 227–231.
Dixit M, Mansur A, Dixit N, Gilman J, Santarina L and Glicklich D (2002) The role of ACE gene polymorphism in rapidity of progression of focal segmental glomerulosclerosis. J Postgrad Med 48, 266–269.[Medline]
Donnez J, Smoes P, Gillerot S, Casanas-Roux F and Nisolle M (1998) Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod 13, 1686–1690.
Doria A, Warram JH, Rich SS and Krolewski AS (1994) Angiotensin I-converting enzyme (ACE): estimation of DNA haplotypes in unrelated individuals using denaturing gradient gel blots. Hum Genet 94, 117–123.[ISI][Medline]
Fornage M, Amos CI, Kardia S, Sing CF, Turner ST and Boerwinkle E (1998) Variation in the region of the angiotensin-converting enzyme gene influences interindividual differences in blood pressure levels in young white males. Circulation 97, 1773–1779.
Harrap SB, Davidson HR, Connor JM, Soubrier F, Corvol P, Fraser R, Foy CJ and Watt GC (1993) The angiotensin I converting enzyme gene and predisposition to high blood pressure. Hypertension 21, 455–460.
Hsieh YY, Chang CC, Tsai FJ, Yeh LS, Lin CC and Peng CT (2004) T allele for VEGF gene-460 polymorphism at the 5''-untranslated region: association with a higher susceptibility to endometriosis. J Reprod Med 49, 468–472.[ISI][Medline]
Inan S, Kuscu NK, Vatansever S, Ozbilgin K, Koyuncu F and Sayhan S (2003) Increased vascular surface density in ovarian endometriosis. Gynecol Endocrinol 17, 143–150.[ISI][Medline]
Kehoe PG, Katzov H, Feuk L, Bennet AM, Johansson B, Wiman B, de Faire U, Cairns NJ, Wilcock GK, Brookes AJ et al. (2003) Haplotypes extending across ACE are associated with Alzheimer's disease. Hum Mol Genet 12, 859–867.
Kennon B, Ingram MC, Friel EC, Anderson NH, MacKenzie SM, Davies E, Shakerdi L, Wallace AM, Fraser R and Connell JM (2004) Aldosterone synthase gene variation and adrenocortical response to sodium status, angiotensin II and ACTH in normal male subjects. Clin Endocrinol (Oxf) 61, 174–181.[CrossRef][Medline]
McKenzie CA, Abecasis GR, Keavney B, Forrester T, Ratcliffe PJ, Julier C, Connell JM, Bennett F, McFarlane-Anderson N, Lathrop GM et al. (2001) Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE). Hum Mol Genet 10, 1077–1084.
Mello G, Parretti E, Gensini F, Sticchi E, Mecacci F, Scarselli G, Genuardi M, Abbate R and Fatini C (2003) Maternal–fetal flow, negative events, and preeclampsia: role of ACE I/D polymorphism. Hypertension 41, 932–937.
Omran H, Haffner K, Vollmer M, Pigulla J, Wagner G, Caridi G and Hildebrandt F (1999) Exclusion of the candidate genes ACE and Bcl-2 for six families with nephronophthisis not linked to the NPH1 locus. Nephrol Dial Transplant 14, 2328–2331.
Parsa A, Peden E, Lum RF, Seligman VA, Olson JL, Li H, Seldin MF and Criswell LA (2002) Association of angiotensin-converting enzyme polymorphisms with systemic lupus erythematosus and nephritis: analysis of 644 SLE families. Genes Immun 1, Suppl. 3. S42–S46.[CrossRef]
Sayed-Tabatabaei FA, Houwing-Duistermaat JJ, van Duijn CM and Witteman JC (2003) Angiotensin-converting enzyme gene polymorphism and carotid artery wall thickness: a meta-analysis. Stroke 34, 1634–1639.
Schurmann M, Reichel P, Muller-Myhsok B, Dieringer T, Wurm K, Schlaak M, Muller-Quernheim J and Schwinger E (2001) Angiotensin-converting enzyme (ACE) gene polymorphisms and familial occurrence of sarcoidosis. J Intern Med 249, 77–83.[CrossRef][ISI][Medline]
Sethi AA, Nordestgaard BG and Tybjaerg-Hansen A (2003) Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease: a meta-analysis. Arterioscler Thromb Vasc Biol 23, 1269–1275.
Shintani S, Matsuo K, Crohin CC, McBride J, Tsuji T, Donoff RB, Posner M, Todd R and Wong DT (1999) Intragenic mutation analysis of the human epidermal growth factor receptor (EGFR) gene in malignant human oral keratinocytes. Cancer Res 59, 4142–4147.
Shirasawa S, Harada H, Furugaki K, Akamizu T, Ishikawa N, Ito K, Ito K, Tamai H, Kuma K, Kubota S et al. (2004) SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease. Hum Mol Genet 13, 2221–2231.
Tamura T, Johanning GL, Goldenberg RL, Johnston KE and DuBard MB (1996) Effect of angiotensin-converting enzyme gene polymorphism on pregnancy outcome, enzyme activity, and zinc concentration. Obstet Gynecol 88, 497–502.[Abstract]
Toblli JE, Cao G, DeRosa G, Di Gennaro F and Forcada P (2004) Angiotensin-converting enzyme inhibition and angiogenesis in myocardium of obese Zucker rats. Am J Hypertens 17, 172–180.[CrossRef][ISI][Medline]
Treloar SA, O'Connor DT, O'Connor VM and Martin NG (1999) Genetic influences on endometriosis in an Australian twin sample. Fertil Steril 71, 701–710.[CrossRef][ISI][Medline]
Um JY, An NH, Kim SH, Lee KM, Kim YS, Jang H, Cho KH, Moon BS and Kim HM (2003) Genetic susceptibility to ischemic cerebrovascular disease in Koreans. J Mol Neurosci 20, 31–38.[CrossRef][ISI][Medline]
Vigano P, Gaffuri B, Somigliana E, Busacca M, Di Blasio AM and Vignali M (1998) Expression of intercellular adhesion molecule (ICAM)-1 mRNA and protein is enhanced in endometriosis versus endometrial stromal cells in culture. Mol Hum Reprod 4, 1150–1156.
Walther T, Menrad A, Orzechowski HD, Siemeister G, Paul M and Schirner M (2003) Differential regulation of in vivo angiogenesis by angiotensin II receptors. FASEB J 17, 2061–2067.
West MJ, Summers KM, Wong KK and Burstow DJ (1997) Renin–angiotensin system gene polymorphisms and left ventricular hypertrophy. The case against an association. Adv Exp Med Biol 432, 117–122.[ISI][Medline]
Yasumatsu R, Nakashima T, Masuda M, Ito A, Kuratomi Y, Nakagawa T and Komune S (2004) Effects of the angiotensin-I converting enzyme inhibitor perindopril on tumor growth and angiogenesis in head and neck squamous cell carcinoma cells. J Cancer Res Clin Oncol 130, 567–573.[ISI][Medline]
Yildiz A, Yazici H, Cine N, Kazancioglu R, Akkaya V, Sever MS, Ark E and Erginel-Unaltuna N (2003) Angiotensin converting enzyme gene polymorphism and development of post-transplant erythrocytosis. J Nephrol 16, 399–403.[ISI][Medline]
Zhu X, Bouzekri N, Southam L, Cooper RS, Adeyemo A, McKenzie CA, Luke A, Chen G, Elston RC and Ward R (2001) Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet 68, 1139–1148.[CrossRef][ISI][Medline]
Submitted on September 19, 2004; resubmitted on October 18, 2004; accepted on October 22, 2004.
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