Abstract
Angiotensin converting enzyme (ACE; OMIM: 106180) has an important role in the conversion of angiotensin I to angiotensin II and degradation of bradykinin. Genetic polymorphism I/D (rs4646994) in the gene encoding ACE has been well defined. To get more insight into the genetic structure of Iranian populations, the distribution of the ACE I/D polymorphism among Iranians was compared with each other and with other populations. Prevalence of the D allele was 0.5886 (95% CI: 0.5725-0.6047) in Iran. There was significant difference between Iranian populations (x2=27.7, df=6, P<0.001). The major part of this difference was due to difference between Zahedan study and the other populations, as by removing this population, the heterogeneity between populations, remarkably decreased (x2=10.15, df=5, P=0.071). The D allele showed high frequency in Iran which is similar to Caucasians.
Key Words: ACE, Iran, Polymorphism, Population genetics
INTRODUCTION
Angiotensin converting enzyme (EC 3.4.15.1; ACE; OMIM: 106180), is a circulating and membrane bound enzyme. The ACE has an important role in the conversion of angiotensin I to angiotensin II and degradation of bradykinin, a potent vasodilator, which mediates a wide range of cellular functions in different tissues. There is a genetic polymorphism (rs4646994) which is characterized by an insertion/deletion (I/D) within intron 16 in the gene. The D allele has been associated with a higher mRNA level and higher ACE activity [1, 2]. Studies have been demonstrated that this polymorphism is associated with several multifactorial diseases [3, 4].
Iranian population is one of the most heterogeneous populations of the world [5, 6]. To get more insight into the genetic structure of Iranian populations, the present study was carried out.
MATERIALS AND METHODS
Eligible studies having raw data on the I/D polymorphism of ACE in healthy Iranian populations were identified by searching the database in the PubMed (National Center for Biotechnology, National Library of Medicine), DOAJ (Directory of Open Access Journals), ISC (Islamic world Science Citation Center), and SID (Scientific Information Database) for relevant reports published before December 2014 using the following search terms: "ACE", "polymorphism", “ins/del”, “I/D”, and "Iran". Furthermore, references cited in the retrieved articles were screened to trace additional relevant studies. We found 11 studies eligible for our analysis [7-17]. A Chi-square test was performed to determine whether the study samples demonstrated Hardy-Weinberg equilibrium for the mentioned polymorphism. Comparison between populations for prevalence of the D allele was done using a Chi-square test. A probability of P<0.05 was considered statistically significant.
RESULTS AND DISCUSSION
The study samples of the published articles for prevalence of the genotypes of the I/D polymorphism were at Hardy-Weinberg equilibrium. Table 1 shows the prevalence of the D allele in seven Iranian populations using published articles [7-17]. In overall prevalence of the D allele was estimated 0.5886 (95% CI: 0.5725-0.6047) in Iran. There were significant difference between Iranian populations (x2=27.7, df=6, P<0.001). A majority of this difference corresponds to difference between Zahedan study with the other populations, because removing this population, the heterogeneity between populations, remarkably decreased (x2=10.15, df=5, P=0.071).
Table 1.
Distribution of the D allele of ACE I/D polymorphism among several populations
| Province | Ethnicity | Number of subjects | D (%) | References |
|---|---|---|---|---|
| Ardabil | Azaris | 97 | 63.6 | 7 |
| Fars | Persians | 363 | 62.8 | 8 |
| Kermanshah | Kurds | 100 | 54.3 | 9 |
| Sistan va Balochestan | Mixed | 132 | 46.6 | 10 |
| Tehran | Mixed | 744 | 59.0 | 11-14 |
| West Azarbaijan | Kurds | 207 | 54.4 | 15 |
| West Azarbaijan | Azaris | 230 | 59.6 | 16, 17 |
Based on the published articles, there were significant differences in terms of the D allele frequency between the three major ethnic groups. The frequency of the D allele varied among populations, suggesting an ethnic distribution. It seems that the prevalence of the D allele increased from east to west. The prevalence of the D allele was lower among Asian populations (about 25-40%) [3, 4] compared with the Caucasians (generally about 40-60%) [3, 4] and Africans (more than 60%) [18, 19]. The allelic prevalence of the D allele in our sample (about 62.6%) seems to be more similar to the Caucasians than the Asians.
Previous reports on other genetic polymorphisms showed that Iranian gene pool revealed intermediate frequency in comparison with European Caucasians and Asians [6]. However, the present study did not support that conclusion. Some evolutionary forces may be involved for this difference. Arabian populations such as Kuwait, UAE, and Oman showed high prevalence of the D allele (61.0-75.0%) [18, 20]. We know that there was migration between Arab communities and Iranian populations. High prevalence of the D allele among Arabs and their migration into Iranian populations, might be considered at least in part, as the reason for not having the intermediate frequency of the D allele in Iranian population.
Acknowledgements: This study was supported by Shiraz University.
Conflict of Interest: The author declare that he has no competing interest.
References
- 1.Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343–1346. doi: 10.1172/JCI114844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Suehiro T, Morita T, Inoue M, Kumon Y, Ikeda Y, Hashimoto K. Increased amount of the angiotensin-converting enzyme (ACE) mRNA originating from the ACE allele with deletion. Hum Genet. 2004;115:91–96. doi: 10.1007/s00439-004-1136-4. [DOI] [PubMed] [Google Scholar]
- 3.Zhao J, Qin X, Li S, Zeng Z. Association between the ACE I/D polymorphism and risk of ischemic stroke: an updated meta-analysis of 47,026 subjects from 105 case- control studies. J Neurol Sci. 2014;345:37–47. doi: 10.1016/j.jns.2014.07.023. [DOI] [PubMed] [Google Scholar]
- 4.Wang Z, Wang P, Wang X, He X, Wang Z, Xu D, Hu J, Wang B. Significant association between angiotensin-converting enzyme gene insertion/deletion polymorphism and risk of recurrent miscarriage: a systematic review and meta- analysis. Metabolism. 2013;62:1227–38. doi: 10.1016/j.metabol.2013.03.003. [DOI] [PubMed] [Google Scholar]
- 5.Amirshahi P, Sunderland E, Farhud DD, Tavakoli SH, Daneshmand P, Papiha SS. Serum proteins and erythrocyte enzymes of populations in Iran. Hum Hered. 1989;39:75–80. doi: 10.1159/000153838. [DOI] [PubMed] [Google Scholar]
- 6.Rafiee L, Saadat I, Saadat M. Glutathione S-transferase genetic polymorphisms (GSTM1, GSTT1 and GSTO2) in three Iranian populations. Mol Biol Rep. 2010;37:155–158. doi: 10.1007/s11033-009-9565-8. [DOI] [PubMed] [Google Scholar]
- 7.Nickmanesh M, Hosseini-Asl S, Yazdanbod A, Pourfarzi F, Didevar R, Akhavan H. Any significant association between the angiotension-converting enzyme insertion/ deletion polymorphism and gastric cancer in Ardabil province. Ann Oncol. 2011;22:v34. [Google Scholar]
- 8.Mazaheri H, Saadat M. Association between insertion/deletion polymorphism in angiotension converting enzyme and susceptibility to schizophrenia. Iranian J Public Health. 2015;44:369–373. [PMC free article] [PubMed] [Google Scholar]
- 9.Rahimi Z, Rahimi Z, Mozafari H, Parsian A. Preeclampsia and angiotension converting enzyme (ACE) I/D and angiotensin II type-1 receptor (ATIR) A1166C polymorph-isms: association with ACE I/D polymorphism. J Renin-Angiotensin- Aldosterone System. 2013 doi: 10.1177/1470320312448950. DOI: 10.1177/1470320312448950. [DOI] [PubMed] [Google Scholar]
- 10.Salimi S, Mokhtari M, Yaghmael M, Jamshidi M, Naghavi A. Association of angiotension-converting enzyme intron 16 insertion/deletion and angiotensin II type1 receptor A1166C gene polymorphisms with preeclampsia in south east of Iran. J Biomed Biotechnol. 2011 doi: 10.1155/2011/941515. ID 941515. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Keikhaee MR, Hashemi SB, Najmabadi H, Noroozian M. C677T methylentetra- hydrofulate reductase and angiotensin converting enzyme gene polymorphisms in patients with Alzheimer's disease in Iranian population. Neurochem Re. 2006;31:1079–1083. doi: 10.1007/s11064-006-9119-6. [DOI] [PubMed] [Google Scholar]
- 12.Poorgholi L, Saffar H, Fathollahi MS, Davoodi G, Anvari MS, Goodarzynejad H, Ziaee S, Boroumand MA. Angiotensin- converting enzyme insertion/deletion polymorphism and its association with coronary artery disease in an Iranian population. J Tehran Heart Cent. 2013;8:89–94. [PMC free article] [PubMed] [Google Scholar]
- 13.Yenki P, Safari Z, Azimi C. Lack of association between two ACE gene polymorphisms (rs4291 and Alu I/D) and late onset Alzheimer’s disease. Afr J Biotechnol. 2012;11:5982–5987. [Google Scholar]
- 14.Nikzamir A, Esteghamati A, Feghhi M, Nakhjavani M, Rashidi A, Reza JZ. The insertion/deletion polymorphism of the angiotensin-converting enzyme gene is associated with progression, but not development, of albuminuria in Iranian patients with type 2 diabetes. J Renin Angiotensin Aldosterone Syst. 2009;10:109–114. doi: 10.1177/1470320309104872. [DOI] [PubMed] [Google Scholar]
- 15.Hosseini-Khalili AR, Thompson J, Kehoe A, Hopkinson NS, Khoshbaten A, Soroush MR, Humphries SE, Montgomery H, Ghanei M. Angiotensin-converting enzyme genotype and late respiratory complications of mustard gas exposure. BMC Pulm Med. 2008;8:15. doi: 10.1186/1471-2466-8-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Bagheri M, Abedi-Rad I, Omrani MO, Nanbaksh F. Polymorphisms of the angiotension converting enzyme gene in Iranian Azeri Turkish women with unexplain recurrent pregnancy loss. Hum Fertil. 2010;13:79–82. doi: 10.3109/14647273.2010.484844. [DOI] [PubMed] [Google Scholar]
- 17.Abdi-Rad I, Bagheri M. Angiotensin-converting enzyme insertion/deletion gene polymorphism in general population of west Azarbaijan, Iran. Iran J Kidney Dis. 2011;5:86–92. [PubMed] [Google Scholar]
- 18.Bayoumi RA, Simsek M, Yahya TM, Bendict S, Al-Hinai A, Al-Barwani H, Hassan MO. Insertion-deletion polymorphism in the angiotensin-converting enzyme (ACE) gene among Sudanese, Somalis, Emiratis, and Omanis. Hum Biol. 2006;78:103–108. doi: 10.1353/hub.2006.0022. [DOI] [PubMed] [Google Scholar]
- 19.Houcher B, Begag S, Houcher Z, Karabiyik A, Egin Y, Akar N. Prevalence of genetic polymorphisms of methylenetetrahydrofolate reductase C677T and angiotensin I-converting enzyme (insertion/deletion) in Sétif population, Algeria. Mol Biol Res Commun. 2013;2:19–27. [Google Scholar]
- 20.Al-Eisa A, Haider MZ, Srivastva BS. Angiotensin converting enzyme gene insertion/deletion polymorphism in idiopathic nephrotic syndrome in Kuwaiti Arab children. Scand J Urol Nephrol. 2001;35:239–242. doi: 10.1080/003655901750292033. [DOI] [PubMed] [Google Scholar]