|Year : 2017 | Volume
| Issue : 5 | Page : 1021-1026
|Epidemiology of human leukocyte antigens among omani population
Issa Al Salmi1, Abdul Massiah Metry1, Faisal Al Ismaili1, Alan Hola1, Faissal Shaheen2, Hana Fakhoury3, Suad Hannawi4
1 Department of Renal Medicine, The Royal Hospital, Muscat, Oman
2 The Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia
3 Department of Biochemistry and Molecular Medicine, College of Medicine, AlFaisal University, Riyadh, Saudi Arabia
4 Ministry of Health and Prevention, Dubai, United Arab Emirates
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|Date of Web Publication||21-Sep-2017|
| Abstract|| |
Oman is located on the Southeastern coast of the Arabian Peninsula, and its population has high levels of consanguinity. Human leukocytic antigen (HLA) typing analysis in human population holds unexploited potential for elucidating the genetic causes of human disease and possibly leads to personalized medicine. This is a retrospective, descriptive study evaluating HLA frequencies of Omani individuals who underwent workup for kidney transplantation at the Royal Hospital (RH) from 2005 to 2016. Data on 870 subjects were collected from the Oman kidney transplant registry at RH as well from electronic medical record system. The mean age (standard deviation) years for the cohort were 33.2 (13.0). Males constituted 56.3% (490) while females constituted 43.7% (380). Seven HLA-A alleles accounted for more than 70% of the total alleles. Of which, HLA-A2 contributed the highest frequency (24%), followed by HLA A11 (9.4%), and A32 (8.1%). Ten alleles accounted for 70% of HLA-B alleles. Of which, HLA-B51 was the most common (18.9%), followed by HLA-B-35 (13.6%), and HLA-B8 (7.9%). Seven HLA-DRB1 alleles accounted for more than 70% of the total HLA DRB1 alleles, of which HLA- DRB1*16 contributed the highest frequency (29.56%). This was followed by HLA-DRB1*03 (14.57%) and HLA-DRB1*11 (9.48%). While three alleles accounted for more than 75% of the total HLA DQB1alleles. Of which, HLA-DQB1*05 contributed the highest frequency (37.56%). This was followed by allele HLA-DQB1*02 (26.48%) and HLA-DQB1*03 (17.18%). This study showed considerable heterogeneity in both HLA Class I and Class II antigens, which reflects admixture of our population with rest of old world countries. Despite the high levels of consanguinity, this population is genetically highly heterogeneous. These findings may be useful for transplantation programs, noncommunicable diseases, epidemiology of HLA linked diseases, pharmacogenomics, and anthropology.
|How to cite this article:|
Al Salmi I, Metry AM, Al Ismaili F, Hola A, Shaheen F, Fakhoury H, Hannawi S. Epidemiology of human leukocyte antigens among omani population. Saudi J Kidney Dis Transpl 2017;28:1021-6
|How to cite this URL:|
Al Salmi I, Metry AM, Al Ismaili F, Hola A, Shaheen F, Fakhoury H, Hannawi S. Epidemiology of human leukocyte antigens among omani population. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2021 Sep 23];28:1021-6. Available from: https://www.sjkdt.org/text.asp?2017/28/5/1021/215135
| Introduction|| |
The human leukocytic antigen (HLA) is the most polymorphic genetic system described in man. It contains several linked loci which encode for cell surface protein, that present foreign and self-derived peptides to T- lymphocyte., Sequence polymorphisms in the antigen binding domains of the HLA molecules determine the repertoire of peptides that can be presented and in turn influence an individual’s immune response.
Knowledge of HLA data at the level of a specific population or ethnic group level is especially important because of the considerable differentiation in HLA frequencies that has occurred among human populations since our species’ first appearance and subsequent spread across Africa and other continents.,
HLA allele has been implicated as a potential risk in epidemiology and pathogenesis of some diseases such as diabetes and end-stage kidney disease. In addition, in organ transplantation, it was demonstrated that HLA matching between donor and recipient was associated with better graft and patient survival.
Given the outburst of many of noncommu-nicable diseases (NCD) in the Gulf Cooperation Council region that might be correlated partially to the local genetic makeup, knowledge of HLA data at the level of a specific population is highly desirable., This paper aims to determine the frequencies of HLA Class I (A, B, and C) and Class II (DRB1 and DQB1) in Omani population.
| Methodology|| |
This is a retrospective, descriptive study evaluating HLA frequencies of all Omani individuals who underwent workup for kidney transplantation at Royal Hospital (RH), Muscat from 2005 to 2016.
The data of 870 subjects were collected appropriately from the Oman kidney transplant registry at RH and from the electronic medical record system (Al Shifaa).
The demographics collected on those typed individuals included age, gender, region of the country, and HLA typing that was performed in a single immunology laboratory in Sultan Qaboos University Hospital.
HLA Class I typing was conducted using the standard microlymphocytotoxicity test, 15–20 mL of blood taken into ethylenediaminetetra-acetic acid (EDTA) was used. Lymphocytes were separated by density gradient centri-fugation, and HLA typing was performed using a modified two-stage cytotoxicity technique with ethidium bromide/acridine orange staining and observation with a semi-automated fluorescent microscope.
For HLA-class II typing (DRB1 and DQB1), DNA was extracted from 1 mL of EDTA blood using a commercial kit (Puregene, USA). The separated DNA was incubated in a thermal cycler, with Class II primers defining DRB1 and DQB1 alleles (Dynal low-resolution sequence-specific primers, Dynal, UK), together with PCR buffer, Taq Polymerase (Promega), and DNA nucleotides. The products were run on 1.2% agarose gels containing ethidium bromide, examined under ultraviolet illumination, and the Class II specificities were determined.
The study was approved by the medical ethics and research committee at the hospital. The data entry was checked by two researchers. Quality control data were done as per our institute research guidelines. Statistical analysis was done using STATA software v13, (StataCorp, College Station, TX, USA).
| Results|| |
During the period from 2005 to 2016, 870 Omani citizens were HLA typed. The mean age [standard deviation (SD)] years was 33.2 (13.0). Male constituted 56.3% (490) with mean age (SD) years 32.14 (12.29) while female constituted 43.7% (380) with mean age (SD) years 35.59 (13.65) with P = 0.0057. We found that 55.4% (482) were from Muscat whereas the remaining 44.6% (388) were from outside Muscat region.
As shown in [Table 1], seven HLA-A alleles accounted for more than 70% of the total allele counts. Of which, HLA-A2 contributed the highest frequency (24%), followed by HLA-A11 (9.4%), and HLA-A32 (8.1%).
[Table 2] shows that 10 HLA-B alleles account for 70% of total HLA-B alleles. Of which, HLA-B51 was the most common (18.9%), followed by HLA-B35 (13.6%), and HLA-B8 (7.9%).
[Table 3] shows that seven HLA-DRB1 alleles account for more than 70% of the total HLA DRB1 alleles. Of which, HLA-DRB1*16 contribute the highest frequency (29.56 %). This was followed by HLA-DRB1*03 (14.57%) and HLA-DRB1*11 (9.48%).
[Table 4] shows that three HLA-DQB1 alleles account for more than 75% of the total HLA- DQB1 alleles. Of which, HLA-DQB1*05 contributed the highest frequency (37.56%). This was followed by HLA-DQB1*02 (26.48%) and HLA-DQB1*03 (17.18%).
| Discussion|| |
This is the first and largest full HLA – alleles study to analyze the HLA frequencies in the Omani population. It showed that for each HLA locus 7–10 allele accounting for more than 70% of total alleles. HLA-A2, HLA-B51, HLA-DRB1*16, and HLA-DQB1*05 occurring in 24.6%, 18.9%, 29.9%, and 37.56%, respectively were the most frequent alleles in the studied population.
HLA-A-A2 is the highest frequency in our population and that goes in concordance with other studies done in the region [Table 5]. As depicted from [Table 5], HLA-A2 is common in all populations from the region, including the Pakistani population while for HLA-B, B51 was most common in our cohort but also of high frequency in the Saudis and Emirates [Table 5].
|Table 5: Comparison between the frequency of the common HLA alleles in our cohort and other cohorts.|
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Of the HLA –DR, DRB1*16 frequency was highest in our population, Emiraties and Pakistani population [Table 5]. Kenyan and Jordanians have the lowest DRB1*16 frequency followed by Saudis and Iranians [Table 5]. Also, our finding does not support previous study by White et al, that showed that Omani population characterized by a very high incidence of HLA-DR2, which they found it to be 66% but our study showed that DRB1*16 constitute 29.56% and DRB1*15 was 7.64%. They concluded that this high incidence of HLA-DR2 in Oman and disparities in the frequency of other antigens would indicate that there has not been any significant migration from northern Arabia. However, this high incidence is probably not accurate and may have resulted from the low number of participants and older technique of HLA typing. On the other hand, our findings are probably more accurate and go along other findings in the region.
The present study found that of HLA-DQ, DQB1*05 and DQB1*06 alleles accounted for 37.56% and 14.04%, respectively, compared to the previous study by White et al that found HLA-DQ1 76% to be the most common. In addition, other studies in various countries found that the most common allele was DQB1*06 (26%) in KSA, Iran DQ4 (15.2%) and DQ3 (21.8%) in East Africa. Importantly,
HLA-DQB1*05 is a relatively frequent allele in some Southeast Asian peoples, for example, Malaysia (37.1%) and in Pakistan “Baloch” (34%) whereas a very lower frequency of this allele was reported in several Amerindian peoples, for example, Mexico, Brazil, and Argentina. However, the HLA-DQB1*02 is a common allele in different countries and communities although it was noticed with good percentage in few Mediterranean populations and communities, such as in France (24%), Libyan Jews (33.3%), Morocco (30.6%), Spain (48%), and Turkey (23.8%). Therefore, it is possible from this phylogenetic studies that Omanis are closer to West-Asian and Mediterranean peoples than to others populations.
These findings propose that both Class I and Class II alleles polymorphisms of the study subjects portray significant heterogeneity, which reflects admixture of Omani population with European, Asian, and African populations. The HLA class II allele analysis showed that these variants in Omanis, are those that are common in some Southeast Asian and Mediterranean populations, especially the HLA-DRB1*16 and -DRB1*03 variants.,,, The connection of our population to certain groups and countries in Mediterranean may be explained by the fact that Oman is located in a tactical geographical location that links the prehistoric Rich Crescent to the Indian subcontinent area. Hence, it is quite normal to be occupied, and hence settlement, by key forces such as Persians, Portuguese, and Ottomans that leaded to an admixture of the Omani’s genetic admixture. In addition, the possible genetic overlapping between populations from Oman and West-Asian is possibly due to interethnic marriages during the Persian control of the coast of Oman early in history. Furthermore, a good percentage of population of Oman has ancestry from the India Subcontinent and Africa. The Omani empire in East Africa was founded on the Swahili coast, which stretched from Somalia to Cape Delgado in Mozambique. In addition, trading networks provided a valuable intermediary in the population admixture.
The DRB1*03 allele is common many races and people, however, DRB1*16 variant is a shared allele among the Southeast Asian populations such as in, Papua New Guinea (28%), Malaysia (28%), and South American peoples such as in Brazil (37%), Colombia (38%), and Mexico (30.9%) and Vietnam (19.2%). The third frequent HLA-DR allele in Omanis was the DRB 1*11 which is a common allele between several ethnic groups. Since HLA gene characteristics could be a potential risk in the pathogenesis of some diseases or/and an epidemiological risk factor for others, future studies addressing these issues are warranted.,
Many studies confirm the paramount prominence of class I and class II molecules, which are fundamental to fight to infection. Similarly, several associations with autoimmune disorders were found to be specific to a definite HLA types of Class I and Class II alleles., Interestingly, conditions other than infections and autoimmunity are also associated with the HLA classes, including some cancers and neuropathies.,,,, These associations could be subsidiary to the infectious history of a particular individual and population.
Finally, certain HLA alleles affect drug response to treatment and HLA complex will have to be increasingly considered in relation to pharmacological responses and important for personalized drug treatment design (including ethnic groups with specific certain high allele frequencies).,,
One limitation of our study that it was limited to relatively smaller size population and that might possibly underestimate or overestimate some of the HLA loci representations. Therefore, further larger scale studies are needed. Another limitation is the use of Centers for Disease Control and Prevention for HLA typing, which is low-resolution typing technique compared to DNA based typing.
The main challenges presently encountered by HLA laboratories are to infer the complex information provided by these assays and use this to develop a safe and real algorithm for the definition of a clinically relevant HLA profile and hence, there should be more emphasis given to epitopes when interpreting the results of these assays.
| Conclusion|| |
The HLA class II allele analysis showed that the frequent HLA variants in Omanis, are those that are common in some Southeast Asian and Mediterranean populations, especially the HLA-DRB1*16 and DRB1*03 variants. The same findings were also observed when analyzing the HLA-DQB1 gene.
This work will help to advance the study of the kinship between Omanis and others Middle East populations. Furthermore, such studies will be helpful in making HLA allele frequency database that would prove useful in clinical practice, especially in infection predisposition, NCD predisposition, and organ transplantation.
Conflict of interest: None declared.
| References|| |
Shiina T, Blancher A, Inoko H, Kulski JK. Comparative genomics of the human, macaque and mouse major histocompatibility complex. Immunology 2017;150:127-38.
Trowsdale J, Knight JC. Major histocom-patibility complex genomics and human disease. Annu Rev Genomics Hum Genet 2013;14:301-23.
Motozono C, Bridgeman JS, Price DA, Sewell AK, Ueno T. Clonotypically similar hybrid αβ T cell receptors can exhibit markedly different surface expression, antigen specificity and cross-reactivity. Clin Exp Immunol 2015;180: 560-70.
Sewell AK. Why must T cells be cross-reactive? Nat Rev Immunol 2012;12:669-77.
Gragert L, Madbouly A, Freeman J, Maiers M. Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry. Hum Immunol 2013;74:1313-20.
Maiers M, Gragert L, Klitz W. High-resolution HLA alleles and haplotypes in the United States population. Hum Immunol 2007;68: 779-88.
Ramos PS, Shedlock AM, Langefeld CD. Genetics of autoimmune diseases: Insights from population genetics. J Hum Genet 2015; 60:657-64.
Milner J, Melcher ML, Lee B, et al. HLA matching trumps donor age: Donor-recipient pairing characteristics that impact long-term success in living donor kidney transplantation in the era of paired kidney exchange. Transplant Direct 2016;2:e85.
Jamaluddine Z, Sibai AM, Othman S, Yazbek S. Mapping genetic research in non-communicable disease publications in selected Arab countries: First step towards a guided research agenda. Health Res Policy Syst 2016; 14:81.
Rahim HF, Sibai A, Khader Y, et al. Non-communicable diseases in the Arab world. Lancet 2014;383:356-67.
White AG, Leheny W, Kuchipudi P, et al. Histocompatibility antigens in omanis: Comparison with other Gulf populations and implications for disease association. Ann Saudi Med 1999;19:193-6.
Peterson TA, Luo M, Mao X, Brunham RC, Plummer FA. Identification of a novel DPA1 allele, DPA1*010602, in an East African population. Hum Immunol 2008;69:885-6.
Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR. Allele frequency net: A database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res 2011;39:D913-9.
Ali ME, Ahmed MU, Alam S, Rahman MH. HLA-A, -B and -DRB1 allele frequencies in the Bangladeshi population. Tissue Antigens 2008;72:115-9.
Amar A, Kwon OJ, Motro U, et al. Molecular analysis of HLA class II polymorphisms among different ethnic groups in Israel. Hum Immunol 1999;60:723-30.
Lampis R, Morelli L, Congia M, et al. The interregional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studies in complex diseases. Hum Mol Genet 2000;9: 2959-65.
Mohyuddin A, Ayub Q, Khaliq S, et al. HLA polymorphism in six ethnic groups from Pakistan. Tissue Antigens 2002;59:492-501.
Handunnetthi L, Ramagopalan SV, Ebers GC, Knight JC. Regulation of major histocom-patibility complex class II gene expression, genetic variation and disease. Genes Immun 2010;11:99-112.
Hajeer AH, Hutchinson IV. Influence of TNFalpha gene polymorphisms on TNFalpha production and disease. Hum Immunol 2001;62:1191-9.
Uemura Y, Senju S, Fujii S, et al. Specificity, degeneracy, and molecular mimicry in antigen recognition by HLA-class II restricted T cell receptors: Implications for clinical medicine. Mod Rheumatol 2003;13:205-14.
Azumi M, Kobayashi H, Aoki N, et al. Six-transmembrane epithelial antigen of the prostate as an immunotherapeutic target for renal cell and bladder cancer. J Urol 2010; 183:2036-44.
Kumar A, Yadav IS, Hussain S, Das BC, Bharadwaj M. Identification of immuno-therapeutic epitope of E5 protein of human papillomavirus-16: An in silico approach. Biologicals 2015;43:344-8.
Nayak K, Jing L, Russell RM, et al. Identification of novel Mycobacterium tuberculosis CD4 T-cell antigens via high throughput proteome screening. Tuberculosis (Edinb) 2015;95:275-87.
Aruga A, Takeshita N, Kotera Y, et al. Long-term vaccination with multiple peptides derived from cancer-testis antigens can maintain a specific T-cell response and achieve disease stability in advanced biliary tract cancer. Clin Cancer Res 2013;19:2224-31.
Lee MH, Stocker SL, Anderson J, et al. Initiating allopurinol therapy: Do we need to know the patient’s human leucocyte antigen status? Intern Med J 2012;42:411-6.
Naisbitt DJ, Yang EL, Alhaidari M, et al. Towards depersonalized abacavir therapy: Chemical modification eliminates HLA-B*57 : 01-restricted CD8+ T-cell activation. AIDS 2015;29:2385-95.
Issa Al Salmi
Department of Renal Medicine, The Royal Hospital, Muscat
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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