Ferdowsi University of Mashhad

Document Type : Research Articles


1 Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran

2 Institute of Biotechnology, Shahrekord University, Shahrekord, Iran

3 Department of Neurology, Faculty of Medical School, Isfahan University of Medical Sciences, Isfahan, Iran

4 Research Committee of Multiple Sclerosis (IRCOMS), Isfahan, Iran


              Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with unknown etiology. Recent evidences suggest the HLA contribution to Multiple sclerosis (MS) pathogenicity as they may present neuropeptides to cytotoxic lymphocytes. We aimed to investigate the association of some related HLA-A alleles and haplotypes with MS and compare the results with other Universal reports to shed light on some aspects of this universally expanded disease. In this investigation, alleles were genotyped by polymerase chain reaction with sequence-specific primers (PCR-SSP) in 50 MS patients, and 50 unrelated healthy individuals. The analysis was carried out using SPSS V.19 statistical software. The results of this study showed a significant association of HLA-A*03 and HLA-A*24 alleles with MS (P<0.0001), but HLA-A*02 and other alleles did not show any significant association (P>0.05). However, other alleles were not significantly associated (P>0.05). Interestingly, in our study, the HLA-A*31 allele was often in combination with HLA-A*03 and HLA-A*24 as risk haplotypes in MS patients. In the present study, not only HLA-A*03 and HLA-A*24 were highly associated with the risk of MS susceptibility, but also their combinations with HLA-A*31 allele were more frequent in patients. Therefore, HLA-A*31 may be introduced as a new complementary risk factor in MS pathogenesis.


Al-Nashmi M., Taha S., Salem A. H., Alsharoqi I. and Bakhiet M. (2018) Distinct HLA class I and II genotypes and haplotypes are associated with multiple sclerosis in Bahrain. Biomedical reports 9:531-539.
Al-Shammri S., Nelson R. F., Al-Muzairi I. and Akanji A. O. (2004) HLA determinants of susceptibility to multiple sclerosis in an Arabian Gulf population. Multiple Sclerosis Journal 10:381-386.
Amirzargar A. A., Tabasi A., Khosravi F., Kheradvar A., Rezaei N., Naroueynejad M. et al. (2005) Optic neuritis, multiple sclerosis and human leukocyte antigen: results of a 4‐year follow‐up study. European journal of neurology 12:25-30.
Amirzargar, A., Mytilineos, J., Yousefipour, A., Farjadian, S., Scherer, S., Opelz, G. et al.  (1998) HLA class II (DRB1, DQA1 and DQB1) associated genetic susceptibility in Iranian multiple sclerosis (MS) patients. European journal of immunogenetics, 25: 297-301.
Bergamaschi L., Ban M., Barizzone N., Leone M., Ferrante D., Fasano M. E. et al. (2011) Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects. Journal of medical genetics 48:485-492.
Bergamaschi L., Leone M. A., Fasano M. E., Guerini F. R., Ferrante D., Bolognesi E. et al. (2010) HLA-class I markers and multiple sclerosis susceptibility in the Italian population. Genes & Immunity 11:173-180.
Browne P., Chandraratna D., Angood C., Tremlett H., Baker C., Taylor B. V., et al. (2014) Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity. Neurology 83:1022-1024.
Brynedal B., Duvefelt K., Jonasdottir G., Roos I. M., Åkesson E., Palmgren, J.  et al. (2007) HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PloS One 2:664.
Etemadifar M., Janghorbani M, Shaygannejad V. and Ashtari, F. (2006) Prevalence of multiple sclerosis in Isfahan, Iran. Neuroepidemiology 27:39-44.
Etemadifar, M. and Maghzi, A.H. (2011) Sharp increase in the incidence and prevalence of multiple sclerosis in Isfahan, Iran. Multiple Sclerosis Journal 17:1022-1027.
Fogdell‐Hahn A., Ligers A., Grønning M., Hillert J. and Olerup O. (2000) Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue antigens 55:140-148.
Galehdari H., Mohaghegh M., Majdinasab N., Khatami S. R. and Hosseini Behbahani M. (2018) Analysis of HLA-A*03 in Multiple Sclerosis Patients in Khuzestan Province, Iran. Gene, Cell and Tissue 2018; 5.
Ghanavati R., Shafiei M. and Galehdari H. (2018) Association Between HLA-A*02 Genotype and Multiple Sclerosis in Khuzestan Province, Iran.  Jundishapur Journal of Health Sciences 10.
Haff LA. (1994) Improved quantitative PCR using nested primers. Genome Research 3: 332-7.
Harbo HF, Lie BA, Sawcer S, Celius EG, Dai KZ, Oturai A, et al. (2004) Genes in the HLA class I region may contribute to the HLA class II‐associated genetic susceptibility to multiple sclerosis. Tissue antigens 63: 237-47.
Horton R., Wilming L., Rand V., Lovering R. C., Bruford E. A., Khodiyar V. K. et al. (2004) Gene map of the extended human MHC. Nature Reviews Genetics 5:889-899.
Isobe N., Gourraud P. A., Harbo H. F., Caillier S. J., Santaniello A., Khankhanian P. et al. (2013) Genetic risk variants in African Americans with multiple sclerosis. Neurology 81:219-227.
Kalanie H., Kamgooyan M., Sadeghian H. and Kalanie A. R. (2000) Histocompatibility antigen (HLA) associations with multiple sclerosis in Iran. Multiple Sclerosis Journal, 6:317-319.
Kankonkar S., Singhal B. S. and Shankarkumar U. (2012) HLAA, B, Cw. DRB1 and DQB1 Alleles in Multiple Sclerosis Patients in India. International Journal of Human Genetics 12:37-40.
Kloverpris H. N., Stryhn A. and Harndahl M. (2012) HLA-B*57 Micropolymorphism Shapes HLA Allele-Specific Epitope Immunogenicity, Selection Pressure, and HIV Immune Control. Journal of virology 86:919–929.
Link J., Kockum I., Lorentzen Å. R., Lie B. A., Celius E. G., Westerlind H. et al. (2012) Importance of human leukocyte antigen (HLA) class I and II alleles on the risk of multiple sclerosis. PloS One 7:367-379.
Lotfi J., Nikbin B., Derakhshan I., Aghai Z. and Ala F. (1978) Histocompatibility antigens (HLA) in multiple sclerosis in Iran. Journal of Neurology, Neurosurgery & Psychiatry 41:699-701.
McDonald W. I., Compston A., Edan G., Goodkin D., Hartung H. P., Lublin F. D. et al. (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 50:121-127.
Mohammadi-Milasi F., Mahnam K. and Shakhsi-Niaei M. (2020) In silico study of the association of the HLA-A* 31:01 allele (human leucocyte antigen allele 31: 01) with neuroantigenic epitopes of PLP (proteolipid protein), MBP (myelin basic protein) and MOG proteins (myelin oligodendrocyte glycoprotein) for studying the multiple sclerosis disease pathogenesis. Journal of Biomolecular Structure and Dynamics 39: 2526-2542.
Naito S., Namerow N., Mickey M. R. and Terasaki P. I. (1972) Multiple sclerosis: association with HL—A3. Tissue antigens 2:1-4.
Radmehr M, Meghdadi S, Bahmanzadeh M. and Sabbagh S. (2015) Prevalence, demographics and clinical characteristics of multiple sclerosis in North of Khuzestan Province, Iran. Jentashapir. Journal of Cellular and Molecular Biology 6:e23831.
Ramagopalan S. V., Knight J. C. and Ebers G. C. (2009) Multiple sclerosis and the major histocompatibility complex. Current opinion in neurology 22:219-225.
Rioux J.D., Goyette P., Vyse T. J., Hammarström L., Fernando M. M., Green T. et al. (2009) Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proceedings of the National Academy of Sciences 106:18680-18685.
Rubio J. P., Bahlo M., Butzkueven H., van Der Mei I. A., Sale M. M., Dickinson J. L. et al. (2002) Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis. The American Journal of Human Genetics 70:1125-1137.
Silva A. M., Bettencourt A., Pereira C., Santos E., Carvalho C., Mendonça D. et al. (2009) Protective role of the HLA–A*02 allele in Portuguese patients with multiple sclerosis. Multiple Sclerosis Journal 15:771-774.
Tolou-Ghamari Z. (2015) Preliminary Study of Differences Between Prevalence of Multiple Sclerosis in Isfahan and its’ Rural Provinces. Archives of Neuroscience 2:e60043.
Weiner H. L. (2008) A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. Journal of Neurology 255:3-11.
Weissert R. (2013) The immune pathogenesis of multiple sclerosis. Journal of Neuroimmune Pharmacology 8:857-866.
Werneck L. C., Lorenzoni P. J., Arndt R. C., Kay C. S. K. and Scola R. H. (2016) The immunogenetics of multiple sclerosis. The frequency of HLA-alleles class 1 and 2 is lower in Southern Brazil than in the European population. Arquivos de neuro-psiquiatria 74:607-616.
Yeo TW, De Jager PL, Gregory SG, Barcellos LF, Walton A, Goris A, et al. (2007) A second major histocompatibility complex susceptibility locus for multiple sclerosis. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 61: 228-36.