r-n-jРоссийский неврологический журналRussian neurological journal2658-79472686-7192МИА10.30629/2658-7947-2023-28-1-33-40r-n-j-392Research ArticleИССЛЕДОВАНИЯ И КЛИНИЧЕСКИЕ НАБЛЮДЕНИЯCLINICAL RESEARCHES AND CASE REPORTSПолиморфизм HLA-DRB1 и риск рассеянного склероза в детском возрасте и у взрослых: исследование случай–контрольHLA-DRB1 polymorphism and risk of pediatric-onset and adult-onset multiple sclerosis: a case–control studyhttps://orcid.org/0000-0003-4500-4913ЕльчаниноваЕ. Ю.ElchaninovaE. Yu.

Барнаул

Barnaul

https://orcid.org/0000-0002-7947-4529СмагинаИ. В.SmaginaI. V.

Смагина Инна Вадимовна

Барнаул

Smagina Inna Vadimovna

Barnaul

https://orcid.org/0000-0002-7507-3963АфанасьеваА. И.Afanas’evaA. I.

Барнаул

Barnaul

https://orcid.org/0000-0003-2730-615XЕльчаниноваС. А.ElchaninovaS. A.

Барнаул

Barnaul

ФГБОУ ВО «Алтайский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияAltai State Medical UniversityRussian Federation2023160320232813340Copyright © Ельчанинова Е.Ю., Смагина И.В., Афанасьева А.И., Ельчанинова С.А., 20232023Ельчанинова Е.Ю., Смагина И.В., Афанасьева А.И., Ельчанинова С.А.Elchaninova E.Y., Smagina I.V., Afanas’eva A.I., Elchaninova S.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.r-n-j.com/jour/article/view/392

Связь предрасположенности к рассеянному склерозу (РС) с полиморфизмами гена HLA-DRB1 является наиболее сильной. Неясно, различаются ли аллели DRB1, ассоциированные с риском этого заболевания в популяциях взрослых и детей, проживающих в одинаковых экологических условиях.

Цель

Цель: сравнительная оценка ассоциаций полиморфизма гена HLA-DRB1 с риском РС с дебютом в детском возрасте и у взрослых в Алтайском крае.

Материал и методы

Материал и методы. В исследовании случай–контроль приняли участие больные ремиттирующим РС, европеоиды, родившиеся и проживающие в Алтайском крае: 200 пациентов с дебютом РС во взрослом возрасте, 86 пациентов с дебютом РС в возрасте до 18 лет. Группа контроля — 200 добровольцев. Генотипирование проводили методом TaqMan-зондов.

Результаты

Результаты. У европеоидов в Алтайскoм кpае генетическими фактopами pиска РС в детском возрасте, так же как у взрослых, являются аллели 03, 13, 15 гена HLA-DRB1. Протектерное влияние в отношении РС в детском возрасте могут оказывать аллели 01 и 07, у взрослых — аллели 01, 07, 11 и 16 гена HLA-DRB1.

Заключение

Заключение. Можно полагать, что различие возраста дебюта РС не связано с различием аллелей риска этого заболевания гена HLA-DRB1 в возрастных группах до и после 18 лет.

The association of predisposition to multiple sclerosis (MS) with HLA-DRB1 gene polymorphisms is the strongest. It is not clear whether the DRB1 alleles associated with the risk of this disease diff er in adult and pediatric populations living in the same environmental conditions.

Objective

Objective: comparative study of associations of HLA-DRB1 gene polymorphism with the risk of pediatric-onset MS and adult-onset MS in the Altai region.

Material and methods

Material and methods. Caucasian with relapsing-remitting MS, born and living in the Altai region of Russia in the southeast of Western Siberia, participated in the case–control study: 200 patients with adult-onset MS, 86 patients with pediatric-onset MS. The control group included 200 volunteers. Genotyping was performed by TaqMan probes. Results. Alleles 03, 13, 15 of the HLA-DRB1 gene are genetic risk factors for both adult-onset MS and pediatric-onset MS in Caucasians in the Altai region. Alleles 01 and 07 of the HLA-DRB1 gene may have a protective eff ect against pediatric-onset MS, alleles 01, 07, 11 and 16 against adult-onset MS.

Conclusion

Conclusion. It can be assumed that the diff erence in the age of MS onset is not associated with the diff erent infl uence of risk alleles of the HLA-DRB1 gene in populations under and over 18 years of age.

HLA-DRB1рассеянный склерозпедиатрический рассеянный склерозфакторы рискадетиподросткивзрослыеHLA-DRB1multiple sclerosispediatric multiple sclerosisrisk factorschildadolescentadultReferencesШмидт Т.Е., Яхно Н.Н. Рассеянный склероз. М.: МЕДпресс-информ; 2016.Shmidt T.E., Yakhno N.N. Multiple sclerosis. Moscow: MEDpress-inform; 2016. (In Russ.)].Alroughani R., Boyko A. Pediatric multiple sclerosis: a review. BMC neurology. 2018;18(1):27. https://doi.org/10.1186/s12883-018-1026-3Alroughani R., Boyko A. Pediatric multiple sclerosis: a review. BMC neurology. 2018;18(1):27. https://doi.org/10.1186/s12883-018-1026-3Tyshkov C.D., Charvet L.E., Krupp L.B. Multiple Sclerosis in Children. In: Rizvi S., Cahill J., Coyle P. (eds). Clinical Neuroimmunology. Current Clinical Neurology. Humana, Cham. 2020:179–197. https://doi.org/10.1007/978-3-030-24436-1_9Tyshkov C.D., Charvet L.E., Krupp L.B. Multiple Sclerosis in Children. In: Rizvi S., Cahill J., Coyle P. (eds). Clinical Neuroimmunology. Current Clinical Neurology. Humana, Cham. 2020:179–197. https://doi.org/10.1007/978-3-030-24436-1_9Alroughani R., Akhtar S., Ahmed S.F., Behbehani R., Al-Abkal J., Al-Hashel J. Incidence and prevalence of pediatric onset multiple sclerosis in Kuwait: 1994–2013. Journal of the neurological sciences. 2015;353(1–2):107–110. https://doi.org/10.1016/j.jns.2015.04.025Alroughani R., Akhtar S., Ahmed S.F., Behbehani R., Al-Abkal J., Al-Hashel J. Incidence and prevalence of pediatric onset multiple sclerosis in Kuwait: 1994–2013. Journal of the neurological sciences. 2015;353(1–2):107–110. https://doi.org/10.1016/j.jns.2015.04.025Бойко А.Н., Быкова О.В., Сиверцева С.А. Рассеянный склероз у детей и подростков: клиника, диагностика, лечение. М.: МИА; 2016:448 с.Boyko A.N., Bykova O.V., Sivertseva S.A. Multiple sclerosis in children and adolescents: clinic, diagnosis, treatment. Moscow: MIA; 2016:448 p. (In Russ.)].Yan K., Balijepalli C., Desai K., Gullapalli L., Druyts E. Epidemiology of pediatric multiple sclerosis: A systematic literature review and meta-analysis. Multiple sclerosis and related disorders. 2020;44:102260. https://doi.org/10.1016/j.msard.2020.102260Yan K., Balijepalli C., Desai K., Gullapalli L., Druyts E. Epidemiology of pediatric multiple sclerosis: A systematic literature review and meta-analysis. Multiple sclerosis and related disorders. 2020;44:102260. https://doi.org/10.1016/j.msard.2020.102260Jeong A., Oleske D.M., Holman J. Epidemiology of PediatricOnset Multiple Sclerosis: A Systematic Review of the Literature. Journal of child neurology. 2019;34(12):705–712. https://doi.org/10.1177/0883073819845827Jeong A., Oleske D.M., Holman J. Epidemiology of PediatricOnset Multiple Sclerosis: A Systematic Review of the Literature. Journal of child neurology. 2019;34(12):705–712. https://doi.org/10.1177/0883073819845827von Wyl V., Décard B.F., Benkert P., Lorscheider J., Hänni P., Lienert C. et al. Infl uence of age at disease onset on future relapses and disability progression in patients with multiple sclerosis on immunomodulatory treatment. Eur J Neurol. 2020;27(6):1066–1075. https://doi.org/10.1111/ene.14191von Wyl V., Décard B.F., Benkert P., Lorscheider J., Hänni P., Lienert C. et al. Infl uence of age at disease onset on future relapses and disability progression in patients with multiple sclerosis on immunomodulatory treatment. Eur J Neurol. 2020;27(6):1066–1075. https://doi.org/10.1111/ene.14191Padilha I.G., Fonseca A.P.A., Pettengill A.L.M., Fragoso D.C., Pacheco F.T., Nunes R.H. et al. Pediatric multiple sclerosis: from clinical basis to imaging spectrum and diff erential diagnosis. Pediatric radiology. 2020;50(6):776–792. https://doi.org/10.1007/s00247-019-04582-3Padilha I.G., Fonseca A.P.A., Pettengill A.L.M., Fragoso D.C., Pacheco F.T., Nunes R.H. et al. Pediatric multiple sclerosis: from clinical basis to imaging spectrum and diff erential diagnosis. Pediatric radiology. 2020;50(6):776–792. https://doi.org/10.1007/s00247-019-04582-3Bar-Or A., Hintzen R.Q., Dale R.C., Rostasy K., Brück W., Chitnis T. Immunopathophysiology of pediatric CNS infl ammatory demyelinating diseases. Neurology. 2016;87(9):12–19. https://doi.org/10.1212/WNL.0000000000002821Bar-Or A., Hintzen R.Q., Dale R.C., Rostasy K., Brück W., Chitnis T. Immunopathophysiology of pediatric CNS infl ammatory demyelinating diseases. Neurology. 2016;87(9):12–19. https://doi.org/10.1212/WNL.0000000000002821International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365(6460):eaav7188. https://doi.org/10.1126/science.aav7188International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365(6460):eaav7188. https://doi.org/10.1126/science.aav7188Schmidt H., Williamson D., Ashley-Koch A. HLA-DR15 haplotype and multiple sclerosis: a HuGE review. American Journal of Epidemiology. 2007;165(10):1097–1109. https://doi.org/10.1093/aje/kwk118Schmidt H., Williamson D., Ashley-Koch A. HLA-DR15 haplotype and multiple sclerosis: a HuGE review. American Journal of Epidemiology. 2007;165(10):1097–1109. https://doi.org/10.1093/aje/kwk118Ramagopalan S.V., Morris A.P., Dyment D.A., Herrera B.M., DeLuca G.C., Lincoln M.R. et al. The inheritance of resistance alleles in multiple sclerosis. PLoS genetics. 2007;3(9):1607–1613. https://doi.org/10.1371/journal.pgen.0030150Ramagopalan S.V., Morris A.P., Dyment D.A., Herrera B.M., DeLuca G.C., Lincoln M.R. et al. The inheritance of resistance alleles in multiple sclerosis. PLoS genetics. 2007;3(9):1607–1613. https://doi.org/10.1371/journal.pgen.0030150Zhang Q., Lin C.Y., Dong Q., Wang J., Wang W. Relationship between HLA-DRB1 polymorphism and susceptibility or resistance to multiple sclerosis in Caucasians: a meta-analysis of nonfamily-based studies. Autoimmunity reviews. 2011;10(8):474–481. https://doi.org/10.1016/j.autrev.2011.03.003Zhang Q., Lin C.Y., Dong Q., Wang J., Wang W. Relationship between HLA-DRB1 polymorphism and susceptibility or resistance to multiple sclerosis in Caucasians: a meta-analysis of nonfamily-based studies. Autoimmunity reviews. 2011;10(8):474–481. https://doi.org/10.1016/j.autrev.2011.03.003Boiko A.N., Gusev E.I., Sudomoina M.A., Alekseenkov A.D., Kulakova O.G., Bikova O.V. et al. Association and linkage of juvenile MS with HLA-DR2(15) Neurology. 2002;58(4):658–660. https://doi.org/10.1212/wnl.58.4.658Boiko A.N., Gusev E.I., Sudomoina M.A., Alekseenkov A.D., Kulakova O.G., Bikova O.V. et al. Association and linkage of juvenile MS with HLA-DR2(15) Neurology. 2002;58(4):658–660. https://doi.org/10.1212/wnl.58.4.658Disanto G., Magalhaes S., Handel A.E., Morrison K.M., Sadovnick A.D., Ebers G.C. et al. Canadian Pediatric Demyelinating Disease Network. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology. 2011;76:781–786. https://doi.org/10.1212/WNL.0b013e31820ee1cdDisanto G., Magalhaes S., Handel A.E., Morrison K.M., Sadovnick A.D., Ebers G.C. et al. Canadian Pediatric Demyelinating Disease Network. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology. 2011;76:781–786. https://doi.org/10.1212/WNL.0b013e31820ee1cdRamagopalan S.V., Knight J.C., Ebers G.C. Multiple sclerosis and the major histocompatibility complex. Current opinion in neurology. 2009;22(3):219–225. https://doi.org/10.1097/WCO.0b013e32832b5417Ramagopalan S.V., Knight J.C., Ebers G.C. Multiple sclerosis and the major histocompatibility complex. Current opinion in neurology. 2009;22(3):219–225. https://doi.org/10.1097/WCO.0b013e32832b5417Rensel M. Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies. Children (Basel). 2019;6(6):73. https://doi.org/10.3390/children6060073Rensel M. Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies. Children (Basel). 2019;6(6):73. https://doi.org/10.3390/children6060073Simone M., Chitnis T. Use of Disease-Modifying Therapies in Pediatric MS. Current treatment options in neurology. 2016;18(8):36. https://doi.org/10.1007/s11940-016-0420-7Simone M., Chitnis T. Use of Disease-Modifying Therapies in Pediatric MS. Current treatment options in neurology. 2016;18(8):36. https://doi.org/10.1007/s11940-016-0420-7Chitnis T., Pohl D. Pediatric demyelinating disorders Global updates, controversies, and future directions. Neurology. 2016;87(9):S1–S3. https://doi.org/10.1212/WNL.0000000000002882Chitnis T., Pohl D. Pediatric demyelinating disorders Global updates, controversies, and future directions. Neurology. 2016;87(9):S1–S3. https://doi.org/10.1212/WNL.0000000000002882Смагина И.В., Ельчанинова С.А., Золовкина А.Г., Игнатова Ю.Н., Кудрявцева Е.А. Генетические факторы риска рассеянного склероза в популяции Алтайского края. Журнал неврологии и психиатрии им. C.C. Корсакова. 2011;111(5):42– 45.Smagina I.V., Elchaninova S.A., Zolovkina A.G., Ignatova Iu.N., Kudriavtseva E.A. Genetic risk factors for multiple sclerosis in the population of Altay. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2011;111(5):42–45. (In Russ.)].Polman C.H., Reingold S.C., Banwell B., Clanet M., Cohen J.A., Filippi M. et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Annals of neurology. 2011;69(2):292–302. https://doi.org/10.1002/ana.22366Polman C.H., Reingold S.C., Banwell B., Clanet M., Cohen J.A., Filippi M. et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Annals of neurology. 2011;69(2):292–302. https://doi.org/10.1002/ana.22366Kurtzke J.F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–1452. https://doi.org/10.1212/wnl.33.11.1444Kurtzke J.F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–1452. https://doi.org/10.1212/wnl.33.11.1444Riccio M.E., Buhler S., Nunes J.M., Vangenot C., Cuénod M., Currat M. et al. 6(th) IHIW: analysis of HLA population data, with updated results for 1996 to 2012 workshop data (AHPD project report). International journal of immunogenetics. 2013;40(1):21–30. https://doi.org/10.1111/iji.12033Riccio M.E., Buhler S., Nunes J.M., Vangenot C., Cuénod M., Currat M. et al. 6(th) IHIW: analysis of HLA population data, with updated results for 1996 to 2012 workshop data (AHPD project report). International journal of immunogenetics. 2013;40(1):21–30. https://doi.org/10.1111/iji.12033Terasaki P.I., Gjertson D.W., eds. HLA 1997. UCLA Tissue Typing Laboratory. Los Angeles: California; 1997:475 p.Terasaki P.I., Gjertson D.W., eds. HLA 1997. UCLA Tissue Typing Laboratory. Los Angeles: California; 1997:475 p.Banwell B., Bar-Or A., Arnold D.L., Sadovnick D., Narayanan S., McGowan M. et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. The Lancet. Neurology. 2011;10(5):436–445. https://doi.org/10.1016/S1474-4422(11)70045-XBanwell B., Bar-Or A., Arnold D.L., Sadovnick D., Narayanan S., McGowan M. et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. The Lancet. Neurology. 2011;10(5):436–445. https://doi.org/10.1016/S1474-4422(11)70045-XGianfrancesco M.A., Stridh P., Rhead B., Shao X., Xu E., Graves J.S. et al. Network of Pediatric Multiple Sclerosis Centers (2017). Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology. 2017;88(17):1623–1629. https://doi.org/10.1212/WNL.0000000000003849Gianfrancesco M.A., Stridh P., Rhead B., Shao X., Xu E., Graves J.S. et al. Network of Pediatric Multiple Sclerosis Centers (2017). Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology. 2017;88(17):1623–1629. https://doi.org/10.1212/WNL.0000000000003849Anagnostouli M.C., Manouseli A., Artemiadis A.K., Katsavos S. HLA–DRB1* allele frequencies in pediatric, adolescent, and adult–onset multiple sclerosis patients, in a hellenic sample. Evidence for new and established associations. Journal of multiple sclerosis. 2014;1:104. http://dx.doi.org/10.4172/jmso.1000104Anagnostouli M.C., Manouseli A., Artemiadis A.K., Katsavos S. HLA–DRB1* allele frequencies in pediatric, adolescent, and adult–onset multiple sclerosis patients, in a hellenic sample. Evidence for new and established associations. Journal of multiple sclerosis. 2014;1:104. http://dx.doi.org/10.4172/jmso.1000104An Pelt E.D., Mescheriakova J.Y., Makhani N., Ketelslegers I.A., Neuteboom R.F., Kundu S. et al. Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS demyelination. Neurology. 2013;81(23):1996–2001. https://doi.org/10.1212/01.wnl.0000436934.40034ebAn Pelt E.D., Mescheriakova J.Y., Makhani N., Ketelslegers I.A., Neuteboom R.F., Kundu S. et al. Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS demyelination. Neurology. 2013;81(23):1996–2001. https://doi.org/10.1212/01.wnl.0000436934.40034ebWaubant E., Ponsonby A.L., Pugliatti M., Hanwell H., Mowry E.M., Hintzen R.Q. Environmental and genetic factors in pediatric infl ammatory demyelinating diseases. Neurology. 2016;87(9Suppl2):S20–S27. https://doi.org/10.1212/WNL.0000000000003029Waubant E., Ponsonby A.L., Pugliatti M., Hanwell H., Mowry E.M., Hintzen R.Q. Environmental and genetic factors in pediatric infl ammatory demyelinating diseases. Neurology. 2016;87(9Suppl2):S20–S27. https://doi.org/10.1212/WNL.0000000000003029Consortium TIMSGCtWTCC, Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cellmediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–219. https://doi.org/10.1038/nature10251Consortium TIMSGCtWTCC, Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cellmediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–219. https://doi.org/10.1038/nature10251Hollenbach J.A., Oksenberg J.R. The immunogenetics of multiple sclerosis: A comprehensive review. Journal of autoimmunity. 2015;64:13–25. https://doi.org/10.1016/j.jaut.2015.06.010Hollenbach J.A., Oksenberg J.R. The immunogenetics of multiple sclerosis: A comprehensive review. Journal of autoimmunity. 2015;64:13–25. https://doi.org/10.1016/j.jaut.2015.06.010Kwon O.J., Karni A., Israel S., Brautbar C., Amar A., Meiner Z. et al. HLA class II susceptibility to multiple sclerosis among Ashkenazi and non-Ashkenazi Jews. Archives of neurology. 1999;56(5):555–560. https://doi.org/10.1001/archneur.56.5.555Kwon O.J., Karni A., Israel S., Brautbar C., Amar A., Meiner Z. et al. HLA class II susceptibility to multiple sclerosis among Ashkenazi and non-Ashkenazi Jews. Archives of neurology. 1999;56(5):555–560. https://doi.org/10.1001/archneur.56.5.555Cocco E., Sardu C., Pieroni E., Valentini M., Murru R., Costa G. et al. HLA-DRB1-DQB1 haplotypes confer susceptibility and resistance to multiple sclerosis in Sardinia. PloS one. 2012;7(4): e33972. https://doi.org/10.1371/journal.pone.0033972Cocco E., Sardu C., Pieroni E., Valentini M., Murru R., Costa G. et al. HLA-DRB1-DQB1 haplotypes confer susceptibility and resistance to multiple sclerosis in Sardinia. PloS one. 2012;7(4): e33972. https://doi.org/10.1371/journal.pone.0033972Amirzargar A., Mytilineos J., Yousefi pour A., Farjadian S., Scherer S., Opelz G. et al. HLA class II (DRB1, DQA1 and DQB1) associated genetic susceptibility in Iranian multiple sclerosis (MS) patients. European journal of immunogenetics. 1998;25(4):297–301. https://doi.org/10.1046/j.13652370.1998.00101.xAmirzargar A., Mytilineos J., Yousefi pour A., Farjadian S., Scherer S., Opelz G. et al. HLA class II (DRB1, DQA1 and DQB1) associated genetic susceptibility in Iranian multiple sclerosis (MS) patients. European journal of immunogenetics. 1998;25(4):297–301. https://doi.org/10.1046/j.13652370.1998.00101.xBrum D.G., Barreira A.A., Louzada-Junior P., MendesJunior C.T., Donadi E.A. Association of the HLA-DRB1*15 allele group and the DRB1*1501 and DRB1*1503 alleles with multiple sclerosis in White and Mulatto samples from Brazil. Journal of neuroimmunology. 2007;189(1–2):118–124. https://doi.org/10.1016/j.jneuroim.2007.06.009Brum D.G., Barreira A.A., Louzada-Junior P., MendesJunior C.T., Donadi E.A. Association of the HLA-DRB1*15 allele group and the DRB1*1501 and DRB1*1503 alleles with multiple sclerosis in White and Mulatto samples from Brazil. Journal of neuroimmunology. 2007;189(1–2):118–124. https://doi.org/10.1016/j.jneuroim.2007.06.009Quelvennec E., Bera O., Cabre P., Alizadeh M., Smadja D., Jugde F. et al. Genetic and functional studies in multiple sclerosis patients from Martinique attest for a specifi c and direct role of the HLA-DR locus in the syndrome. Tissue antigens. 2003;61(2):166–171. https://doi.org/10.1046/j.0001-2815.2002.00008.xQuelvennec E., Bera O., Cabre P., Alizadeh M., Smadja D., Jugde F. et al. Genetic and functional studies in multiple sclerosis patients from Martinique attest for a specifi c and direct role of the HLA-DR locus in the syndrome. Tissue antigens. 2003;61(2):166–171. https://doi.org/10.1046/j.0001-2815.2002.00008.xBallerini C., Guerini F.R., Rombolà G., Rosati E., Massacesi L., Ferrante P. et al. HLA-multiple sclerosis association in continental Italy and correlation with disease prevalence in Europe. Journal of neuroimmunology. 2004;150(1–2):178–185. https://doi.org/10.1016/j.jneuroim.2004.01.015Ballerini C., Guerini F.R., Rombolà G., Rosati E., Massacesi L., Ferrante P. et al. HLA-multiple sclerosis association in continental Italy and correlation with disease prevalence in Europe. Journal of neuroimmunology. 2004;150(1–2):178–185. https://doi.org/10.1016/j.jneuroim.2004.01.015Fernández O., Fernández V., Alonso A., Caballero A., Luque G., Bravo M. et al. DQB1*0602 allele shows a strong association with multiple sclerosis in patients in Malaga, Spain. Journal of neurology. 2004;251(4):440–444. https://doi.org/10.1007/s00415-004-0350-2Fernández O., Fernández V., Alonso A., Caballero A., Luque G., Bravo M. et al. DQB1*0602 allele shows a strong association with multiple sclerosis in patients in Malaga, Spain. Journal of neurology. 2004;251(4):440–444. https://doi.org/10.1007/s00415-004-0350-2Hillert J., Käll T., Olerup O., Söderström M. Distribution of HLADw2 in optic neuritis and multiple sclerosis indicates heterogeneity. Acta neurologica Scandinavica. 1996;94(3):161–166. https://doi.org/10.1111/j.1600-0404.1996.tb07047.xHillert J., Käll T., Olerup O., Söderström M. Distribution of HLADw2 in optic neuritis and multiple sclerosis indicates heterogeneity. Acta neurologica Scandinavica. 1996;94(3):161–166. https://doi.org/10.1111/j.1600-0404.1996.tb07047.xHensiek A.E., Sawcer S.J., Feakes R., Deans J., Mander A., Akesson E. et al. HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002;72(2):184–187. http://dx.doi.org/10.1136/jnnp.72.2.184Hensiek A.E., Sawcer S.J., Feakes R., Deans J., Mander A., Akesson E. et al. HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002;72(2):184–187. http://dx.doi.org/10.1136/jnnp.72.2.184Fukazawa T., Yamasaki K., Ito H., Kikuchi S., Minohara M., Horiuchi I. et al. Both the HLA-CPB1 and -DRB1 alleles correlate with risk for multiple sclerosis in Japanese: clinical phenotypes and gender as important factors. Tissue Antigens. 2000;55(3):199–205. https://doi.org/10.1034/j.1399-0039.2000.550302.xFukazawa T., Yamasaki K., Ito H., Kikuchi S., Minohara M., Horiuchi I. et al. Both the HLA-CPB1 and -DRB1 alleles correlate with risk for multiple sclerosis in Japanese: clinical phenotypes and gender as important factors. Tissue Antigens. 2000;55(3):199–205. https://doi.org/10.1034/j.1399-0039.2000.550302.xMcDonnell G.V., Mawhinney H., Graham C.A., Hawkins S.A., Middleton D. A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its infl uence on prognosis. J Neurol Sci. 1999;165(1):77–83. https://doi.org/10.1016/S0022-510X(99)00084-2McDonnell G.V., Mawhinney H., Graham C.A., Hawkins S.A., Middleton D. A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its infl uence on prognosis. J Neurol Sci. 1999;165(1):77–83. https://doi.org/10.1016/S0022-510X(99)00084-2Modin H., Olsson W., Hillert J., Masterman T. Modes of action of HLA-DR susceptibility specifi cities in multiple sclerosis. American journal of human genetics. 2004;74(6):1321–1322. https://doi.org/10.1086/420977Modin H., Olsson W., Hillert J., Masterman T. Modes of action of HLA-DR susceptibility specifi cities in multiple sclerosis. American journal of human genetics. 2004;74(6):1321–1322. https://doi.org/10.1086/420977Marrosu M.G., Murru M.R., Costa G., Cucca F., Sotgiu S., Rosati G. et al. Multiple sclerosis in Sardinia is associated and in linkage disequilibrium with HLA-DR3 and -DR4 alleles. American journal of human genetics. 1997;61(2):454–457. https://doi.org/10.1016/S0002-9297(07)64074-9Marrosu M.G., Murru M.R., Costa G., Cucca F., Sotgiu S., Rosati G. et al. Multiple sclerosis in Sardinia is associated and in linkage disequilibrium with HLA-DR3 and -DR4 alleles. American journal of human genetics. 1997;61(2):454–457. https://doi.org/10.1016/S0002-9297(07)64074-9Кaimen-Maciel D.R., Reiche E.M., Borelli S.D., Morimoto H.K., Melo F.C., Lopes J. et al. HLA-DRB1* allele-associated genetic susceptibility and protection against multiple sclerosis in Brazilian patients. Molecular medicine reports. 2009;2(6):993–998. https://doi.org/10.3892/mmr_00000204Кaimen-Maciel D.R., Reiche E.M., Borelli S.D., Morimoto H.K., Melo F.C., Lopes J. et al. HLA-DRB1* allele-associated genetic susceptibility and protection against multiple sclerosis in Brazilian patients. Molecular medicine reports. 2009;2(6):993–998. https://doi.org/10.3892/mmr_00000204Ramagopalan S.V., Morris A.P., Dyment D.A., Herrera B.M., DeLuca G.C., Lincoln M.R. et al. The inheritance of resistance alleles in multiple sclerosis. PLoS genetics. 2007;3(9):1607–1613. https://doi.org/10.1371/journal.pgen.0030150Ramagopalan S.V., Morris A.P., Dyment D.A., Herrera B.M., DeLuca G.C., Lincoln M.R. et al. The inheritance of resistance alleles in multiple sclerosis. PLoS genetics. 2007;3(9):1607–1613. https://doi.org/10.1371/journal.pgen.0030150

The authors declare that there are no conflicts of interest present.