Cited by 212Multiple Sclerosis Research StudiesGenetic Associations and EpidemiologyPsoriasis: Treatment and Pathogenesis

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HLA-DR15 Haplotype and Multiple Sclerosis: A HuGE Review

Schmidt, Hollie, Williamson, Dhelia, Ashley-Koch, Allison·2007·American Journal of Epidemiology

DOI 10.1093/aje/kwk118

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Abstract

An association between multiple sclerosis (MS) and the human leukocyte antigen (HLA) complex, a dense cluster of genes on the short arm of chromosome 6, was first noted over 30 years ago. In Caucasian populations of Northern European descent, the DR15 haplotype (DRB1*1501-DQA1*0102-DQB1*0602) has been hypothesized to be the primary HLA genetic susceptibility factor for MS. However, studies of other populations have produced varying results. Thus, the authors reviewed the literature for articles on the association between the DR15 haplotype and MS. They identified 72 papers meeting the inclusion criteria: human genetic studies written in English that were published between 1993 and 2004 and that reported allele frequencies for HLA-DRB1*1501, HLA-DQA1*0102, or HLA-DQB1*0602 or the frequency of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. Most of the studies identified used a case-control design (n = 60), while the remainder used a family-based design (n = 22). In most of these papers, investigators reported a higher frequency of the DR15 haplotype and/or its component alleles among MS cases than among controls. However, the authors' confidence in these results is tempered by factors related to study design that may have biased the outcomes.

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Background
HLA-DRB1*14 is a protective allele for multiple sclerosis in an admixed Colombian population
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“Although HLA-DRB1 * 15 allele has been classically reported as a risk factor for MS in European descendants, 1 it has also been found in other Caucasian, 5 African, 3 and Latin American populations, including studies from Brazil, 5 Argentina, 21 and Martinique.”
Result
Hypothesis: Multiple sclerosis is caused by three-hits, strictly in order, in genetically susceptible persons
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Background
Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma
Zhang, C., de Smith, A. D., Smirnov, I., Wiencke, J., Wiemels, J., Witte, J., & Walsh, K. (2017) · Journal of Neuro-Oncology · doi:10.1007/s11060-017-2569-7 · Cited by 11
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“Several studies have identified the HLA-DRB1*1501 allele as the variant associated with increased risk, having an odds ratio (OR) of approximately 3 across various ethnic groups including Caucasian, Japanese, Middle Eastern, and African descent (Hafler et al., 2007; Schmidt et al., 2007).”
BackgroundInfluential
Berberine: A natural modulator of immune cells in multiple sclerosis
Yazdanpanah, E., Dadfar, S., Shadab, A., Orooji, N., Nemati, M., Pazoki, A., Esmaeili, S., Baharlou, R., & Haghmorad, D. (2024) · Immunity Inflammation and Disease · doi:10.1002/iid3.1213 · Cited by 10
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Background
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“(MHC) exerts the most important contribution, specifically the DR15 haplotype [10].”
Background
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“HLA-DRB1*15:01 confers the strongest risk for multiple sclerosis (Masterman et al., 2000; Lincoln et al., 2005; Schmidt et al., 2007).”
Background
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“This allele is particularly prevalent among Caucasian individuals but is also common in Middle Eastern and Japanese populations [11,86,87].”
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“The HLA-DRB1 * 15:01 allele, a major genetic risk factor of MS (Schmidt et al, 2007), is also associated with susceptibility to allergic bronchopulmonary aspergillosis (ABPA) (Chauhan et al, 2000; Nasir et al, 2023).”
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“A major function of MHC Class II molecule is to present antigens derived from extracellular proteins for recognition by T‑cells.”
Background
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“It has been observed that patients who smoke tobacco and have certain genetic risk factors, such as the absence of HLA-DRB5*01 (DR2a) and HLA-DRB1*15 (or DR2b) (two alleles that take part in DR15 haplotype), produce auto-reactive T cells in the lungs with an altered peptide antigen presentation capacity that promotes…”
Background
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“La région des gènes qui codent pour le CMH constitue la principale zone du génome humain associée à la SEP. Au sein de cette région, le HLADRB1*1501 est un site majeur de prédisposition à la SEP (Schmidt et al. 2007 ; Disanto et al., 2010 ; Banwell et al., 2011).”
The HLA-DRB1 and HLA-DQB1 alleles are associated with multiple sclerosis disability progression in Slovak population
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“Each HLA-DR molecule in humans contains an alpha chain and a beta chain, which associate inside the cell, bind to a peptide and travel to the cell surface to present the peptide to T-cells [15].”
Background
Distinct HLA class I and II genotypes and haplotypes are associated with multiple sclerosis in Bahrain
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“Although the HLA-DRB1*15 haplotype may represent the main disease risk factor in populations of North European origin, several dissimilar allelic associations have been identified in Southern European populations, Israel (35) and other countries (30).”
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“Given that the role of CD33 rs3865444 in MS susceptibility was reported only in a single paper [19], we decided to perform a case-control study to evaluate the impact of this SNP on MS risk in the Slovak population and further examine whether its association with the disease is affected by the HLA-DRB1*15:01 allele as…”
Background
High‐resolution HLA class II sequencing of Swedish multiple sclerosis patients
Akel, O., Zhao, L. P., Geraghty, D. E., & Lind, A. (2022) · International Journal of Immunogenetics · doi:10.1111/iji.12594 · Cited by 6
The +190 G/A (rs1799864) polymorphism in the C–C chemokine receptor 2 (CCR2) gene is associated with susceptibility to multiple sclerosis in HLA-DRB1*15:01-negative individuals
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“Among more than 100 risk gene variants accounting for estimated quarter of reported heritability [38], major histocompatibility complex (MHC) class II genes are the most important determinants of MS susceptibility, with HLA-DRB1*15:01 allele conferring the highest risk in Caucasians ([18]; [39]).”
Background
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“Two main groups of high-throughput genotyping analyses: candidate gene approaches and genome-wide association studies (GWAS) have identified polymorphisms in the human leukocyte antigen (HLA) region as the strongest susceptibility loci for MS (Schmidt et al., 2007).”
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Holt, E. A., Tyler, A. L., Lakusta-Wong, T. M., Lahue, K. G., Hankes, K. C., Teuscher, C., Lynch, R., Ferris, M. T., Mahoney, J. M., & Krementsov, D. N. (2024) · JCI Insight · doi:10.1172/jci.insight.184138 · Cited by 4
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“The present study has demonstrated for the first time that HLA-DRB1*15 allele is associated with susceptibility to MS in the Lithuanian population as it was found previously in many studies, especially in Caucasian populations (5).”
Result
Estudos Genéticos em Doentes Portugueses com Esclerose Múltipla
Bettencourt, A., SILVA, A. C. F. D., Costa, P., & da Silva, B. M. (2012) · Acta Médica Portuguesa · doi:10.20344/amp.66 · Cited by 5
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“pediatric MS centers it was shown that HLA-DRB*15 and A*02 were strongly associated with the pediatric onset of MS (Anagnostouli and Gontika, 2018; Čierny et al., 2018; Schmidt et al., 2007).”
HLA-class II genes association with multiple sclerosis: An immunogenetic prediction among multiple sclerosis Jordanian patients
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“Within the residues 85-99 of MPB; valine residue at location 89 and phenylalanine residue at location 92 were discovered to be located in the P1 and P4 anchor residues of the HLA-DRB1 * 15:01 peptide binding groove [10,14,15].”
Epistasis between HLA-DRB1 parental alleles in a Spanish cohort with multiple sclerosis
Romero-Pinel, L., Pujal, J. M., Martínez‐Yélamos, S., Gubieras, L., Matas, E., Bau, L., Torrabadella, M., Azqueta, C., & Arbizu, T. (2010) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2010.07.026 · Cited by 4
“The associationofMSwithDRB1*15has beenwell established [3] although it is known that the interaction of this allele with other alleles as well as other loci and even with environmental factors play an important role in increasing or decreasing the MS susceptibility.”
Background
Rôles bénéfiques de la vitamine D sur la neurodégénérescence et les troubles mentaux
Millet, P., Landel, V., Virard, I., Morello, M., & Feron, F. P. (2014) · Cahiers de Nutrition et de Diététique · doi:10.1016/j.cnd.2014.03.006 · Cited by 4
“[170] Schmidt H, Williamson D, Ashley-Koch A.”
The Role of Adaptive Immunity in Idiopathic Pulmonary Fibrosis: Hiding in Plain Sight
Duncan, S. R. (2013) · Humana Press eBooks · doi:10.1007/978-1-62703-682-5_7 · Cited by 4
Analysis of ICAM1 gene polymorphism in Slovak multiple sclerosis patients
Shawkatová, I., Javor, J., Párnická, Z., Bucová, M., Čopíková‐Cudráková, D., Michalík, J., Gmitterová, K., Čierný, D., Buc, M., & Ďurmanová, V. (2017) · Folia Microbiologica · doi:10.1007/s12223-017-0499-6 · Cited by 7
“The HLA association was fine mapped to the HLADRB5*01:01-DRB1*15:01-DQA1*01:02-DQB1*06:02 extended haplotype, with the HLA-DRB1*15:01 allele conferring the highest risk in Caucasians (Lincoln et al. 2005; Schmidt et al. 2007; Sawcer et al. 2011; Sadovnick 2012).”
Background
HLA Class II Genotype Does Not Affect the Myelin Responsiveness of Multiple Sclerosis Patients
Derdelinckx, J., Nkansah, I., Ooms, N., Bruggen, L. V., Emonds, M., Daniëls, L., Reynders, T., Willekens, B. M. P., Cras, P. P., Berneman, Z. N., et al. (2020) · Cells · doi:10.3390/cells9122703 · Cited by 3
“The HLA-DRB1*15:01 allele is often combined with HLA-DQB1*06:02 and HLA-DQA1*01:02 in the HLA-DR15 haplotype [15].”
BackgroundInfluential
Association of HLA DRB1-DQB1 Haplotypes with the Risk for Neuromyelitis Optica among South Indians
Kanikannan, M. A., Kathgave, R., Yareeda, S., Katkam, S. K., Kumaraswamy, K., & Kutala, V. K. (2022) · Neurology India · doi:10.4103/0028-3886.355130 · Cited by 3
Confirmation of CD19+ B-Lymphocyte Depletion Prior to Intake of the Second Dose of Ocrelizumab in Multiple Sclerosis Patients
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“…Rainero et al. (2011) Miscellaneous neurological conditions Acoustic schwannoma Low hypocretin level No No Yes Ehde, Osborne, Hanley, and Kraft (2006), Schmidt, Williamson, and Ashley-Koch (2007) Fibromyalgia Normal No Yes Yes Myung and Jin-Sang (2004), Nampiaparampil (2008) Epilepsy Low…”
Background
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“Similarly, DQB1*06:02 is known to raise the risk of MS among Caucasians and Europeans [23], was seen in 10% of MS patients.”
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“Accordingly, the prevalence of DR15 in MS patient populations is higher than in healthy controls, with several studies reporting that over 50% of cases carry this allele [20], a substantial increase from the estimated 14.51% of the European-American population [21].”
Influential
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“Among all the genetic factors associated with MS susceptibility, the association between the HLA and MS is the strongest 45 .”
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HLA-DRB1*15:01 is associated with a reduced likelihood of longevity in northern European men
Mejía, N. M., Kolbe, D., Özer, O., Dose, J., Torres, G. G., Franke, A., Nygaard, M., & Nebel, A. (2025) · Genome Medicine · doi:10.1186/s13073-025-01554-1 · Cited by 1
“The results revealed that the association between DRB1*15:01:01 and longevity was linked to DRB1*15:01:01 ~ DQB1*06:02:01 (OR = 0.64) — a well-known haplotype in Europeans that encodes the DR15 serotype [46, 47].”
Influential
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“HLA-DRB1 * 15:01 has also been reported to be associated with multiple sclerosis [32], systemic lupus erythematosus [33], nar-colepsy [34], anti-glomerular basement membrane disease [35] and leprosy [36].”
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“Another study used Phage Immunoprecipitation Sequencing and the Department of Defense serum repository to identify novel autoantibodies present during the pre-clinical phase of MS [62].”
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“As Class II molecules can bind and present certain self-peptides, several studies indicated that HLAs class II have been associated to several autoimmune or immune mediated disorders, including MS [29].”
Background
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“This allelewas found to be present in over 50% of MS cases [25, 26].”
Background
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Association of various genes with susceptibility to multiple sclerosis in Lebanese population of Bekaa region: A preliminary study
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“Unlike the majority of previous studies that confirmed a high correlation between HLADRB1*1501 and MS (DE BAKKER et al., 2006; SCHMIDT et al., 2007; ALCINA et al., 2012; AL JUMAH et al., 2018), our preliminary study did not reproduce the contribution of this allele to the disease in the Lebanese MS…”
Result
Genética de la esclerosis múltiple: papel del HLA-DRB1 en la susceptibilidad y expresión fenotípica
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“showed that DR15 haplotype and/or its component alleles has a higher frequency in MS patients than controls[58].”
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Biomarker Identification in Patients with Multiple Sclerosis Treated with Autologous Hematopoietic Stem Cell Transplantation
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“In a review published by Schmidt et al., 72 papers published between 1993 and 2004 were analyzed and revealed that in most studies, the frequency of DRB1*15:01 was higher in cases than in controls [15].”

Authors: Schmidt, H., Williamson, D., & Ashley-Koch, A.
Affiliations: Accelerated Cure Project for Multiple Sclerosis (US)
Centers for Disease Control and Prevention (US)
ORCID: Schmidt, Hollie
Williamson, Dhelia
Venue: American Journal of Epidemiology
Publisher: Oxford University Press (OUP)
Published: 2007-02-28
Volume: 165
Issue: 10
Pages: 1097-1109
ISSN: 0002-9262 (ISSN-L)
1476-6256
DOI: 10.1093/aje/kwk118
OpenAlex: W2146798707
Cited by: 212
References: 146
Citations by year: 2026: 10 · 2025: 9 · 2024: 10 · 2023: 5 · 2022: 12 · 2021: 8 · 2020: 14 · 2019: 10 · 2018: 16 · 2017: 13 · 2016: 9 · 2015: 14 · 2014: 7 · 2013: 15 · 2012: 13
FWCI: 0.96
Type: journal article
Language: en
Open access: closed
Locations: American Journal of Epidemiology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords: multiple sclerosis, HLA-DRB1*1501, HLA-DQA1*0102, HLA-DQB1*0602, genetic susceptibility, HLA complex, allele frequency, case-control study, family-based association study, study design bias
MeSH terms: Alleles, Multigene Family, Haplotypes, HLA-D Antigens, Humans, Multiple Sclerosis

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HLA-DR15 Haplotype and Multiple Sclerosis: A HuGE Review

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