Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects

ABSTRACT Objective: To investigate the potential relationship between the human leukocyte antigen (HLA) type (class I and II) and the response to several disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS). Methods: We analyzed clinical data of 87 patients with MS at the beginning and end of each type of DMT including the disease duration, Expanded Disability Status Scale and Multiple Sclerosis Severity Score (MSSS). Genotyping of HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-A, HLA-B and HLA-C alleles were identified using high-resolution techniques. Statistical correlation between the HLA type and response to DMTs was done using the initial and final MSSS. Results: Statistical relationships (p < 0.05) were found for only 15 of 245 alleles tested. There was a reduction in the MSSS for patients treated with corticosteroids (DRB1*15:01, DPB1*04:01, DQB1*02:01 and DQB1*03:01), azathioprine (DRB1*03:01, DPB1*04:01, DQB1*03:02, DQB1*06:02, HLA-C*07:02), interferon β-1a 22 mcg (DRB1*11:04, DQB1*03:01 and DQB1*03:02), interferon β-1a 30 mcg (DPB1*02:01, HLA-C*05:01) and interferon β-1b (DQB1*02:01). Conclusion: These findings suggest a few relationships between the HLA and response to DMTs in the disability for some types of HLA class I and II alleles in a specific subset of MS patients.

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High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility

Frontiers in Immunology ◽

10.3389/fimmu.2021.644838 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kazutoyo Osoegawa ◽

Lisa E. Creary ◽

Gonzalo Montero-Martín ◽

Kalyan C. Mallempati ◽

Sridevi Gangavarapu ◽

...

Keyword(s):

Multiple Sclerosis ◽

Statistical Significance ◽

Hla Class I ◽

Protective Effects ◽

Genetic Associations ◽

Hla Alleles ◽

Hla Genes ◽

Haplotype Allele ◽

Family Based ◽

Hla Haplotypes

Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p < 2.20e-16; mTDT: p =1.61e-07; CC: p < 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS.

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Soluble HLA class I and class II antigens in patients with multiple sclerosis

Tissue Antigens ◽

10.1111/j.1399-0039.1998.tb03106.x ◽

2008 ◽

Vol 51 (3) ◽

pp. 301-304 ◽

Cited By ~ 24

Author(s):

M. Ott ◽

K. Stecker ◽

C. Seidl ◽

E. Seifried ◽

U. Westhoff ◽

...

Keyword(s):

Multiple Sclerosis ◽

Hla Class I ◽

Class Ii ◽

Class I ◽

Soluble Hla ◽

Class Ii Antigens

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Infectious mononucleosis-linked HLA class I single nucleotide polymorphism is associated with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458510376778 ◽

2010 ◽

Vol 16 (11) ◽

pp. 1303-1307 ◽

Cited By ~ 3

Author(s):

Naghmeh Jafari ◽

Linda Broer ◽

Ilse A Hoppenbrouwers ◽

Cornelia M van Duijn ◽

Rogier Q Hintzen

Keyword(s):

Multiple Sclerosis ◽

Single Nucleotide Polymorphism ◽

Infectious Mononucleosis ◽

Risk Allele ◽

Hla Class I ◽

Class I ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Major Class ◽

A Minor

Background: Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism. Objectives: Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis. Methods: Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501. Results: HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10 -5). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 ( p = 0.003) for HLA-A. Conclusions: HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.

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Elevated levels of soluble HLA class I in the serum of multiple sclerosis patients

Journal of Neuroimmunology ◽

10.1016/0165-5728(94)90385-9 ◽

1994 ◽

Vol 54 (1-2) ◽

pp. 172

Author(s):

S.J. Khoury ◽

I. Adamashvili ◽

E. Milford ◽

M.H. Sayegh ◽

J.C. McDonald ◽

...

Keyword(s):

Multiple Sclerosis ◽

Hla Class I ◽

Class I ◽

Soluble Hla ◽

Multiple Sclerosis Patients

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Immunogenetic Epidemiology of Multiple Sclerosis in 14 Continental Western European Countries

Journal of Immunological Sciences ◽

10.29245/2578-3009/2021/2.1216 ◽

2021 ◽

Vol 5 (2) ◽

pp. 40-46

Author(s):

Lisa M. James ◽

Apostolos P. Georgopoulos

Keyword(s):

Multiple Sclerosis ◽

Human Leukocyte ◽

Hla Class I ◽

European Countries ◽

Class I ◽

Hla Alleles ◽

Susceptibility Effect ◽

Pathogen Elimination ◽

Western European

Human leukocyte antigen (HLA), a system involved in immune response to foreign antigens and in autoimmunity, has been strongly implicated in multiple sclerosis (MS). Prior research has shown that HLA DRB1*15:01 exerts the strongest susceptibility effect, although other HLA alleles have been implicated in both susceptibility to, and protection against, MS. Here we utilized an immunogenetic epidemiological approach to evaluate correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of MS in 14 Continental Western European countries to identify an HLA profile for MS. The results of these analyses, which largely corroborated prior findings and revealed several novel and highly robust HLA associations with MS, revealed a larger number of protective HLA alleles than susceptibility alleles, particularly for HLA Class I. Given the role of HLA in pathogen elimination and autoimmunity, these findings point to a contributory role of exposure to pathogens in the absence of protective HLA in underlying the inflammation and autoimmunity associated with MS.

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Additive Contribution of HLA Class I Alleles in the Immune Control of HIV-1 Infection

Journal of Virology ◽

10.1128/jvi.00320-10 ◽

2010 ◽

Vol 84 (19) ◽

pp. 9879-9888 ◽

Cited By ~ 112

Author(s):

Alasdair Leslie ◽

Philippa C. Matthews ◽

Jennifer Listgarten ◽

Jonathan M. Carlson ◽

Carl Kadie ◽

...

Keyword(s):

Hla Class I ◽

Cd4 Count ◽

Class I ◽

Strong Impact ◽

Protective Effects ◽

Hla Alleles ◽

Individual Level ◽

Additive Contribution ◽

The Individual ◽

Hiv 1

ABSTRACT Previous studies have identified a central role for HLA-B alleles in influencing control of HIV infection. An alternative possibility is that a small number of HLA-B alleles may have a very strong impact on HIV disease outcome, dominating the contribution of other HLA alleles. Here, we find that even following the exclusion of subjects expressing any of the HLA-B class I alleles (B*57, B*58, and B*18) identified to have the strongest influence on control, the dominant impact of HLA-B alleles on virus set point and absolute CD4 count variation remains significant. However, we also find that the influence of HLA on HIV control in this C-clade-infected cohort from South Africa extends beyond HLA-B as HLA-Cw type remains a significant predictor of virus and CD4 count following exclusion of the strongest HLA-B associations. Furthermore, there is evidence of interdependent protective effects of the HLA-Cw*0401-B*8101, HLA-Cw*1203-B*3910, and HLA-A*7401-B*5703 haplotypes that cannot be explained solely by linkage to a protective HLA-B allele. Analysis of individuals expressing both protective and detrimental alleles shows that even the strongest HLA alleles appear to have an additive rather than dominant effect on HIV control at the individual level. Finally, weak but significant frequency-dependent effects in this cohort can be detected only by looking at an individual's combined HLA allele frequencies. Taken together, these data suggest that although individual HLA alleles, particularly HLA-B, can have a strong impact, HIV control overall is likely to be influenced by the additive effect of some or all of the other HLA alleles present.

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