DRB1*03:01 Haplotypes: Differential Contribution to Multiple Sclerosis Risk and Specific Association with the Presence of Intrathecal IgM Bands

Abstract

BackgroundMultiple sclerosis (MS) is a multifactorial disease with a genetic basis. The strongest associations with the disease lie in the Human Leukocyte Antigen (HLA) region. However, except for the DRB1*15:01 allele, the main risk factor associated to MS so far, no consistent effect has been described for any other variant. One example is HLA-DRB1*03:01, with a heterogeneous effect across populations and studies. We postulate that those discrepancies could be due to differences in the diverse haplotypes bearing that allele. Thus, we aimed at studying the association of DRB1*03:01 with MS susceptibility considering this allele globally and stratified by haplotypes. We also evaluated the association with the presence of oligoclonal IgM bands against myelin lipids (OCMB) in cerebrospinal fluid.MethodsGenotyping of HLA-B, -DRB1 and -DQA1 was performed in 1068 MS patients and 624 ethnically matched healthy controls. One hundred and thirty-nine MS patients were classified according to the presence (M+, 58 patients)/absence (M−, 81 patients) of OCMB. Comparisons between groups (MS patients vs. controls and M+ vs. M−) were performed with the chi-square test or the Fisher exact test.ResultsAssociation of DRB1*03:01 with MS susceptibility was observed but with different haplotypic contribution, being the ancestral haplotype (AH) 18.2 the one causing the highest risk. Comparisons between M+, M− and controls showed that the AH 18.2 was affecting only M+ individuals, conferring a risk similar to that caused by DRB1*15:01.ConclusionsThe diverse DRB1*03:01-containing haplotypes contribute with different risk to MS susceptibility. The AH 18.2 causes the highest risk and affects only to individuals showing OCMB.

HLA-DRB1 Alleles Are Associated with the Susceptibility to Sporadic Parkinson’s Disease in Chinese Han Population

“…HLA-DRB1*0301 has been reported contribute to the genetic susceptibility of some autoimmune diseases such as type 1 diabetes and multiple sclerosis [53] – [54] . In our study, the allele frequency of HLA-DRB1*0301 was significantly higher in PD patients than in healthy controls (0.0811 vs. 0.0449, pc = 4.572E-3, statistic power >0.75).…”

T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson's Disease

“…According to the autoimmune nature of PD, alleles HLA-DQB1 * 06 and HLA-DRB1 * 0301 have been shown to be significantly more frequent in PD patients (120, 121). Notably, the allele HLA-DRB1 * 0301 (121) has also been associated to the genetic susceptibility of some classical autoimmune diseases such as diabetes (122) and multiple sclerosis (MS) (123). In addition, a recent study analysed the binding of different alleles of class II MHC to peptides derived from autoantigens associated to PD and found a positive association between alleles HLA-DRB1 * 1501, HLA-DRB1 * 0304, and HLA-DRB5 * 0101 and the binding to autoantigens-derived peptides in PD patients (41).…”

HLA and Celiac Disease Susceptibility: New Genetic Factors Bring Open Questions about the HLA Influence and Gene-Dosage Effects

“…The DQA1*05 , DQB1*02 and DRB1*03∶01 alleles can be present in two different haplo-specific contexts and constitute the so-called ancestral haplotypes (AH) 8.1 and AH 18.2; they can also be found within non-specific allelic combinations and constitute other less frequent haplotypes (hereafter called non-conserved haplotypes). The DRB1*03∶01 allele, and consequently, DRB1*03∶01 haplotypes, have been associated to numerous immune-mediated disorders, as type 1 diabetes, multiple sclerosis or selective IgA deficiency, among many others; in some cases with the different DRB1*03∶01 haplotypes showing a differential contribution to disease risk [2] , [3] . A differential behaviour between AH 18.2 and AH 8.1 has also been described in CD [4] , [5] , although no relevance has been given to this observation.…”