Using flow cytometry we measured surface expression of CD40 and CD86 in B cells from 68 patients and 162 healthy controls that were genotyped for the multiple sclerosis associated single nucleotide polymorphisms (SNPs) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene.
In 772 patients with MS, we see no evidence that rs1800693(G) strongly influences clinical or radiographic indices of disease course and treatment response; thus, rs1800693(G) appears to be primarily involved in the onset of MS. At the molecular level, this validated susceptibility allele generates an RNA isoform, TNFRSF1A Δ6, that lacks the transmembrane and cytoplasmic domains.
Here we describe linked intronic variants of MGAT5 that are associated with reduced N-glycan branching, CTLA-4 surface expression and MS (p=5.79×10(-9), n=7,741), the latter additive with the MGAT1, IL2RA and IL7RAMS risk variants (p=1.76×10(-9), OR=0.67-1.83, n=3,518).
We investigated the influence of KIR genes on MS susceptibility in 447 MS Portuguese patients, and also whether genetic interactions between specific KIR genes and their HLA class I ligands could contribute to the pathogenesis of MS. We observed a negative association between the activating KIR2DS1 gene and MS (adjusted OR=0.450, p=0.030) independently from the presence of HLA-DRB1*15 allele.
The TNF-α inverse association with relapse was only present among persons carrying the wild-type of the functional SNP rs1800693 in TNFRSF1A that has been previously associated with MS risk.
The HLA-DR2 haplotype (DRB1*1501, DQB1*0602) on chromosome 6p21 has consistently demonstrated both association and linkage with multiple sclerosis (MS) in case-control and family studies, particularly in Caucasians of Northern European descent.
However, we show for the first time that HLA-DRB1*15 allele modulates the course of MS for relapsing-remitting (RR) onset patients likely by precipitating the secondary progressive (SP) phase.
CLEC16A is in a locus genetically linked to autoimmune diseases including multiple sclerosis, but the function of this gene in the nervous system is unknown.
The relevant role of the IL2RA gene on MS susceptibility adds support to its common effect on autoimmune risk and the suggestive association of IL2/IL21 warrants further investigation.
For example, nucleotide variation in the interleukin 7 receptor (IL7RA), the interleukin 2 receptor (IL2RA), the CD58 and the c-type lectin domain family 16 member A (CLEC16A) genes has been consistently associated with MS in several populations.
Lack of evidence for an association between two genetic polymorphisms in the tumor necrosis factor receptor 1 gene and multiple sclerosis in Ashkenazi Jews.
Cross-ethnic comparison between the two HLA haplotypes associated with MS in Sardinians and the DRB1*1501 (DR2)-DQA1*0102-DQB1* 0602 haplotype, associated with MS in other Caucasian populations, failed to identify any shared epitopes in the DR and DQ molecules that segregated with disease susceptibility.
Moreover, the risky genotypes TT and TC were showed to be associated with an increased MS risk, and this was aggravated by the homozygous carriage of the HLA-DRB1*15:01 allele (OR = 2.82 vs. 4.86, p < .0001).
Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk.
While in these 397 families, 8 markers showed significant association with MS, through conditional tests we determined that these MOG variants were not associated with MS independently of the main DRB1-DQB1 disease associations.
CNS-specific ANA were more frequent in MS than in NMOSD patients or HCs (13.5% vs 0% for both comparisons, both p < .05) and were associated with HLA-DRB1*15:01 (p = .0174).