HLA-DRB1* Allele Frequencies in Pediatric, Adolescent and Adult-Onset Multiple Sclerosis Patients, in a Hellenic Sample. Evidence for New and Established Associations

Abstract

Studies in many populations consistently have showed that the human leukocyte antigens (HLA) and especially the DRB1 * 15 allele has by far the strongest genetic association with multiple sclerosis (MS). The aim of this study was to investigate the role of HLA-DRB1 * alleles in MS risk/resistance and onset. A sample of 165 Hellenic MS patients (18 with pediatric-, 24 with adolescent-and 123 with adult-onset MS) and 107 healthy volunteers were examined with molecular techniques. Comparisons were made according to the Benjamini-Yekutieli method for p value correction. Both adult-onset MS patients and early-onset MS patients (age at onset below 20 years-old) had a significantly higher frequency of the DRB1 * 15 allele and a significantly lower frequency of the DRB1 * 11 allele compared to controls. For the early-onset vs. healthy group comparison, subgroup analyses revealed that both the pediatric-and the adolescent-onset MS groups contributed to the aforementioned DRB1 * 15 significant difference, while the DRB1*11 difference was ascribed solely to the adolescent-MS onset vs. healthy group comparison. Within MS patients comparisons revealed that early-onset MS patients had a tendency for higher DRB1 * 03 allele and a lower DRB1 * 16 allele frequency frequencies compared to adult-onset MS patients, although both non-significant. Notably, pediatric-onset MS patients showed complete absence of the DRB1 * 16 allele, along with a non-significant tendency for higher DRB1 * 15 allele frequency relative to the adult-onset group. Finally, the adolescent-onset MS group was presented with a lower DRB1 * 11 allele frequencies compared both to the pediatric-and the adult-onset MS group. Our findings confirm previous studies on the role of HLA-DRB1 * in MS. New findings that need to be confirmed by further studies are the pathogenetic role of DRB1 * 03 for early-onset MS and the putative protective role of the DRB1*16 allele in the pediatric-onset MS.

HLA-DPB1*03 as Risk Allele and HLA-DPB1*04 as Protective Allele for Both Early- and Adult-Onset Multiple Sclerosis in a Hellenic Cohort

“…In our study, we replicated the well-established predominance of the HLA-DRB1*15 genotype in Hellenic patients with MS compared to HC, independently of age at disease onset [11].…”

“…Additionally, according to our results, the most common HLA-DPB1-haplotypes in Hellenic patients with MS were HLA-DPB1*04/DPB1*04 (27%), followed by HLA-DPB1*02/DPB1*04 (13%), HLA-DPB1*03/DPB1*04 (11%) and HLA-DPB1*10/DPB1*04 (6%). Thus, the emerging protective role of the HLA-DP*04 allele is in parallel with the HLA-DR*11 allele, which is the most common in the Hellenic population, and the protective HLA-DRB1 allele in Hellenic patients with MS [11].…”

“…HLA class II (HLA-DRB1 and HLA-DPB1) frequencies were determined by molecular techniques for all the specificities included in the HLA Nomenclature of 2012 (we present only the first two or four digits of each allele, for low or high resolution respectively) [31]. HLA-DRB1 genotyping had been previously performed, using a PCR-SSO (Polymerase-Chain-Reaction, PCR, Sequence-Specific Oligonucleotide, SSO) technique (Elpha Bio-Rad, High resolution), as described elsewhere [11]. HLA-DPB1 genotyping was performed using a different PCR-SSO technique, based on a method that depends on reverse hybridization (Line Probe Assay, INNO-LiPA, Low Resolution, Innogenetics, Fujirebio, Europe) according to the manufacturer's protocol.…”

“…Recent studies have further established the role of HLA-DRB1*15:01 in early-onset (pediatric and adolescent) MS (EOMS), which accounts for 3-5% of all MS cases, while the role of HLA-DRB1*04 and HLA-DRB1*03 remains to be clarified [9][10][11].…”

“…The present study attempts to expand the existing data on HLA and MS by investigating the influence of HLA-DPB1* alleles on disease risk and resistance in a Hellenic sample of 100 patients of both EOMS and AOMS, using healthy controls (HC) for comparisons, given the pre-existing difference in HLA-DRB1 allele frequencies in EOMS and AOMS in our ethnic group [11] and the total absence of information on HLA-DPB1 genotyping in the Hellenic MS population.…”