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.

Immune-mediated genesis of multiple sclerosis

“…HLA-DRB1*11 was also found to be protective in the Brazilian [ 20 ], Canadian [ 21 ] and Greek [ 22 ] populations. The protective role of the HLA-A*02:01 has been confirmed in many different populations and remains the most widely studied HLA Class I allele in MS [ 23 ].…”

HLA Allele Frequencies in Pediatric and Adolescent Multiple Sclerosis Patients

“…Regarding HLA alleles, DRB1*15 association with early-onset MS has been noted by a series of studies [12,[19][20][21][22]. In 2000, a study of 286 Norwegians MS patients demonstrated that the HLA-DR2, DQ6 haplotype is negatively correlated with age at diagnosis [23].…”

“…Anagnostouli et al attributed this discrepancy either to a possible parent of origin effect, relying on Ramagopalan et al' observation that only maternally transmitted DRB1*15 promotes a lower age of MS [44], or to fluctuations of vitamin D levels among different populations[45]. New findings in this former are the putative predisposing role of DRB1*03 allele and the protective role of the DRB1*16 allele for early-onset MS[20].…”

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

“…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.…”