مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
A Systematic Review of HLA-DRB1*15:01 and Non-HLA Genetic Risk Factors Associated with MRI Lesion Burden in Relapsing-Remitting Multiple Sclerosis Patients
A Systematic Review of HLA-DRB1*15:01 and Non-HLA Genetic Risk Factors Associated with MRI Lesion Burden in Relapsing-Remitting Multiple Sclerosis Patients
Alireza Pourrahim,1,*Mohammad Mahdi Pourrahim,2Alireza Vasiee,3Omid Raiesi,4
1. Student Research Committee, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran. 2. Student Research Committee, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran. 3. Department of Nursing, Faculty of Nursing and Midwifery, Ilam University of Medical Sciences, Ilam, Iran. 4. Department of Parasitology, School of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran.
Introduction: Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system characterized by inflammatory demyelination and progressive neurodegeneration. Among the over 200 genetic loci identified as contributing to MS susceptibility, the strongest and most consistently replicated is the human leukocyte antigen (HLA) class II allele DRB1*15:01, located on chromosome 6p21 within the major histocompatibility complex (MHC) region. HLA-DRB1*15:01 is the strongest genetic susceptibility allele in MS and has been implicated not only in disease risk but also in lesion accumulation on magnetic resonance imaging (MRI). Non-HLA loci identified through genome-wide studies may additionally modulate tissue damage, but their imaging correlates are less well characterized. We performed a systematic review to quantify the associations between HLA-DRB1*15:01 (and other MS risk alleles) and MRI-derived lesion metrics in relapsing-remitting MS (RRMS) cohorts.
Methods: A comprehensive literature search was performed in accordance with PRISMA guidelines. The databases searched included PubMed/MEDLINE, Embase, Scopus, and Web of Science up to May 2025. The search strategy incorporated a combination of keywords and boolean operators such as “relapsing-remitting multiple sclerosis”, “major histocompatibility complex”, “MRI lesion burden”, “T2-weighted lesion volume” and their related MeSH terms. Titles and abstracts were screened independently by two reviewers to identify original, peer-reviewed studies reporting quantitative associations between HLA-DRB1*15:01 (or other MS susceptibility alleles) and MRI lesion metrics in adult or pediatric RRMS cohorts. Extracted data comprised allele status, annualized lesion volume change, effect sizes (mean differences or standardized β), odds ratios (OR), and p-values. The quality of the included studies was assessed using the Newcastle–Ottawa Scale, with all scoring ≥5/9, indicating moderate to high quality.
Results: Across five studies encompassing 1,731 RRMS patients, carriers of HLA-DRB1*15:01 consistently exhibited greater accumulation of T2-weighted lesion volume compared to non-carriers, with annualized mean differences ranging from 0.30 to 0.45 mL (weighted mean +0.38 mL/year; all p < 0.025) and standardized β-coefficients of 0.12–0.20 (p < 0.05). In a cohort of 586 individuals, higher cumulative HLA genetic burden; principally driven by DRB1*15:01, was linked to markedly increased cerebral white-matter lesion volume (median HLAGB 0.7 vs. 0 in controls; P = 1.8×10⁻²⁷). Non-HLA variants exerted smaller effects: HLA-B44:02 showed a modest protective association (β ≈ +0.10; P ≈ 0.036), while other non-DRB1 alleles did not correlate significantly with lesion metrics. In pediatric-onset RRMS (n = 50), HLA-DRB103 carriers demonstrated 2.3-fold higher odds of thoracic spinal cord lesions (OR = 2.3; P = 0.043). Two additional cohorts (total n = 668) reported no significant association between DRB1*15:01 and T2 lesion volume or count (p > 0.05), underscoring variability in imaging protocols and genetic-burden assessments.
Conclusion: Overall, DRB1*15:01 carriers exhibit an accelerated accrual of T2 lesion volume in RRMS, with a mean annual increase of approximately 0.38 mL (standardized β = 0.12–0.20). Non-HLA alleles show more modest or inconsistent effects. Heterogeneity in MRI protocols and genetic burden definitions underscores the need for harmonized, longitudinal studies and individual-patient meta-analyses to refine genotype–imaging phenotype relationships in MS.