Genetic and molecular architecture of multiple sclerosis in gulf cooperation council populations: A scoping review and regional precision-neurology perspective.

BACKGROUND: Multiple sclerosis (MS) is increasingly recognized across Gulf Cooperation Council (GCC) countries, where rising disease burden intersects with distinctive ancestry, family structure, consanguinity patterns, vitamin D deficiency, rapid environmental transition, and an unevenly developed genetic literature. Most global MS genetic models have been derived from European-ancestry datasets and may not fully capture susceptibility patterns, allele frequencies, familial structure, or gene-environment interactions in Arabian Gulf populations. A regionally focused synthesis is therefore needed, while recognizing that the available GCC evidence remains too limited, heterogeneous, and insufficiently replicated for conventional pooled meta-analysis.

OBJECTIVE: To map and critically synthesize available HLA, non-HLA, vitamin D pathway, transcriptomic, biomarker, familial, registry-related, and emerging mitochondrial evidence relevant to MS genetic and molecular susceptibility in GCC populations, and to define research priorities that could support future precision-neurology approaches.

METHODS: A PRISMA-ScR-informed scoping review and narrative evidence synthesis was conducted. PubMed, Embase, Scopus, Web of Science, Cochrane Library, and selected regional sources were searched for publications from January 2000 to February 2026, with an update before resubmission in June 2026. Eligible sources included GCC-based MS studies reporting HLA, non-HLA SNP, transcriptomic, serum biomarker, vitamin D pathway, familial, registry, or molecular evidence relevant to MS susceptibility or disease biology. Study-level effect estimates were extracted when available. No pooled meta-analysis was performed because repeated variant-level data across independent GCC cohorts were unavailable for most loci.

RESULTS: Fourteen studies were included in the scoping synthesis; four provided directly extractable study-level effect estimates. The available evidence suggests, but does not prove, that MS susceptibility in GCC populations may be heterogeneous and not fully explained by Western-derived HLA-DRB1×15:01-centered models. Bahrain contributes HLA and transcriptomic/biomarker evidence, including inflammatory molecular signals involving IL-1RA, OASL, TNF-AIP6, CLC, DOCK4, and TMEM66 that require prospective validation. Saudi Arabia contributes familial and registry-based observations, with exploratory mitochondrial studies representing an additional future-oriented non-HLA research layer. Kuwait provides the most extractable non-HLA replication and vitamin D pathway data, including immune, metabolic, vitamin D receptor, and vitamin d-binding protein signals. Qatar, the United Arab Emirates, and Oman remain underrepresented in accessible primary MS genetic literature. Across all layers, the evidence is biologically informative but constrained by small cohorts, single-country designs, incomplete extractability, limited replication, and heterogeneous methods. Importantly, transcriptomic, biomarker, familial, registry, and mitochondrial findings were interpreted separately from inherited DNA-level association studies to avoid overstating clinical readiness or combining biologically related but methodologically distinct evidence types.

CONCLUSIONS: GCC MS genetics should be interpreted as an emerging, fragmented, and hypothesis-generating field rather than a mature meta-analytic evidence base. Its value lies in clarifying evidence layers, identifying reproducibility gaps, and defining the infrastructure needed for future regional validation. Harmonized GCC registries, high-resolution HLA typing, non-HLA genotyping, vitamin D phenotyping, family-structured recruitment, biomarker validation, biobanking, mitochondrial substudies, ancestry documentation, transparent allele/genotype reporting, and registry-linked longitudinal outcomes could support future precision-neurology research without implying current readiness for routine genetic risk prediction or treatment selection, or individualized therapeutic stratification in routine clinical practice across the Arabian Gulf at present.