Mitochondrial Haplogroup U and multiple sclerosis risk in Arab and Near Eastern populations: a systematic review and meta-analysis

Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease with incompletely understood aetiology beyond the HLA-DRB1 locus. Mitochondrial haplogroup U, prevalent in Middle Eastern and Near Eastern populations, encodes functional variants in NADH dehydrogenase subunits associated with elevated reactive oxygen species (ROS) production. A 2022 study (Al-Kafaji et al., PLoS ONE) reported a nominal association between haplogroup U and RRMS in Saudi Arab patients (OR 6.26; 95% CI 0.82-48.10) in a single, small (n = 47) cohort. We conducted a systematic review and meta-analysis to determine whether this signal is supported by independently verifiable case-control data from other Arab or Near Eastern populations.

PRISMA 2020 systematic review. PubMed/MEDLINE was searched to 15 July 2026 using a concept-level strategy - ("mitochondrial DNA"[tiab] OR "mtDNA"[tiab] OR "DNA, Mitochondrial"[MeSH] OR "Mitochondria"[MeSH]) AND ("haplogroup"[tiab] OR "haplogroups"[tiab] OR "haplotype"[tiab]) AND ("multiple sclerosis"[tiab] OR "Multiple Sclerosis"[MeSH] OR "demyelinating"[tiab] OR "RRMS"[tiab]) - with no population terms applied at the search stage; population eligibility (Arab or Near Eastern cohort) was assessed during screening rather than baked into the search string, to maximise sensitivity. Eligible studies were case-control studies reporting mitochondrial haplogroup U frequency in MS cases versus healthy controls in an Arab or Near Eastern population, with data sufficient to construct a 2 × 2 table. Odds ratios were pooled using a fixed-effect inverse-variance model.

The search identified 30 records. After screening and full-text assessment, two studies met full inclusion criteria for quantitative pooling: Al-Kafaji et al. [1] (Saudi Arabia, n = 47) and Hassani-Kumleh et al. [2] (Iran, n = 154); total pooled N = 201 (77 MS cases, 124 controls). The fixed-effect pooled OR was 4.11 (95% CI 1.25-13.55; p = 0.020), with no meaningful heterogeneity (I²=0%, Cochran's Q = 0.25, df = 1). Two further Near Eastern studies (Houshmand et al. [3]; Ghabaee et al. [4]) reported related but non-poolable data - haplogroup J association and a haplogroup U case-series prevalence without a control arm, respectively - and are discussed narratively.

Across two independently verified Near Eastern case-control cohorts, mitochondrial haplogroup U is significantly associated with increased MS risk (pooled OR 4.11, 95% CI 1.25-13.55). The evidence base remains small, and the wide confidence interval reflects this. A larger, prospective, adequately powered study in Arab and Near Eastern MS cohorts is needed to confirm and refine this association.