IL2RA Variants and Multiple Sclerosis Susceptibility
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system in which immune-mediated mechanisms contribute to demyelination and neuroaxonal injury. A major objective in MS genetics is to identify variants that perturb immune homeostasis in biologically interpretable pathways. In this article, Rangani and colleagues focus on IL2RA (CD25), which encodes the alpha chain of the interleukin-2 receptor and is expressed across regulatory and effector T cells, among other immune subsets; mechanistically, IL-2–IL2RA signaling is central to regulatory T-cell development and function, and altered signaling can shift the balance between tolerance and autoimmunity. The study addresses two intronic single-nucleotide polymorphisms (SNPs)—rs2104286 and rs12722489—that have been repeatedly examined in MS but with inconsistent results across cohorts, a pattern that can arise from limited power, ancestry-specific allele frequencies, and between-study methodological variability.
Study design overview: coupling regional case–control genetics with a systematic meta-analysis
The investigators apply a dual strategy: (i) a new case–control study in eastern Iranian populations and (ii) a systematic review and meta-analysis to synthesize global evidence and to specifically assess Iranian data as its own stratum. For the case–control component, 400 individuals were enrolled (200 MS cases and 200 controls) sampled from two provinces—North Khorasan and Sistan & Baluchistan—with inclusion criteria intended to reduce recent admixture (residency for at least three generations). Genotyping for rs2104286 was performed using PCR followed by restriction fragment length polymorphism (RFLP) analysis, with confirmatory sequencing of selected genotypes. For the evidence synthesis, the authors searched major bibliographic databases up to September 2023, followed PRISMA guidance, specified inclusion/exclusion criteria (e.g., English language, available genotype/allele data or effect estimates, non-familial designs), and pre-planned analyses to address heterogeneity and publication bias.
Case–control results: rs2104286 shows a statistically significant association in eastern Iran
In the Iranian cohorts, the authors report that rs2104286 is associated with MS susceptibility at both allelic and genotypic levels when pooling the eastern Iranian samples, with an allelic odds ratio (OR) of 1.55 (95% CI 1.17–2.06; P = 0.002) for A versus G and strong genotype-level significance overall (P < 0.0001). Stratified analyses suggest the signal is particularly evident in North Khorasan (allelic P = 0.003), while Sistan & Baluchistan shows a clear genotypic association (P = 0.001) but a weaker allelic comparison (P = 0.16), consistent with the possibility of regional differences in background allele frequencies, linkage disequilibrium structure, or sampling variance. The study also presents subtype- and sex-stratified summaries (e.g., elevated allelic ORs in RRMS and SPMS strata), though such subgroup analyses should be interpreted cautiously because they tend to reduce effective sample size and increase uncertainty even when nominal P-values appear compelling.
Systematic review and meta-analytic methods: handling heterogeneity and bias with standard tools
A central technical contribution of the paper is the careful treatment of heterogeneity—an expected feature of immune-genetic association studies spanning diverse ancestries and designs. The authors quantify between-study heterogeneity using Cochran’s Q and I², select fixed- versus random-effects models accordingly (including DerSimonian–Laird random-effects where appropriate), and assess publication bias with Egger’s and Begg’s tests complemented by funnel plots (with the Schwarzer test used when the number of studies is small). Importantly, they use Baujat plots to identify influential studies driving heterogeneity and perform sensitivity analyses by removing one study at a time to check robustness. The PRISMA flow diagram indicates that, after duplicate removal and screening, 22 studies were retained overall for the meta-analysis program, with 20 contributing to rs2104286 and 13 to rs12722489 analyses (with some studies contributing only allele-level estimates).
Global evidence for rs2104286: consistent direction of effect across major ancestry groups
In the worldwide meta-analysis of rs2104286 (after excluding a highly heterogeneity-influencing study identified by diagnostic plots), the dataset comprises 24,931 MS patients and 36,036 controls. The pooled estimate indicates that the A allele is associated with increased MS risk (OR 1.21, 95% CI 1.18–1.25; P ≈ 1.28 × 10⁻³⁴), and genotype-model analyses (dominant, recessive, and AA vs GG contrasts) are also reported as significant in the overall population. Subgroup analyses show broadly similar risk direction in both Asian and Caucasian strata, supporting the interpretation that rs2104286 (or a linked functional variant) may represent a relatively generalizable immunogenetic contributor to MS susceptibility rather than a strictly population-specific signal. The authors further report symmetry in funnel plots and largely non-significant Egger/Begg tests across models, which—while not definitive—reduces concern that small-study effects alone explain the association.
Iranian-focused synthesis: why a separate stratum is methodologically defensible
Because “Iranian” cohorts may not map cleanly onto coarse “Asian” versus “Caucasian” bins, the authors run a dedicated Iranian meta-analysis using four studies totaling 730 cases and 791 controls. In that focused synthesis, the A allele remains significantly associated with MS risk (OR 1.36, 95% CI 1.14–1.61; P = 0.0004). Notably, the dominant model (AA+AG vs GG) trends toward risk but does not reach conventional significance (P = 0.09), illustrating a key interpretive point: allele-level associations can be more stable than specific genotype contrasts when sample sizes are moderate and genotype frequencies vary between regions. The paper also contextualizes these findings by discussing minor allele frequency differences across broad continental reference panels and by noting that Iranian ethnolinguistic diversity may contribute to within-country allele frequency heterogeneity—an observation that supports the authors’ decision to analyze Iranian data separately rather than forcing it into a larger ancestry bin.
rs12722489 and biological interpretation: what the results imply and what remains unresolved
For rs12722489, the meta-analysis includes 19,797 MS patients and 32,085 controls, and the principal positive signal emerges in a dominant genotypic model (CC+CT vs TT: OR 1.25, 95% CI 1.01–1.55; P = 0.04), while allelic association is not significant in the overall population but appears significant in Caucasian cohorts (with substantial heterogeneity noted). Biologically, both rs2104286 and rs12722489 reside in the first intron of IL2RA, consistent with a regulatory mechanism (e.g., effects on transcription-factor binding or enhancer activity) rather than protein-coding change; the manuscript highlights prior evidence linking rs2104286 to altered soluble IL2RA levels and discusses regulatory motif disruption hypotheses for rs12722489. At the same time, the authors appropriately acknowledge limitations that temper causal claims: restricted sample size in the new case–control component, residual heterogeneity across studies, limited statistical power for some ancestry-stratified rs12722489 comparisons, and the absence of direct gene–environment or MS subtype–specific analyses. Taken together, the work strengthens the evidentiary case that IL2RA intronic variation—particularly rs2104286—tracks with MS susceptibility across multiple populations, while also making clear that functional validation and integrative models (genotype → immune phenotype → clinical subtype/progression) remain the critical next steps.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Rangani, F., Rakhshi, N., Mezerji, Z. K., Alikhah, A., Dehghanzad, R., Abbasi, B., ... & Kakhki, M. P. (2025). Association of IL2RA and multiple sclerosis risk: A case control, systematic review, and meta-analysis study. Journal of the Neurological Sciences, 123461.
