rs1414273 — CD58

Intronic CD58 variant hosting the miR-548ac stem-loop; the C allele creates a G-U wobble base pair that enhances Drosha cleavage, increasing miR-548ac while reducing CD58 mRNA — the mechanistic anchor of the CD58 MS-risk haplotype

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CD58 rs1414273 — The miR-548ac Switch That Defines the MS-Risk Haplotype

Every CD58 intronic variant associated with multiple sclerosis risk — rs2300747, rs12044852, rs1016140, rs1335532 — sits within the same tightly linked haplotype block in the first intron of CD58 on chromosome 1. Among them, rs1414273 holds a mechanistically unique position11 rs1414273 holds a mechanistically unique position
rs1414273 lies directly within the hairpin sequence of hsa-miR-548ac, the microRNA co-encoded from the same primary transcript as CD58 mRNA: it is the functional anchor through which the risk haplotype disrupts the balance between CD58 and an immunoregulatory microRNA.

CD58, also known as LFA-3 (Lymphocyte Function-Associated Antigen 3)22 LFA-3 (Lymphocyte Function-Associated Antigen 3)
LFA-3 is a glycoprotein expressed on antigen-presenting cells and non-immune tissues; it binds CD2 on T cells to stabilise the immune synapse and transmit co-stimulatory signals that licence regulatory T cell induction, governs whether a T-cell encounter with an antigen-presenting cell produces immune tolerance or inflammatory activation. This signalling axis sits at the centre of multiple sclerosis genetics: the CD58 locus is one of the most robustly replicated non-HLA MS susceptibility regions.

The Mechanism

The miR-548ac gene is embedded within CD58 intron 1. Like all microRNAs, it begins as part of a longer primary transcript (pri-miRNA) that is cropped by the nuclear Drosha-DGCR8 endonuclease complex33 Drosha-DGCR8 endonuclease complex
Drosha cleaves the pri-miRNA at the base of the hairpin stem-loop to release the 60–70 nt precursor (pre-miRNA), which is then exported to the cytoplasm and processed by Dicer into the mature ~22 nt miRNA. Because CD58 mRNA and miR-548ac are transcribed from the same genomic locus, Drosha cleavage efficiency has a reciprocal effect: more efficient cleavage favours miR-548ac production at the expense of full-length CD58 mRNA reaching the cytoplasm for translation.

rs1414273 sits at the precise base of the miR-548ac stem-loop. The reference allele is C on the plus strand — corresponding to G on the coding (minus) strand — which pairs with a uridine in the opposite strand of the hairpin to form a G-U wobble base pair. The alternate T allele (coding-strand A) forms an A-U Watson-Crick base pair, which is less efficiently recognised by Drosha. The consequence:

  • C allele (risk): G-U wobble → enhanced Drosha recognition → more miR-548ac, less CD58 mRNA
  • T allele (protective): A-U Watson-Crick → reduced Drosha efficiency → less miR-548ac, more CD58 mRNA

In cell-culture experiments, the G-containing construct (risk allele) produced 1.5-fold more mature miR-548ac at 24 hours and 3.4-fold more at 48 hours compared to the A-containing construct, after normalisation to precursor RNA. In population-level eQTL analyses spanning HapMap, Geuvadis, and MS patient cohorts, risk allele carriers showed significantly lower CD58 transcript levels and significantly higher miR-548ac levels44 risk allele carriers showed significantly lower CD58 transcript levels and significantly higher miR-548ac levels
The paradoxical inverse relationship between CD58 mRNA and miR-548ac co-encoded from the same locus is explained by Drosha-mediated uncoupling: cleavage of the stem-loop interrupts full-length mRNA synthesis while liberating the microRNA hairpin.

miR-548ac targets validated in this mechanistic framework include SDC4 (syndecan-4)55 SDC4 (syndecan-4)
SDC4 regulates T-cell motility and heparan sulfate proteoglycan signalling, SEL1L66 SEL1L
SEL1L participates in endoplasmic reticulum-associated protein degradation (ERAD) and proteostasis under inflammatory stress, and TNFAIP3 (A20)77 TNFAIP3 (A20)
TNFAIP3/A20 is a master ubiquitin-editing enzyme that terminates NF-κB signalling; miR-548ac-mediated suppression of A20 would sustain inflammatory NF-κB activity. A broader computational screen identified 333 predicted miR-548ac targets enriched in cytokine signalling, MAPK pathways, and protein folding — consistent with a broadly immunomodulatory role for this microRNA.

The Evidence

The functional significance of rs1414273 was first proposed by Galarza-Munoz et al. 201588 Galarza-Munoz et al. 2015
1000 Genomes sequencing data used to identify rs1414273 as the only SNP at the base of the miR-548ac stem-loop in strong LD with the MS-associated haplotype, who recognised that its position within the Drosha recognition element made it a strong candidate for the causal variant within the CD58 MS locus.

The full mechanistic and eQTL evidence was published by Hecker et al. 2019 PLoS Genetics99 Hecker et al. 2019 PLoS Genetics
Expression QTL analysis across >1,000 subjects from HapMap and Geuvadis cohorts combined with in vitro Drosha cleavage experiments and real-time PCR of 32 MS patients. This study demonstrated both the population-level expression effects and the molecular mechanism in a single unified study, making rs1414273 the best-characterised functional variant at the CD58 MS locus.

The variant is in near-complete LD (r² ≈ 1, D' ≈ 1) with rs1335532, the GWAS lead SNP for the CD58 MS locus in European cohorts. Correlated alleles on the forward strand are: rs1414273 C = rs1335532 A (both risk alleles); rs1414273 T = rs1335532 C (both protective alleles). This tight LD means rs1414273 and rs1335532 are functionally interchangeable for GWAS-level MS association signals, but rs1414273 uniquely maps the molecular effect to Drosha recognition.

Population genetics provide an instructive layer. The C (risk) allele is the major allele in Europeans (~87%) — matching the high-frequency risk pattern seen throughout the CD58 locus (rs12044852, rs2300747). In contrast, East Asian and African populations carry the T (protective) allele at ~59% and ~51% respectively. This mirrors the population-level MS burden: the disease is considerably rarer in East Asian populations where the protective T allele predominates.

A pilot replication study in a Malaysian/Kuwaiti cohort found CD58 rs1414273 to be significantly associated with MS in an Arab population (p = 0.00007, OR 2.2, 95% CI 1.5–3.2 in exome analysis), though a separate genotyping-only Kuwaiti replication did not reach significance, likely reflecting population-specific LD structure between rs1414273 and the GWAS signals.

Practical Actions

Since the C allele is the major allele in Europeans (~87%), CC homozygotes represent the largest fraction of the population — and carry the highest miR-548ac burden and lowest CD58 expression at this locus. There is no supplement that directly inhibits miR-548ac or compensates for reduced CD58, but vitamin D is the best-characterised modifiable factor that supports FoxP3+ regulatory T cell function1010 FoxP3+ regulatory T cell function
FoxP3 is the master transcription factor for Tregs; vitamin D drives FoxP3 expression via VDR binding at the FoxP3 promoter, providing a parallel Treg-supporting input to the CD58 co-stimulatory signal through mechanisms independent of CD58.

Interactions

rs1414273 is in near-complete LD with rs1335532 and is strongly correlated with rs12044852 (r² = 0.929 between rs12044852 and rs2300747, with rs1414273 in the same haplotype). The four CD58 intronic variants — rs2300747, rs12044852, rs1016140, rs1414273 — collectively define the CD58 MS-risk haplotype. The rs1016140 G allele has an independent signal for NMO risk and autoimmune thyroid disease via a mechanistically distinct direction, illustrating that the intronic haplotype block contains variants with both shared and divergent functional effects.

miR-548ac's validated target TNFAIP3 (A20) connects this variant to the NF-κB inflammatory pathway, creating a potential interaction with cytokine-pathway SNPs (e.g. TNFRSF1A rs1800693 in the same immune-gut category).

Genotype Interpretations

What each possible genotype means for this variant.

TT Protective Genotype Beneficial

Two protective T alleles — A-U Watson-Crick base pairing reduces Drosha efficiency, raising CD58 and lowering miR-548ac

You carry two copies of the protective T allele at rs1414273. This is a rare genotype — approximately 2% of Europeans carry it, though it is the majority genotype in East Asian and African populations. The T allele forms an A-U Watson-Crick base pair at the miR-548ac stem-loop, which the Drosha-DGCR8 complex recognises less efficiently than the risk allele's G-U wobble pair. This results in the lowest miR-548ac levels and highest CD58 mRNA among the three genotypes. Higher CD58 (LFA-3) expression strengthens the co-stimulatory signal to regulatory T cells — the same protective mechanism seen with protective alleles at other CD58 regulatory positions. Your MS susceptibility from the CD58 rs1414273 locus is at or below the population reference level.

CT Partial Protection Intermediate

One protective T allele moderates Drosha efficiency — intermediate CD58 expression and miR-548ac levels

The CT genotype is present in approximately 23% of Europeans. The additive model for rs1414273 predicts an intermediate phenotype: CD58 eQTL data show a graded expression effect where each T allele incrementally raises CD58 mRNA and lowers miR-548ac levels. The effect of one T allele is approximately half that of TT homozygosity.

In practical terms, the CT genotype carries a modestly lower CD58-locus MS risk than CC, but the absolute reduction in risk from a single T allele is not large enough to substantially change MS surveillance recommendations. Vitamin D optimisation remains the principal actionable lever.

CC Risk Haplotype Homozygote High Risk

Two copies of the risk allele — enhanced miR-548ac, reduced CD58 mRNA, highest MS-locus susceptibility

The mechanistic significance of rs1414273 is that it identifies the functional base change underlying the CD58 MS haplotype. Previous GWAS studies detected a strong association between the CD58 intronic region and MS risk, but the causal variant was uncertain — rs1335532, rs12044852, and rs2300747 were all candidates, and all are in strong LD. rs1414273 is the only one of these variants positioned directly within a microRNA processing element (the Drosha recognition stem-loop), giving it a mechanistically privileged status as the likeliest causal driver.

For CC carriers, the biological consequence is a double dose of the Drosha-enhancing allele: both chromosomes produce more efficient miR-548ac processing, resulting in the lowest CD58 mRNA levels observed in eQTL studies across HapMap, Geuvadis, and MS patient cohorts. miR-548ac's three validated targets (SDC4, SEL1L, TNFAIP3) and its broader enrichment in cytokine-signalling and MAPK pathways suggest a widespread immunomodulatory effect beyond the simple CD58 reduction already captured by the GWAS signal.

The C allele is the ancestral/common allele in Europeans, meaning most Europeans carry the genetic configuration associated with higher MS risk from this locus. This is consistent with the European-predominant MS burden: high-frequency risk alleles at CD58, combined with HLA-DRB1*15:01 and other MS loci, collectively explain a significant fraction of the European–East Asian differential in MS prevalence.

Absolute MS risk from this single variant remains modest — MS affects roughly 1 in 500 Europeans, and this locus contributes an estimated odds ratio in the 1.3–2.6 range depending on the study. However, among people carrying multiple CD58 risk genotypes (CC at rs1414273, AA at rs2300747, CC at rs12044852), the cumulative effect on CD58 pathway suppression is additive.