rs1016140 — CD58

Intronic CD58 variant with a dual role — the G allele increases T-cell activity and NMO susceptibility by facilitating AQP4-antibody CNS entry, while the TT genotype reduces CD58 surface expression and suppresses regulatory T cells, conferring autoimmune thyroid disease risk

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CD58 rs1016140 — A Dual-Risk Intronic Variant in T-Cell Adhesion

CD58, also known as LFA-3 (Lymphocyte Function-Associated Antigen 3)11 LFA-3 (Lymphocyte Function-Associated Antigen 3)
LFA-3 is a cell-surface glycoprotein expressed on antigen-presenting cells, endothelium, and non-immune cells; it binds CD2 on T cells to stabilise the immune synapse and transmit co-stimulatory signals, is a pivotal regulator of T-cell activation and immune tolerance. rs1016140 sits within the CD58 gene's intronic region (chromosome 1, position 116533925 on GRCh38) and has been independently associated with susceptibility to neuromyelitis optica (NMO) and autoimmune thyroid disease through distinct mechanisms — making it a noteworthy second signal at the CD58 locus beyond the well-characterised rs2300747.

Unlike rs2300747, where the G allele is protective by raising CD58 expression and boosting regulatory T-cell (Treg) function, rs1016140 exhibits a more complex allelic landscape: the G allele increases T-cell activity (raising NMO susceptibility), while the homozygous TT genotype reduces CD58 surface expression on antigen-presenting cells (raising autoimmune thyroid disease susceptibility). Both mechanisms converge on dysregulation of T-cell tolerance, but through opposite directions of CD58 function.

The Mechanism

G allele and NMO: In silico analysis of the four CD58 intronic SNPs associated with NMO found no evidence of alternative splicing or exonic splicing effects. However, the Korean study by Kim et al. proposed that the rs1016140 G allele enhances T-cell co-stimulatory activity22 rs1016140 G allele enhances T-cell co-stimulatory activity
CD2–LFA-3 signalling amplifies T-cell receptor responses; when these signals are heightened, inflammatory T cells may more readily breach the blood–brain barrier, creating the neuroinflammatory milieu required for AQP4 antibodies to access the central nervous system and damage astrocytes. In NMO, unlike MS, the primary injury is antibody-mediated destruction of aquaporin-4 (AQP4)33 aquaporin-4 (AQP4)
AQP4 is the most abundant water channel in the CNS, expressed on astrocyte endfeet; NMO-IgG autoantibodies bind AQP4 and trigger complement-mediated astrocyte destruction on astrocytes — but T-cell-driven inflammation is required to open the blood–brain barrier and allow these antibodies to reach their target.

TT genotype and autoimmune thyroid disease: Zhao et al. (2020) found that the TT genotype at rs1016140 is significantly more common in both Graves' disease and Hashimoto's thyroiditis patients than in healthy controls, and is associated with reduced CD58 (LFA-3) surface expression on monocytes. Lower LFA-3 levels weaken the CD2–CD58 co-stimulatory signal in regulatory T cells44 CD2–CD58 co-stimulatory signal in regulatory T cells
FoxP3+ regulatory T cells require CD2-mediated signalling to maintain their suppressive phenotype; reduced LFA-3 availability impairs Treg induction and peripheral tolerance, analogous to the mechanism proposed for the rs2300747 A allele in MS — both converge on deficient Treg activity, but via different allelic directions at different positions in the CD58 intron.

The Evidence

The primary NMO association was established by Kim et al. 2014 in BMC Neurology55 Kim et al. 2014 in BMC Neurology
98 NMO patients and 237 controls from a Korean population; genotyping of six CD58 SNPs. rs1016140 showed a significant allelic association with NMO (OR 1.76, 95% CI 1.25–2.47, P = 0.005; corrected P = 0.02): the G allele was present in 53.5% of NMO patients compared to 39.5% of controls. rs1016140 was also a constituent of the NMO-associated haplotypes CD58_ht1 and CD58_ht3, both of which reached statistical significance after multiple-testing correction.

Replication across populations has been partial but consistent. A Han Chinese study (Guo et al. 2017, Journal of Neuroimmunology) confirmed rs1016140 among five CD58 SNPs significantly associated with NMOSD risk, alongside rs2300747, rs1335532, rs56302466, and rs12044852. The converging evidence from two independent East Asian populations strengthens the case for a real, if modest, independent contribution of rs1016140 to NMO susceptibility.

For autoimmune thyroid disease, Zhao et al. 202066 Zhao et al. 2020
177 Graves' disease patients, 193 Hashimoto's thyroiditis patients, 116 healthy controls; PCR-RFLP genotyping demonstrated that the TT genotype at rs1016140 (SNP4 in their notation) was significantly enriched in both autoimmune thyroid disease patient groups relative to controls, and functionally confirmed that these CD58 risk genotypes correlate with lower CD58 surface expression on monocytes.

The overall evidence level is rated moderate: the NMO signal has been replicated in two East Asian populations but not yet in European cohorts, sample sizes are modest (the Korean study included only 98 NMO cases), and the molecular mechanism of rs1016140 specifically has not been resolved at the same level of detail as rs2300747.

Practical Actions

For individuals carrying the GG genotype (two G alleles), awareness of NMO as a distinct demyelinating condition is clinically relevant. NMO differs from MS in its reliance on AQP4-IgG and in preferring the spinal cord and optic nerves as primary targets; misdiagnosis as MS can lead to suboptimal treatment. Vitamin D optimisation supports Treg function through parallel FoxP3-related pathways and is the principal modifiable lever available.

For TT carriers, the finding that reduced CD58 expression suppresses regulatory T cells points to the same Treg-support strategy relevant throughout the CD58 locus: vitamin D sufficiency is the best-characterised modifiable intervention.

There is no supplement or medication that directly compensates for altered CD58 expression at this locus. Interventions are therefore primarily monitoring- and awareness-focused.

Interactions

rs1016140 is located within the same CD58 intronic locus as rs2300747 (the well-characterised MS signal). The two variants are not in complete linkage disequilibrium — the NMO study showed rs1016140 providing a distinct association signal, and the AITD study focused on rs1016140 independently. The degree of LD between rs1016140 and rs2300747 in different ancestry groups has not been fully characterised, but the divergent risk-allele directions (G = risk at rs1016140 for NMO; G = protective at rs2300747 for MS) strongly implies they are not simply tagging the same functional variant.

The CD58 locus also converges with rs6897932 (IL7R)77 rs6897932 (IL7R)
IL7R regulates T-cell homeostasis and regulatory T-cell survival, a pathway overlapping with CD58-mediated Treg co-stimulation and rs2476601 (PTPN22)88 rs2476601 (PTPN22)
PTPN22 modulates TCR-proximal activation thresholds; together with CD58, it contributes to the cumulative genetic burden on T-cell tolerance. Individuals carrying high-risk alleles at multiple T-cell regulatory loci face compounding effects on immune tolerance.

Genotype Interpretations

What each possible genotype means for this variant.

GT One G Allele — Intermediate Risk Intermediate

One G allele confers intermediate T-cell activation tone and partial NMO susceptibility

You carry one G allele and one T allele at rs1016140. This heterozygous state places you between the GG homozygote (highest NMO susceptibility at this locus) and the TT homozygote (lowest NMO susceptibility but higher autoimmune thyroid risk). The per-allele odds ratio for NMO is approximately 1.76 in Korean populations, so one G allele confers intermediate elevation above TT baseline. About 21% of people globally carry the GT genotype. The T allele frequency varies substantially by ancestry — it is rare in Europeans (~9%) but common in East Asians (~58%) — meaning GT is considerably more frequent in East Asian populations.

GG Elevated NMO-Risk Genotype High Risk

Two copies of the G allele associated with heightened T-cell activity and increased NMO susceptibility

Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing demyelinating disease preferentially targeting the optic nerves and spinal cord, driven by pathogenic IgG autoantibodies against aquaporin-4 (AQP4-IgG). Unlike MS, where T-cell-mediated inflammation is itself the primary driver of demyelination, in NMO the T cells serve as gatekeepers: they create the inflammatory environment necessary for AQP4-IgG to gain access to the CNS and destroy astrocytes. A genetic variant that raises T-cell activation at the blood–brain interface would therefore preferentially increase NMO susceptibility rather than MS susceptibility — consistent with the finding that rs1016140 was identified in a Korean NMO cohort rather than in MS GWAS studies.

The GG genotype at rs1016140 is associated with this heightened T-cell co-stimulatory tone. Importantly, this mechanism is mechanistically distinct from rs2300747, where the protective G allele raises CD58 mRNA levels and strengthens Treg function. At rs1016140, the G allele appears to enhance effector T-cell stimulation rather than specifically boosting Tregs. The molecular resolution of this difference — whether it reflects altered transcription factor binding, differential splicing regulation, or effects on an as-yet-uncharacterised regulatory element — has not been published.

NMO is rare (prevalence ~1–2 per 100,000 in European populations, higher in East Asian populations), so even an OR of 1.76 confers only modest absolute risk elevation. However, the condition carries substantial morbidity: relapses cause permanent vision loss and spinal cord disability, and the disease is often misdiagnosed as MS early in its course, delaying appropriate treatment.

TT Lowest NMO Risk — Elevated Thyroid Risk Decreased

Two T alleles associated with lowest NMO susceptibility but reduced CD58 expression and autoimmune thyroid disease risk

The finding that TT reduces CD58 surface expression is consistent with the broader biology of the CD58 locus: reduced LFA-3 on antigen-presenting cells weakens the CD2–CD58 co-stimulatory signal required for optimal FoxP3 induction in CD4+CD25high regulatory T cells. Without adequate Treg support, organ-specific autoimmunity — in this case targeting thyroid antigens such as thyroglobulin and thyroid peroxidase — can develop more readily. The thyroid is one of the most immunologically active tissues and among the first to be affected when Treg tone is impaired.

Autoimmune thyroid disease (AITD) is common: Graves' disease affects about 0.5% and Hashimoto's thyroiditis about 2–5% of the general population, with women disproportionately affected. The CD58 contribution to AITD is one of many genetic factors; CTLA-4, PTPN22, and HLA-DR3/DR4 have larger individual effects. Nonetheless, reduced CD58 expression at the TT genotype adds a measurable, biologically coherent increment to susceptibility.