rs2105325 — LOC100506023 LOC100506023 rs2105325

TNFSF4/PRDX6-AS1 1q25.1 — A Regulatory Checkpoint for Rheumatoid Arthritis Risk

Rheumatoid arthritis (RA) is one of the most heritable common autoimmune diseases. Beyond the HLA region¹¹ HLA region
Human Leukocyte Antigen region on chromosome 6 — the strongest genetic determinant for RA and many other autoimmune diseases, encoding proteins that present antigens to T cells, more than 150 confirmed non-HLA loci contribute modestly but measurably to RA susceptibility. rs2105325 sits at chromosome 1q25.1, a region containing two genes with well-documented immune relevance: TNFSF4, encoding the T-cell costimulatory protein OX40 Ligand, and LOC100506023 (now reclassified as PRDX6-AS1), a long non-coding antisense RNA positioned near the oxidative stress regulator PRDX6.

The common C allele at rs2105325 is associated with modestly elevated RA risk in GWAS studies spanning European, East Asian, African-American, and South Asian populations. The effect size is modest (OR ~1.12 per C allele) but highly consistent — this locus has been replicated across four independent multi-ethnic studies with p-values ranging from 10⁻⁸ to 10⁻¹³, meeting the gold standard for GWAS significance.

The Mechanism

rs2105325 is an intronic variant²² intronic variant
Located within a non-coding intron region; does not change the amino acid sequence of any protein but may affect gene expression through regulatory elements embedded in introns in both TNFSF4 and LOC100506023. It does not alter any protein directly. Instead, it is thought to influence gene regulation — either by tagging a haplotype block that modulates TNFSF4 expression or by affecting the function of the PRDX6-AS1 lncRNA.

TNFSF4 encodes OX40 Ligand (OX40L, CD252)³³ OX40 Ligand (OX40L, CD252)
A type II transmembrane protein expressed on antigen-presenting cells that binds OX40 (CD134) on activated T cells, providing a costimulatory signal that promotes T-cell survival and cytokine production, a co-stimulatory ligand expressed on dendritic cells and macrophages. When OX40L engages OX40 on activated T cells, it amplifies and prolongs T-cell survival, proliferation, and cytokine production — functions that are beneficial in fighting infection but detrimental when directed against self-antigens. Variants near TNFSF4 that alter its expression in inflammatory contexts could tip the balance toward sustained T-cell activation against joint antigens in RA.

PRDX6-AS1 is an antisense RNA transcribed from the complementary strand of PRDX6, a peroxiredoxin⁴⁴ peroxiredoxin
Peroxiredoxins are a family of antioxidant enzymes that reduce reactive oxygen species; PRDX6 is unique in also having phospholipase A2 activity with both antioxidant and phospholipase activity. Antisense RNAs commonly regulate their sense-strand partners; PRDX6-AS1 may modulate PRDX6 expression and thus oxidative stress handling in immune cells. Oxidative stress is a known driver of synovial inflammation in RA, providing a plausible pathway from PRDX6-AS1 dysregulation to joint damage. The specific direction and magnitude of this effect at rs2105325 remain to be formally characterized.

The Evidence

The clearest evidence for rs2105325 comes from large-scale GWAS analyses. A multi-ancestry GWAS⁵⁵ multi-ancestry GWAS
Study included participants from European, East Asian, and African-American ancestry groups to identify loci with shared and ancestry-specific RA effects by Laufer et al. 2018 (GWAS Catalog GCST006959, 916 AA cases / 1,392 controls plus European and East Asian replication) reported the A allele protective beta of -0.1024 (95% CI 0.067–0.137, p=1×10⁻⁸ in the European meta-analysis), with an M-value of 0.928 in African-Americans — indicating high statistical confidence that the protective A-allele effect is genuine in that population. An independent GWAS (GCST002318) confirms rs2105325-C with OR 1.12 (95% CI 1.08–1.15) at p=7×10⁻¹³.

Replication has been demonstrated across South Asian populations⁶⁶ demonstrated across South Asian populations
Pakistani cohort study confirming GWAS-implicated RA loci including rs2105325, underscoring that the 1q25.1 signal is not European-specific. Allele frequencies do vary substantially by ancestry: the protective A allele is present at ~27.6% in Europeans but is very rare in African and East Asian populations (~1–8%), meaning the proportion of people carrying any protective A is much smaller outside European-ancestry groups.

A Mendelian randomization study⁷⁷ Mendelian randomization study
An approach that uses genetic variants as instrumental variables to test causal hypotheses between exposures and outcomes, analogous to a randomized trial leveraging RA GWAS variants (including rs2105325) as instruments found that higher genetic liability for RA was inversely associated with hepatocellular carcinoma risk in East Asians (OR 0.86, p=0.003), an unexpected finding suggesting immune activation from RA risk alleles may confer incidental protection against liver cancer — although this should be interpreted cautiously given the complexity of Mendelian randomization assumptions.

Practical Implications

For the small minority carrying two copies of the protective A allele (AA genotype, ~4% of Europeans), no targeted intervention is needed from this variant — this represents favorable genetics at this locus.

For the majority who carry one or two C alleles — the common situation — the OR of ~1.12 per allele translates to a modest but real contribution to RA risk. Considered alongside other RA risk factors (family history, HLA-DRB1 shared epitope alleles, PTPN22 R620W, smoking), this locus helps stratify cumulative genetic risk. The practical implication is not treatment of a single SNP but rather heightened vigilance for early RA symptoms when multiple risk factors co-occur.

Early RA symptoms — symmetric joint swelling in small joints, morning stiffness lasting more than 30 minutes, elevated anti-CCP or rheumatoid factor antibodies, or unexplained fatigue with inflammatory markers — warrant prompt rheumatology evaluation. Anti-CCP antibodies can precede clinical RA by up to a decade, creating a window for preventive intervention in genetically predisposed individuals.

Interactions

The 1q25.1 locus interacts with the broader genetic architecture of RA. Carriers of multiple confirmed RA risk alleles — including rs2476601 (PTPN22 R620W), rs6920220 (TNFAIP3 upstream), and shared HLA-DRB1 epitopes — accumulate risk additively. No specific compound heterozygosity effect between rs2105325 and other 1q25 variants has been formally modeled, but the OX40L pathway converges on T-cell costimulation, which also intersects with CTLA-4 (abatacept targets this pathway) — relevant context for patients who progress to biologic therapy.