rs4845625 — IL6R

IL6R Intronic Variant — Haplotype Tag for IL-6 Signaling Tone and Biologic Response

Tucked in the first intron of the interleukin-6 receptor gene, rs4845625 does not change a single amino acid — but it doesn't have to. This intronic variant¹¹ intronic variant
Intronic variants can act as cis-regulatory elements that alter transcription factor binding, splicing enhancer activity, or overall gene expression without touching the coding sequence sits within a haplotype block that shapes IL-6 receptor expression levels and, consequently, how strongly IL-6 signaling propagates through the JAK1/STAT3 axis. Its main clinical relevance is threefold: cardiovascular risk, inflammatory biomarker levels, and — most distinctively — response to tocilizumab and sarilumab, the IL-6 receptor-blocking biologics used in rheumatoid arthritis and other autoimmune conditions.

The Mechanism

IL6R encodes the alpha subunit (CD126) of the interleukin-6 receptor, which pairs with the co-receptor gp130 (IL6ST) to initiate JAK/STAT signaling. The rs4845625 variant lies in intron 1 of IL6R at chr1:154,449,591 (GRCh38), approximately 5 kb upstream of the well-characterised missense variant Asp358Ala (rs2228145). The two SNPs are in partial linkage disequilibrium²² partial linkage disequilibrium
Linkage disequilibrium (LD) means nearby variants are inherited together more often than by chance. Partial LD means they co-segregate frequently but not always — some chromosomes carry one without the other and tag overlapping but non-identical haplotypes across the IL6R locus.

The T allele at rs4845625 forms part of a haplotype (rs4845625*T / rs4537545*C) associated with elevated classical IL-6 signaling tone. While the exact molecular mechanism — altered splicing, transcription factor binding affinity, or expression level — has not been precisely characterised at this variant, the downstream phenotypic consequences point consistently toward subtly enhanced pro-inflammatory classical IL-6 signaling rather than the trans-signaling shift driven by Asp358Ala.

The Evidence

The clearest mechanistic fingerprint comes from an Arguinano et al. population study³³ Arguinano et al. population study
Arguinano AA et al., Genes & Immunity 2017; European population cohort examining IL6R haplotypes and multiple cardiometabolic biomarkers. The rs4845625*T / rs4537545*C haplotype was independently associated with simultaneously elevated CRP (p=0.011), LDL cholesterol (p=0.007), and apolipoprotein B (p=0.009). The rs4845625 SNP alone explained 3.49% of LDL-C variance and 5.57% of ApoB variance — a modest but statistically robust independent effect on cardiometabolic risk markers.

A cardiac electrophysiology study⁴⁴ cardiac electrophysiology study
Wu G et al., PLoS One 2014; 278 consecutive patients undergoing catheter ablation for atrial fibrillation in a Chinese Han population found that the T allele substantially increased the risk of AF recurrence both early (OR 1.84, 95% CI 1.31–2.59, p=4.1×10⁻⁴ within 4 weeks) and late (OR 1.92, 95% CI 1.30–2.81, p=0.001 at 3–12 months) after ablation, independent of age, sex, hypertension, and diabetes. AF recurrence after ablation is partly driven by persistent atrial inflammation, making IL-6 receptor variation a plausible mechanistic candidate.

The pharmacogenomic evidence spans two related studies from the same Spanish group. Sainz et al. (Pharmaceutics 2022)⁵⁵ Sainz et al. (Pharmaceutics 2022)
88 RA patients on tocilizumab IV, retrospective cohort at 6 months; six IL6R variants tested found that rs4845625 was the only variant among six IL6R SNPs tested to be associated with all three treatment response measures at six months. A follow-up toxicity study⁶⁶ toxicity study
Sainz et al., J Pers Med 2022; same 88-patient cohort, adverse event analysis found rs4845625 was specifically associated with dyslipidemia as a tocilizumab adverse event — consistent with the variant's independent effect on LDL and ApoB. In a separate sarilumab cohort⁷⁷ sarilumab cohort
Sainz et al., Arthritis Res Ther 2023; 62 RA patients on subcutaneous sarilumab, rs4845625 again emerged as a significant predictor of treatment response, suggesting the association extends across IL-6R-blocking drug classes.

Practical Actions

The T allele's combination of elevated LDL, ApoB, and CRP — together with its association with AF recurrence and CAD risk — makes standard lipid and inflammatory monitoring more important for TT homozygotes and CT heterozygotes. In the pharmacogenomic context, clinicians initiating tocilizumab or sarilumab in T-allele carriers should monitor lipid panels more closely, as the variant is associated with both dyslipidemia adverse events and differential treatment response. The evidence is currently at the level of replicated associations rather than clinical guidelines; no CPIC or DPWG recommendations exist for this intronic variant.

Interactions

rs4845625 lies within 5 kb of the Asp358Ala missense variant rs2228145 and is in partial LD with it. The Asp358Ala C allele drives the dominant functional effect at this locus (increased receptor shedding, enhanced trans-signaling, cardiovascular protection, asthma risk). rs4845625 contributes an independent, partially overlapping signal — its T allele tags a haplotype with elevated LDL and CRP, overlapping but not identical to the rs2228145 AA haplotype. Patients assessed for biologic therapy carry signal at both variants; together they give a more complete picture of baseline IL-6 receptor biology than either alone. rs12133641 is a third IL6R intronic variant approximately 6,216 bp from rs4845625 with its own bidirectional atopic/cardiovascular association, and rs4537545 is the direct haplotype partner of rs4845625 in the Arguinano 2017 analysis.