rs11265611 — IL6R

IL-6 Receptor Signaling and Atrial Fibrillation Risk

The interleukin-6 receptor (IL-6R) encoded by IL6R is the gateway through which interleukin-6, one of the body's primary inflammatory messengers, communicates its instructions to target cells. When IL-6 binds its receptor, it triggers STAT3 phosphorylation¹¹ STAT3 phosphorylation
Signal Transducer and Activator of Transcription 3 — a transcription factor that turns on inflammatory gene programs, driving the liver to produce acute-phase proteins including C-reactive protein (CRP), fibrinogen, and serum amyloid A. Chronically elevated IL-6 signaling through IL-6R accelerates atherosclerosis, promotes atrial fibrosis, and contributes to the pro-inflammatory milieu that sustains cardiac arrhythmias. The rs11265611 variant sits within an intron of IL6R and serves as a tag for a functional haplotype block that modulates IL-6 receptor signaling efficiency.

The Mechanism

rs11265611 is an intronic variant that does not directly change the IL-6 receptor protein sequence. Instead, it marks — via linkage disequilibrium²² linkage disequilibrium
LD: the tendency for certain allele combinations to be inherited together more often than chance predicts — a haplotype block spanning the IL6R locus that influences receptor expression or signaling capacity. This locus is in strong LD (r²=0.69) with rs4845625, an IL6R intronic variant whose T allele is associated with elevated CRP, LDL-C, and apolipoprotein B, and with rs2228145 (Asp358Ala), a missense variant that alters receptor shedding efficiency and thereby controls the balance between membrane-bound (pro-inflammatory) and soluble (anti-inflammatory) forms of IL-6R.

The G allele at rs11265611 corresponds to the higher-signaling haplotype: carriers tend to have higher baseline IL-6 pathway activity, producing more CRP and fibrinogen and maintaining a more pro-inflammatory systemic state. This persistent low-grade inflammation is mechanistically linked to atrial fibrosis — the structural remodeling of atrial tissue that creates the electrical substrate for atrial fibrillation to initiate and sustain itself.

The Evidence

The primary evidence for rs11265611 comes from the CHARGE Targeted Sequencing Study³³ CHARGE Targeted Sequencing Study
Lin et al. Targeted sequencing in candidate genes for atrial fibrillation. Heart Rhythm, 2014, which sequenced candidate genes in 948 AF cases and 3,330 controls from four major cohorts (ARIC, CHS, Framingham, MGH). The study found rs11265611 associated with a 30% reduction in AF risk per protective allele (OR 0.70, 95% CI 0.58–0.85, p=1.70×10⁻⁶ after Bonferroni correction) — a finding that prior genome-wide studies had not captured because this specific variant was not genotyped or imputed.

The nearby rs4845625 provides additional mechanistic evidence. Its T allele — which the rs11265611 G allele tags — was independently associated with AF recurrence after catheter ablation⁴⁴ AF recurrence after catheter ablation
Wu et al. A variant of IL6R is associated with the recurrence of atrial fibrillation. Heart Rhythm, 2014 in 278 Chinese Han patients (early recurrence OR 1.84, late recurrence OR 1.92). These findings from European and East Asian populations support a cross-ancestry role for IL6R variation in AF susceptibility.

At the Mendelian randomization level, Cupido et al. (2022)⁵⁵ Cupido et al. (2022)
Dissecting the IL-6 pathway in cardiometabolic disease: a Mendelian randomization study. Br J Clin Pharmacol, 2022 demonstrated that genetically lower CRP mediated by IL6R variants causally reduces AF risk (OR 0.90, 95% CI 0.86–0.95 per 1 mg/L lower CRP). This establishes that the IL6R-inflammation pathway is not merely associated with AF but is likely in the causal chain — a finding with direct implications for anti-inflammatory cardiovascular prevention strategies.

Practical Actions

For G allele carriers, the primary implication is elevated baseline IL-6 pathway activity contributing to higher atrial fibrillation risk. This genotype reinforces the case for monitoring systemic inflammation via high-sensitivity CRP (hs-CRP) and for targeted anti-inflammatory strategies where evidence supports them. Colchicine has demonstrated reduction in post-ablation AF recurrence in meta-analyses Kommu et al., Cureus 2023⁶⁶ Kommu et al., Cureus 2023 (RR 0.57–0.58 at 3 and 12 months), making it a genotype-informed option to discuss with a cardiologist before ablation procedures.

Interactions

rs11265611 is in LD with rs4845625 (r²=0.69) and rs2228145 (Asp358Ala), and functions as part of a broader IL6R haplotype block. The Asp358Ala variant (rs2228145) directly alters IL-6 receptor ectodomain shedding and has independent mechanistic evidence for changing soluble IL-6R levels, CRP, and cardiovascular risk. Users carrying risk haplotypes across multiple IL6R markers may experience compounded effects on IL-6 signaling. Downstream, IL-6R risk haplotypes interact with other inflammatory loci — particularly CRP gene variants (rs1205, rs1130864) — because CRP production is itself a readout of IL-6 receptor signaling.