rs11265611 — IL6R

Intronic IL6R variant in LD with the IL-6 receptor signaling locus; G allele associates with increased atrial fibrillation risk

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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.

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.

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 0.91, 95% CI 0.84–0.97 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 higher atrial fibrillation risk.

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.

Genotype Interpretations

What each possible genotype means for this variant.

AA Low IL-6 Signaling Normal

Common protective variant — lower IL-6 pathway activity and reduced AF risk

You carry two copies of the A allele at rs11265611, the common protective form of this IL6R intronic variant. About 34% of people share this genotype (Hardy-Weinberg estimate from global frequencies). The CHARGE Targeted Sequencing Study found this allele associated with a 30% lower AF risk per copy.

AG Intermediate IL-6 Signaling Intermediate

One risk copy — modestly elevated IL-6 pathway activity

You carry one G allele and one A allele at rs11265611. About 49% of people share this heterozygous genotype. The effect is additive — each G allele contributes incrementally to atrial fibrillation risk. A single copy confers partial but not full risk elevation compared to GG homozygotes.

GG Elevated IL-6 Signaling High Risk

Two risk copies — higher IL-6 pathway activity and elevated atrial fibrillation risk

The nearby rs4845625 T allele (tagged by the rs11265611 G allele) was independently associated with AF recurrence after catheter ablation (OR 1.84 for early recurrence, OR 1.92 for late recurrence in Chinese Han patients).