rs16944 — IL1B -511C>T

IL-1 Beta Promoter Variant — A Master Regulator of Inflammation

The IL1B gene encodes interleukin-1 beta (IL-1β), one of the most potent pro-inflammatory cytokines in the human body¹¹ one of the most potent pro-inflammatory cytokines in the human body
IL-1β drives inflammation, activates immune cells, and plays a central role in atherosclerosis, sepsis, and autoimmune disease. The rs16944 variant sits in the promoter region at position -511, where it functions as a genetic dimmer switch controlling how much IL-1β your cells produce²² where it functions as a genetic dimmer switch controlling how much IL-1β your cells produce
The A allele is associated with higher IL-1β mRNA expression, while the G allele produces less.

This isn't just an academic curiosity — rs16944 influences your risk of sepsis, cardiovascular disease mortality, and inflammatory complications across dozens of conditions³³ rs16944 influences your risk of sepsis, cardiovascular disease mortality, and inflammatory complications across dozens of conditions
From aspirin-induced asthma to coronary artery lesions in children, this variant shapes inflammatory outcomes.

The Mechanism

The -511 position in the IL1B promoter contains a binding site for transcription factors that regulate gene expression⁴⁴ contains a binding site for transcription factors that regulate gene expression
The C-to-T change (G-to-A on the forward strand) alters the binding affinity of these regulatory proteins. The A allele creates a promoter configuration that permits higher transcription rates⁵⁵ The A allele creates a promoter configuration that permits higher transcription rates
This results in elevated IL-1β mRNA and protein levels after immune stimulation.

IL-1β itself drives a cascade of inflammatory responses: it induces other cytokines like IL-6, activates endothelial cells to express adhesion molecules, promotes prostaglandin synthesis, and recruits immune cells to sites of inflammation⁶⁶ drives a cascade of inflammatory responses: it induces other cytokines like IL-6, activates endothelial cells to express adhesion molecules, promotes prostaglandin synthesis, and recruits immune cells to sites of inflammation
This amplification loop means a small genetic change in IL-1β production gets magnified throughout the immune system.

Critically, IL-1β is the key output of the NLRP3 inflammasome⁷⁷ IL-1β is the key output of the NLRP3 inflammasome
When danger signals like cholesterol crystals, uric acid, or pathogens activate this molecular complex, IL-1β is cleaved from its inactive precursor and released. Your rs16944 genotype determines how much raw material is available for this process.

The Evidence

The clearest evidence comes from sepsis studies. In 471 preterm infants, the AA genotype was significantly more common in those with early-onset sepsis (p=0.012) and was even more strongly associated with lethal outcomes (p=0.011)⁸⁸ In 471 preterm infants, the AA genotype was significantly more common in those with early-onset sepsis (p=0.012) and was even more strongly associated with lethal outcomes (p=0.011). In adult sepsis, AA carriers showed higher mortality risk⁹⁹ In adult sepsis, AA carriers showed higher mortality risk.

For cardiovascular disease, a 15-year follow-up of 2,010 Northern Ireland men found the A allele associated with increased all-cause mortality (HR 1.18, p=0.005)¹⁰¹⁰ a 15-year follow-up of 2,010 Northern Ireland men found the A allele associated with increased all-cause mortality (HR 1.18, p=0.005). The effect was dose-dependent: one A copy increased risk 18%, two copies increased it 43%¹¹¹¹ The effect was dose-dependent: one A copy increased risk 18%, two copies increased it 43%. This aligns with extensive evidence that IL-1β drives atherosclerosis progression¹²¹² extensive evidence that IL-1β drives atherosclerosis progression
The CANTOS trial demonstrated that blocking IL-1β with canakinumab reduces cardiovascular events in high-risk patients.

In more specific inflammatory conditions, AA homozygotes show 2.98-fold increased risk of aspirin-exacerbated respiratory disease¹³¹³ AA homozygotes show 2.98-fold increased risk of aspirin-exacerbated respiratory disease, and in children under 12 months with Kawasaki disease, GG carriers (lower IL-1β producers) had significantly reduced risk of coronary artery lesions¹⁴¹⁴ in children under 12 months with Kawasaki disease, GG carriers (lower IL-1β producers) had significantly reduced risk of coronary artery lesions.

A meta-analysis found the variant associated with silent myocardial ischemia in diabetic patients¹⁵¹⁵ A meta-analysis found the variant associated with silent myocardial ischemia in diabetic patients
Under multiple inheritance models, the CC/CT genotypes (corresponding to AA/AG in forward orientation) increased risk with OR of 4.68 for homozygotes.

Practical Implications

If you carry one or two A alleles, you have a genetic predisposition to mount stronger IL-1β responses. This is a double-edged sword: potentially more effective at clearing infections initially, but prone to excessive inflammation that damages your own tissues¹⁶¹⁶ prone to excessive inflammation that damages your own tissues
Chronic low-grade inflammation accelerates atherosclerosis, increases thrombosis risk, and contributes to age-related disease.

The cardiovascular connection is particularly important. IL-1β induces IL-6 production, which drives hepatic synthesis of fibrinogen, plasminogen activator inhibitor, and C-reactive protein¹⁷¹⁷ IL-1β induces IL-6 production, which drives hepatic synthesis of fibrinogen, plasminogen activator inhibitor, and C-reactive protein
This shifts hemostasis toward a prothrombotic state while creating an inflammatory milieu that destabilizes atherosclerotic plaques. If you're AA and have existing cardiovascular risk factors, you're in a higher-risk category for events.

The sepsis association matters for surgical planning and critical illness. AA carriers may benefit from more aggressive infection monitoring and earlier intervention when signs of systemic inflammation appear.

Interactions

This variant sits within a tightly linked haplotype block with rs1143627 (-31C>T), another functional IL1B promoter SNP¹⁸¹⁸ tightly linked haplotype block with rs1143627 (-31C>T), another functional IL1B promoter SNP
The two variants are in nearly complete linkage disequilibrium, meaning they're usually inherited together. When evaluating IL-1β-related risk, consider both variants as a unit.

The IL-1 gene cluster on chromosome 2q13 also includes IL1A and IL1RN (encoding the IL-1 receptor antagonist). Variants in IL1RN can modulate the overall balance between pro- and anti-inflammatory signaling¹⁹¹⁹ Variants in IL1RN can modulate the overall balance between pro- and anti-inflammatory signaling
High IL-1Ra production may partially buffer the effects of high IL-1β.

From a pathway perspective, IL-1β functions upstream of many inflammatory cascades. Variants in downstream genes like IL6, TNF, and CRP may compound or mitigate the effects of rs16944 on disease risk.