rs4073 — IL8 -251A>T

The Inflammatory Architect — How a Promoter Variant Shapes Your Cardiovascular Risk

Interleukin-8 (IL-8), also called CXCL8, is one of the body's most powerful chemokines — chemical signals that recruit neutrophils and other immune cells to sites of inflammation. This variant sits in the promoter region¹¹ promoter region
The promoter is the "on switch" for a gene, controlling how much protein gets made of the IL8 gene at position -251, where it directly influences how much IL-8 your cells produce when triggered by inflammatory stimuli like bacterial endotoxin or tissue damage. The A allele increases IL-8 transcription, leading to higher circulating levels during inflammation — and potentially a greater cumulative inflammatory burden over a lifetime.

This matters because chronic low-grade inflammation is now recognized as a central driver of atherosclerosis, the process where arterial plaques form and grow. IL-8 doesn't just mark inflammation; it actively participates in every stage of atherosclerosis²² every stage of atherosclerosis
From endothelial activation to plaque rupture and thrombosis, recruiting inflammatory cells into artery walls, promoting plaque instability, and contributing to the acute events that cause heart attacks. Individuals carrying the A allele may experience elevated IL-8 production throughout life, translating to measurably higher cardiovascular risk — particularly in populations of East Asian ancestry.

The Mechanism

The rs4073 variant is a T-to-A substitution located precisely at the transcription factor binding site in the IL8 gene promoter. This position overlaps with NF-κB and other transcription factor binding regions³³ NF-κB and other transcription factor binding regions
NF-κB (nuclear factor kappa B) is the master regulator of inflammatory gene expression that control how strongly the gene responds to inflammatory signals. When your immune system detects a threat — infection, tissue damage, oxidized LDL cholesterol in artery walls — it activates NF-κB, which binds to the IL8 promoter and turns on transcription.

The A allele alters this binding affinity, resulting in stronger transcriptional activation compared to the T allele. In vitro studies show that cells carrying the A allele produce significantly more IL-8 protein when stimulated with lipopolysaccharide⁴⁴ significantly more IL-8 protein when stimulated with lipopolysaccharide, a bacterial toxin that mimics infection. This isn't a subtle difference — it's a meaningful shift in how aggressively your inflammatory machinery responds to triggers. The AA genotype consistently shows the highest IL-8 levels, AT shows intermediate levels, and TT shows the lowest.

Once secreted, IL-8 acts as a powerful neutrophil chemoattractant. It binds to CXCR1 and CXCR2 receptors on neutrophils and monocytes, guiding them along concentration gradients toward inflamed tissues. In the context of atherosclerosis, this means more immune cells infiltrating arterial plaques, releasing proteases that destabilize the fibrous cap, and increasing the risk of plaque rupture and thrombosis.

The Evidence

The cardiovascular implications of rs4073 have been rigorously studied in multiple populations. A 2019 meta-analysis⁵⁵ A 2019 meta-analysis
Wang et al., published in Medical Science Monitor pooled data from 9 studies comprising 8,244 patients and found that the A allele was significantly associated with increased coronary artery disease (CAD) risk across multiple genetic models: dominant model (AA + AT vs TT) showed OR 1.42 (95% CI 1.16–1.76, P<0.001), recessive model (AA vs AT + TT) showed OR 1.30 (95% CI 1.12–1.52, P<0.001), and the homozygote model (AA vs TT) showed OR 1.59 (95% CI 1.21–2.08, P<0.001). The effect was strongest in East Asian populations and absent in Caucasians, suggesting ethnic-specific modulation by genetic background or environmental factors.

A second meta-analysis⁶⁶ A second meta-analysis
Published in Gene, examining 3,752 cases and 4,219 controls confirmed these findings: the AA genotype conferred a 26% increased risk of CAD compared to TT (OR 1.26, 95% CI 1.01–1.56, P=0.037). The allelic model showed OR 1.14 (95% CI 1.02–1.27, P=0.02), and the recessive model showed OR 1.15 (95% CI 1.03–1.27, P=0.01). Notably, the association was robust in East Asian subgroups but inconsistent in Caucasians, with high heterogeneity in the latter group.

Population studies⁷⁷ Population studies
North Indian case-control study, n=300 cases and 300 controls have replicated these findings outside East Asia, demonstrating that the association is not limited to a single ancestry but may be modified by population-specific haplotype structure and environmental exposures. The A allele has also been linked to higher IL-8 serum levels in Chinese sepsis patients and worse prognosis in gastric cancer⁸⁸ higher IL-8 serum levels in Chinese sepsis patients and worse prognosis in gastric cancer, underscoring its functional impact on inflammatory phenotypes across diseases.

Mechanistic studies⁹⁹ Mechanistic studies
Biomarker meta-analyses including 175,778 individuals show that elevated inflammatory markers, including IL-8, independently predict cardiovascular events even after adjusting for traditional risk factors like LDL cholesterol and blood pressure. This positions IL-8 as both a mechanistic contributor and a prognostic biomarker, with genetic variants like rs4073 serving as lifelong modulators of this pathway.

Practical Actions

For individuals carrying the A allele, the goal is to minimize cumulative inflammatory burden through targeted diet, supplementation, lifestyle modifications, and biomarker monitoring. Omega-3 fatty acids (EPA and DHA)¹⁰¹⁰ Omega-3 fatty acids (EPA and DHA)
Meta-analyses demonstrate consistent anti-inflammatory effects at 1–3 g/day doses have been shown to significantly reduce circulating IL-6, IL-1β, and TNF-α in randomized controlled trials, with IL-6 decreasing by 22% after 8 weeks of EPA+DHA supplementation. While IL-8 was not directly measured in these trials, the omega-3 lipid mediators resolvin E1 and protectin D1 inhibit neutrophil transendothelial migration and reduce IL-1β and TNF production — pathways that directly intersect with IL-8 signaling.

Mediterranean dietary patterns¹¹¹¹ Mediterranean dietary patterns
Long-term PREDIMED trial showed sustained reductions in inflammatory biomarkers have demonstrated robust anti-inflammatory effects, including significant reductions in plasma IL-8 levels after 3 years of adherence. The mechanisms involve polyphenol-rich extra-virgin olive oil suppressing NF-κB signaling, thereby reducing transcription of IL-8 and other pro-inflammatory cytokines. Nuts, fatty fish, and abundant vegetables further contribute through antioxidant and fiber-mediated pathways.

Aerobic exercise¹²¹² Aerobic exercise
Systematic reviews of randomized controlled trials in healthy adults produces consistent reductions in IL-6, TNF-α, and CRP, with long-term training (>12 weeks) showing the most robust effects. Physical activity interventions specifically reduce IL-8 biomarkers, likely through improved endothelial function, enhanced mitochondrial efficiency, and reduced visceral adiposity. Combined aerobic and resistance training appears optimal for lowering arterial stiffness and inflammatory markers.

Statins, particularly atorvastatin and rosuvastatin¹³¹³ atorvastatin and rosuvastatin
Rosuvastatin 20 mg/day more effective than atorvastatin 40 mg/day at lowering CRP, exert potent anti-inflammatory effects beyond their LDL-lowering action. Atorvastatin markedly decreases NLRP3 inflammasome activation and plasma IL-1β and IL-18 levels. For individuals with the AA genotype and additional cardiovascular risk factors, a statin may provide dual benefit: lipid reduction and inflammation suppression.

Biomarker monitoring is particularly valuable. High-sensitivity CRP (hsCRP)¹⁴¹⁴ High-sensitivity CRP (hsCRP)
Strongly predicts recurrent cardiovascular events with linear risk between 1–5 mg/L is the most validated inflammatory biomarker for cardiovascular risk stratification. While IL-8 is not routinely measured clinically, hsCRP serves as a proxy for systemic inflammation and can guide treatment intensity. Individuals with elevated hsCRP despite optimal LDL may particularly benefit from intensified anti-inflammatory interventions.

Finally, smoking cessation is non-negotiable¹⁵¹⁵ smoking cessation is non-negotiable
Smokers secrete significantly higher IL-8 levels from whole blood ex vivo. Smoking induces chronic elevation of IL-8 and CRP, amplifying the genetic predisposition conferred by the A allele. Heavy alcohol intake similarly increases inflammatory burden, though moderate consumption (≤1 drink/day) may have neutral or mildly anti-inflammatory effects.

Interactions

The IL-8 pathway does not act in isolation. Gene-gene interactions with IL-6 (rs1800795), TNF-α (rs1800629), and CRP gene variants¹⁶¹⁶ Gene-gene interactions with IL-6 (rs1800795), TNF-α (rs1800629), and CRP gene variants
IL-6 associations remained significant after adjusting for CRP, but not vice versa modulate overall inflammatory tone. IL-6 receptor haplotypes, for instance, regulate circulating levels of CRP, fibrinogen, IL-8, and soluble IL-6 receptor across multiple populations. Individuals carrying risk alleles in multiple inflammatory genes may experience compounded effects, while protective variants in one gene may partially offset risk from another.

Within the IL8 gene itself, rs4073 exists on haplotypes with rs2227307 (intron +396T>G) and rs2227306 (exon +781C>T)¹⁷¹⁷ rs2227307 (intron +396T>G) and rs2227306 (exon +781C>T)
. The haplotype structure differs between East Asians and Caucasians, which may partly explain the ethnic variation in disease associations. The rs2227306 variant, located in exon 1, influences IL-8 at both mRNA and protein levels, potentially amplifying the transcriptional effects of rs4073 when inherited together.

Post-surgical inflammation represents a clinically relevant interaction. IL-8 is a strong predictor of acute kidney injury and need for inotropic support following cardiac surgery¹⁸¹⁸ a strong predictor of acute kidney injury and need for inotropic support following cardiac surgery, correlating with cardiopulmonary bypass time and surgical complexity. Individuals with the AA genotype may experience exaggerated inflammatory responses to surgical trauma, warranting closer postoperative monitoring and potentially more aggressive perioperative anti-inflammatory strategies.