rs1800795 — IL6 -174G/C

Interleukin-6: The Exercise Cytokine With a Double Edge

Interleukin-6 (IL-6) is one of the most versatile signalling molecules in the human body. Produced by immune cells, fat tissue, and — critically — by working skeletal muscle, it acts as both a pro-inflammatory cytokine¹¹ pro-inflammatory cytokine
a signalling protein that promotes inflammation as part of the immune response and an anti-inflammatory myokine²² myokine
a cytokine released by muscle fibres during contraction, with systemic metabolic effects. The -174G/C promoter variant (rs1800795) sits 174 base pairs upstream of the IL6 gene on chromosome 7 and directly controls how much IL-6 your cells produce.

The Mechanism

The G allele at position -174 creates a promoter sequence with higher transcriptional activity³³ transcriptional activity
the rate at which a gene is read and converted into mRNA, which then becomes protein. In reporter gene assays, the G allele drives roughly 2-fold higher IL6 transcription compared to the C allele. This difference is mediated by a binding site for the transcription factor NF-1⁴⁴ NF-1
Nuclear Factor 1, a transcription factor that represses IL6 expression when bound to the -174C sequence: the C allele creates this repressive binding site, while the G allele abolishes it, allowing uninhibited transcription.

The consequence is straightforward: GG homozygotes produce the most IL-6 at baseline and under stress, CG heterozygotes produce intermediate amounts, and CC homozygotes produce the least. After stimulation by LPS⁵⁵ LPS
lipopolysaccharide, a bacterial endotoxin that triggers immune activation or IL-1, the G allele construct shows a robust increase in expression while the C allele construct remains largely unresponsive.

The Evidence

The -174G/C variant is one of the most studied cytokine polymorphisms, with evidence spanning cardiovascular disease, diabetes, exercise physiology, and ageing.

Cardiovascular risk: A meta-analysis of 74 studies with 86,229 subjects⁶⁶ meta-analysis of 74 studies with 86,229 subjects
Rodriguez-Perez et al. Interleukin 6 (rs1800795) gene polymorphism is associated with cardiovascular diseases. EXCLI Journal, 2019 found the C allele associated with increased cardiovascular disease risk (dominant model OR 1.12, 95% CI 1.07-1.18). The association was strongest for coronary artery disease (homozygous OR 1.50) and in Chinese populations (allelic OR 1.36).

Exercise-induced muscle damage: Yamin et al.⁷⁷ Yamin et al.
IL6 (-174) and TNFA (-308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise. Eur J Appl Physiol, 2008 demonstrated that CC homozygotes had a greater than 3-fold increased risk of massive creatine kinase⁸⁸ creatine kinase
an enzyme released from damaged muscle fibres; elevated CK after exercise is a marker of muscle damage (CK) response following eccentric exercise. Paradoxically, despite producing less IL-6 at baseline, the CC genotype appears to mount a more exaggerated muscle damage response.

Power athlete association: Ruiz et al.⁹⁹ Ruiz et al.
The -174 G/C polymorphism of the IL6 gene is associated with elite power performance. J Sci Med Sport, 2010 found the GG genotype overrepresented among elite power athletes (sprinters, jumpers, throwers) with an OR of 2.47 compared to controls, suggesting the higher inflammatory response may benefit explosive performance.

Diabetes: A comprehensive meta-analysis of 42,150 participants¹⁰¹⁰ comprehensive meta-analysis of 42,150 participants
IL-6 gene rs1800795 polymorphism and diabetes mellitus. Diabetol Metab Syndr, 2022 found the G allele associated with decreased type 2 diabetes risk in some populations, while the C allele showed a protective effect against fasting hyperglycaemia.

Glucose metabolism: A joint analysis of 17 studies¹¹¹¹ joint analysis of 17 studies
Huth et al. Joint analysis of individual participants' data from 17 studies on the association of the IL6 variant -174G>C. Ann Med, 2009 found C-allele carriers had significantly lower fasting glucose (-0.091 mmol/L, P=0.014).

Practical Implications

The functional consequence of this variant — higher or lower IL-6 production — has different implications depending on context:

For exercise recovery, GG carriers mount a stronger inflammatory response to training, which may support adaptation for power sports but also means managing recovery is important. CC carriers, despite lower baseline IL-6, show elevated muscle damage markers after eccentric exercise and may need longer recovery between intense sessions.

For cardiovascular health, the C allele carries modestly increased risk, making anti-inflammatory lifestyle measures and regular monitoring more relevant for CC and CG individuals.

For metabolic health, the C allele is associated with slightly lower fasting glucose, offering a minor metabolic advantage, while the G allele may carry a modest type 2 diabetes risk in certain populations.

Anti-inflammatory strategies — omega-3 fatty acids, adequate sleep, managing chronic stress, and maintaining a diet rich in colourful vegetables and polyphenols — are beneficial for all genotypes but especially important for GG carriers with higher baseline inflammation.

Interactions

The -174G/C variant (rs1800795) is in strong linkage disequilibrium with rs1800797 (-597G/A) in the same IL6 promoter region (r-squared = 0.92), meaning these two variants are almost always inherited together. The nearby rs1800796 (-572G/C) variant is an independent functional polymorphism that can compound the effect on IL-6 levels, though it is primarily polymorphic in East Asian populations. IL-6 signalling also interacts with the broader inflammatory cascade — TNF-alpha and CRP levels are influenced by IL-6, so this variant has downstream effects on systemic inflammation markers.