rs8065080 — TRPV1 Ile585Val

The Capsaicin Receptor — How Your Genes Shape Pain Perception

TRPV1 is the molecular gateway to pain in your sensory neurons, a calcium channel that opens in response to noxious heat (above 43°C), acids, and capsaicin — the compound that makes chili peppers burn. The Ile585Val variant¹¹ Ile585Val variant
rs8065080, also known as I585V or c.1191A>G, causes an amino acid substitution from isoleucine to valine at position 585 of the TRPV1 protein affects how sensitively this channel responds to pain-inducing stimuli.

TRPV1 isn't just a heat sensor. When tissue injury occurs, inflammatory mediators like bradykinin and prostaglandins sensitize TRPV1²² inflammatory mediators like bradykinin and prostaglandins sensitize TRPV1
lowering its activation threshold from ~43°C to as low as 34°C, which is why inflamed tissue hurts even at body temperature. This sensitization process is central to chronic pain conditions, making genetic variants in TRPV1 clinically meaningful beyond simple thermal sensitivity.

The Mechanism

The Ile585Val substitution sits in a critical region of the TRPV1 channel near the S4-S5 linker, an area involved in channel gating and sensitivity to vanilloid ligands like capsaicin. The isoleucine at position 585 is a hydrophobic amino acid; replacing it with valine (also hydrophobic but slightly smaller) appears to alter the channel's conformational response to activation³³ appears to alter the channel's conformational response to activation
studies suggest the Val variant may change channel morphology or stimulus-dependent gating.

Functional studies show that Val-Val carriers (GG genotype) exhibit higher capsaicin sensitivity⁴⁴ Val-Val carriers (GG genotype) exhibit higher capsaicin sensitivity
measured as lower detection thresholds for capsaicin-induced burning, while Ile-Ile carriers demonstrate reduced sensitivity to thermal pain, capsaicin, and inflammatory pain. The heterozygous state shows intermediate function, consistent with codominant inheritance.

The Evidence

The most compelling evidence comes from a meta-analysis of 8,220 individuals across seven cohorts⁵⁵ meta-analysis of 8,220 individuals across seven cohorts
Valdes et al. genotyped 3,270 symptomatic knee osteoarthritis cases, 1,098 asymptomatic OA cases, and 3,852 controls from the UK, USA, and Australia. The Ile-Ile genotype was associated with 25% lower risk of symptomatic knee OA compared to healthy controls (OR 0.75, 95% CI 0.64-0.88, p=0.00039) after adjusting for age, sex, and BMI. Crucially, no difference was seen between asymptomatic OA cases and controls, suggesting the genetic effect operates through pain perception rather than joint damage itself.

A Japanese study of 134 healthy adults⁶⁶ Japanese study of 134 healthy adults
Okamoto et al. measured burning pain thresholds using a 48°C hot plate and capsaicin sensitivity using topical application. Val-Val homozygotes showed significantly higher capsaicin sensitivity compared to Ile carriers, though associations with thermal pain were more complex, likely due to redundancy in heat-sensing mechanisms (TRPV1, TRPA1, TRPM3 all contribute).

A controlled study of 25 healthy volunteers⁷⁷ controlled study of 25 healthy volunteers
subjects with the GG genotype showed 82% less capsaicin-induced warm hypoesthesia and 22% less heat pain sensitivity gain after topical capsaicin compared to AA/AG carriers, demonstrating altered channel function under physiological conditions.

A preliminary study of 46 migraine patients⁸⁸ preliminary study of 46 migraine patients
AA genotype frequency was 61% in chronic migraine patients versus 34% in episodic migraine and 38% in controls, with complete absence of GG genotype in chronic migraine group, though a subsequent larger study and meta-analysis failed to replicate this association⁹⁹ subsequent larger study and meta-analysis failed to replicate this association
349 migraine patients showed no significant difference in rs8065080 genotype distribution.

Interestingly, a Korean diabetes study of 8,842 subjects¹⁰¹⁰ Korean diabetes study of 8,842 subjects
minor allele (Ile/A) carriers had lower HOMA-IR and reduced type 2 diabetes risk specifically when consuming high-fat diets, suggesting gene-nutrient interactions beyond pain perception.

Practical Implications

Your rs8065080 genotype influences how you experience pain from heat, inflammation, and irritating chemicals. Ile-Ile carriers (AA) experience less intense pain from these stimuli and may have higher pain tolerance, while Val-Val carriers (GG) are more sensitive and may be more prone to chronic pain conditions when tissue damage is present.

This has implications for spicy food tolerance — Val carriers genuinely experience capsaicin as more intensely burning. It may also influence susceptibility to chronic pain syndromes where TRPV1 sensitization plays a role, including inflammatory arthritis, neuropathic pain, and potentially migraine (though evidence is mixed).

For thermal injury prevention, Val carriers' higher sensitivity may offer some protective benefit by triggering withdrawal reflexes earlier. However, in chronic inflammation, this same sensitivity may amplify pain signaling and contribute to disability even when structural damage is modest.

Interactions

TRPV1 rs8065080 has been studied alongside other TRPV1 coding variants, including rs222747 (M315I) and rs222749 (P91S)¹¹¹¹ rs222747 (M315I) and rs222749 (P91S)
both also affect TRPV1 function and pain perception. While these variants show linkage disequilibrium in some populations, their combined effects on pain perception have not been systematically characterized in compound heterozygote studies.

TRPV1 functionally interacts with TRPA1 (a chemical irritant receptor)¹²¹² TRPA1 (a chemical irritant receptor)
both channels can heterodimerize and TRPA1 variants also modulate heat and capsaicin sensitivity. The combined genotype effects remain an area of active research.

Since TRPV1 is upregulated by inflammatory mediators, genetic variants affecting inflammatory pathways (COX-2, TNF-alpha signaling) may interact with TRPV1 variants to modulate chronic pain risk, though specific gene-gene interaction studies are lacking.