rs1934953 — CYP2C8

CYP2C8 rs1934953 — Epoxygenase Pathway Variant

The CYP2C8 gene encodes one of the major phase I drug-metabolizing enzymes in the liver, responsible for clearing a clinically important set of medications including the chemotherapy drug paclitaxel, diabetes medications rosiglitazone and pioglitazone, and the antimalarial amodiaquine. Beyond drug metabolism, CYP2C8 plays a second, often underappreciated role: it is the primary hepatic and vascular enzyme that converts arachidonic acid into epoxyeicosatrienoic acids (EETs)¹¹ epoxyeicosatrienoic acids (EETs)
EETs are lipid signaling molecules with vasodilatory and anti-inflammatory properties, a family of lipid mediators that relax blood vessel walls, protect the heart, and modulate inflammation. rs1934953 sits in an intron of CYP2C8 and appears to influence this epoxygenase function.

The Mechanism

rs1934953 is an intronic variant — it does not change the CYP2C8 protein sequence. Instead, it likely acts as a regulatory variant, influencing CYP2C8 expression levels or splicing efficiency. The C allele (present at approximately 33% frequency in Europeans) has been linked to altered EET production. CYP2C8-derived EETs promote vasodilation via hyperpolarization of vascular smooth muscle and have protective effects in cerebrovascular and cardiovascular contexts. When CYP2C8 epoxygenase activity is reduced, EET levels fall and the balance shifts toward more vasoconstriction and inflammation. The C allele has also been studied in the context of carcinogen metabolism — CYP2C8 processes procarcinogens in the bladder, and altered expression may change how efficiently those compounds are activated or detoxified.

The Evidence

A 2017 Russian cohort study²² 2017 Russian cohort study
Polonikov A et al. Contribution of CYP2C gene subfamily involved in epoxygenase pathway to hypertension. Clin Exp Hypertens, 2017 of 816 participants found that rs1934953 showed borderline significant association with essential hypertension risk (P ≤ 0.04), alongside a stronger signal from the nearby CYP2C8 variant rs7909236 (OR 2.99, 95% CI 1.39–6.44). The same group studied CYP2C8 rs1934953 in coronary heart disease³³ studied CYP2C8 rs1934953 in coronary heart disease
Polonikov A et al. Polymorphisms of CYP2C8, CYP2C9, CYP2C19 and CHD risk. Gene, 2017 in 1,255 participants but found no significant independent association.

A 2015 study of subarachnoid hemorrhage⁴⁴ 2015 study of subarachnoid hemorrhage
Donnelly MK et al. EET metabolic pathway variants and aneurysmal subarachnoid hemorrhage outcomes. J Cereb Blood Flow Metab, 2015 demonstrated that CYP2C8 variants in the EET pathway significantly affected outcomes, with the CYP2C8*4 allele associated with 44–36% lower CSF EET/DHET levels and 2.2–2.5x higher risk of delayed cerebral ischemia — establishing the clinical relevance of CYP2C8 epoxygenase function in cerebrovascular biology.

The most striking association comes from bladder cancer: a 2022 case-control study⁵⁵ 2022 case-control study
Qu W et al. Impact of CYP2C8 genetic variants on bladder cancer susceptibility. Front Endocrinol, 2022 found the TT genotype strongly protective against bladder cancer (OR 0.26, 95% CI 0.14–0.47, p = 1.20E-05, codominant model), with the T allele showing consistent protection across dominant (OR 0.62) and recessive (OR 0.31) models. A 2023 Mexican population study⁶⁶ 2023 Mexican population study
Ambrocio-Ortiz E et al. CYP2C8 SNPs and COPD from biomass-burning smoke. Curr Issues Mol Biol, 2023 linked CYP2C8 variants including rs1934953 to COPD susceptibility in the setting of biomass-burning smoke exposure.

Practical Implications

The direct pharmacogenomic relevance of rs1934953 for specific drug dosing is not established by CPIC or DPWG guidelines — these focus on coding variants (CYP2C8*2, *3, *4). However, the broader context of CYP2C8 activity through EET production has implications for cardiovascular health and for individuals on CYP2C8-metabolized drugs. Individuals with the CC genotype have the lowest EET-producing capacity among common genotypes and may warrant closer cardiovascular monitoring. The variant's association with COPD from biomass smoke exposure suggests environmental interactions — individuals with the C allele who have heavy biomass/occupational smoke exposure may face heightened respiratory risk.

Interactions

rs1934953 operates in the same epoxygenase pathway as CYP2J2 (rs10509681) and EPHX2 variants, which together govern EET production and degradation. The functional CYP2C8*3 variant rs11572080 (p.Arg139Met) is a missense variant in strong linkage disequilibrium with haplotype blocks in the same region; individuals with both rs1934953 C allele and reduced-function coding variants in CYP2C8 may have compounded reduction in EET output. No CPIC compound-genotype recommendations currently exist for this combination, but the pathway logic is well established.