rs1934953 — CYP2C8

Intronic CYP2C8 variant linked to hypertension susceptibility, COPD risk, and bladder cancer protection

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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.

The Mechanism

rs1934953 is an intronic variant — it does not change the CYP2C8 protein sequence.

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).

Drug Interactions

paclitaxel dose_adjustment literature
repaglinide dose_adjustment literature
rosiglitazone dose_adjustment literature
pioglitazone dose_adjustment literature
ibuprofen dose_adjustment literature
amodiaquine dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

TT High EET Producer Normal

Common CYP2C8 genotype — full epoxygenase activity expected

You carry two T alleles at rs1934953, the most common genotype in most populations (about 45% of Europeans and 64% of Africans share this genotype). This genotype is associated with the strongest protective signal against bladder cancer in the available research (OR 0.26 vs CC in the codominant model).

CT Intermediate EET Producer Intermediate

One copy of the C allele — moderately reduced epoxygenase activity

The borderline hypertension association observed in Russian cohort studies (P ≤ 0.04) suggests a contribution to blood pressure regulation, though effect size is small.

CC Low EET Producer Reduced

Homozygous C allele — lowest epoxygenase activity, elevated disease risk

The bladder cancer finding (OR 0.26 for TT vs CC) is striking and was replicated across multiple inheritance models.