rs1113129 — CYP2C8

CYP2C8 Haplotype C — Slower Drug Clearance Across Multiple Drug Classes

The CYP2C8 enzyme handles a wide portfolio of important drugs — from paclitaxel chemotherapy to antidiabetic thiazolidinediones, the antimalarial amodiaquine, and common NSAIDs like ibuprofen. rs1113129 is an intronic variant that serves as a tagging marker for CYP2C8 haplotype C¹¹ CYP2C8 haplotype C
a co-inherited pattern of variants across the CYP2C8 gene that travels together through generations, a low-activity version of the gene associated with reduced drug clearance and altered eicosanoid metabolism.

The Mechanism

rs1113129 (G>C) sits in intron 5 of CYP2C8 at chromosome 10 position 95,051,288 (GRCh38). It does not change the protein sequence directly but is one of four tightly co-inherited variants — rs2275622, rs7909236, rs1113129, and rs11572080 — that together define haplotype C. This haplotype produces reduced CYP2C8 enzyme activity²² reduced CYP2C8 enzyme activity
measured as lower 6α-hydroxylation of paclitaxel and reduced urinary excretion of dihydroxyeicosatrienoic acids (DHETs), downstream products of arachidonic acid metabolism, probably through effects on mRNA splicing or transcription regulation rather than protein structure. The net effect is slower metabolism of CYP2C8 substrates, meaning drugs stay in circulation longer and at higher concentrations.

CYP2C8 also converts arachidonic acid to epoxyeicosatrienoic acids (EETs), which have vasodilatory, anti-inflammatory, and renoprotective effects. Reduced CYP2C8 activity therefore lowers EET production, which Kirchheiner et al. 2008³³ Kirchheiner et al. 2008
Impact of genetic polymorphisms in CYP2C8 and rosiglitazone intake on the urinary excretion of dihydroxyeicosatrienoic acids. Pharmacogenomics, 2008 propose could contribute to cardiovascular effects seen in CYP2C8 association studies.

The Evidence

Rodriguez-Antona et al. 2008⁴⁴ Rodriguez-Antona et al. 2008
Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism. Pharmacogenomics J, 2008 characterized haplotype C in 49 human liver samples and in vivo in healthy Caucasian volunteers. Haplotype C caused significantly reduced paclitaxel 6α-hydroxylation in vitro and was associated with increased repaglinide AUC (i.e., higher drug exposure) in subjects who were also carriers of the SLCO1B1 transport variant.

The clinically most important CYP2C8 variant — CYP2C8*3, defined by rs10509681 and rs11572080 — is in partial linkage disequilibrium with haplotype C. Studies on CYP2C8*3 provide the best available proxy for haplotype C effects. In 411 breast cancer patients, Hertz et al. 2013⁵⁵ Hertz et al. 2013
CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel. Breast Cancer Res Treat, 2013 showed that each CYP2C8*3 allele approximately doubled the risk of grade 2+ peripheral neuropathy (HR≈2.0, P=0.004). A smaller study of 111 patients found CYP2C8*3 carriers had dramatically higher complete response to paclitaxel (55% vs 23%, OR=3.92) alongside a trend toward more severe neuropathy ⁶⁶ Hertz et al. CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel. Breast Cancer Res Treat, 2012.

For thiazolidinediones, CYP2C8 haplotype C results in reduced drug clearance — rosiglitazone and pioglitazone AUC are 20–40% higher in haplotype C carriers compared to non-carriers, leading to greater blood-glucose lowering but also heightened risk of dose-dependent side effects including edema and weight gain.

Practical Actions

Carriers of the C allele at rs1113129 (haplotype C) have meaningfully slower CYP2C8 activity. For paclitaxel therapy, this translates to higher drug exposure and a substantially elevated risk of peripheral neuropathy — the most common dose-limiting toxicity. Inform your oncologist about this genotype before paclitaxel-based chemotherapy so neuropathy symptoms can be monitored proactively and doses adjusted early if needed.

For antidiabetic drugs, slower clearance of rosiglitazone and pioglitazone means lower doses often achieve equivalent glucose control. Starting at the lower end of the dosing range is appropriate for haplotype C carriers.

For ibuprofen and other CYP2C8-metabolized NSAIDs, higher plasma levels at standard doses may increase gastrointestinal bleeding risk in prolonged use situations.

Interactions

The haplotype C effect is most clinically significant when combined with other CYP2C8 reduced-function alleles (rs10509681 / CYP2C8*3 K399R) — a person carrying haplotype C on one chromosome and CYP2C8*3 on the other has compound heterozygous reduced CYP2C8 activity with correspondingly greater drug exposure and toxicity risk. The SLCO1B1 transporter SNP rs4149056 also interacts with CYP2C8 haplotypes in repaglinide pharmacokinetics; haplotype C combined with SLCO1B1 reduced-function alleles produces the highest repaglinide exposure.