rs1934980 — CYP2C8

Intronic CYP2C8 variant linked to altered enzyme expression and associated with bisphosphonate-related jaw complications and clopidogrel response

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CYP2C8 rs1934980 — Intronic Variant Shaping Drug Metabolism and Bone Risk

CYP2C811 CYP2C8
Cytochrome P450 family 2, subfamily C, member 8 — a liver enzyme responsible for metabolizing roughly 5% of marketed drugs is a workhorse of hepatic drug clearance. Unlike its close relative CYP2C9, CYP2C8 handles a distinct substrate portfolio: the cancer drug paclitaxel, the diabetes drugs rosiglitazone and repaglinide, the antimalarial amodiaquine, and the NSAIDs ibuprofen and diclofenac. Beyond drug metabolism, CYP2C8 converts arachidonic acid into epoxyeicosatrienoic acids (EETs)22 epoxyeicosatrienoic acids (EETs)
signaling lipids with anti-inflammatory and vasodilatory properties, making it relevant to cardiovascular homeostasis. The intronic variant rs1934980 (G allele, ~19% globally) appears to influence CYP2C8 activity — not by changing the enzyme's amino acid sequence, but likely by altering how much protein the gene produces.

The Mechanism

rs1934980 sits within an intron of CYP2C8 on chromosome 10 (GRCh38 position 95,049,216). Intronic variants can affect mRNA splicing efficiency, transcription factor binding sites, or enhancer activity, all of which alter enzyme expression levels without changing the protein's structure. The G allele falls within a haplotype cluster — rs1934951, rs1934980, rs1341162, and rs17110453 — that segregates together across the CYP2C8 gene due to linkage disequilibrium33 linkage disequilibrium
tendency for nearby variants to be inherited as a unit rather than independently. Saito et al. (2007)44 Saito et al. (2007)
CYP2C8 haplotype structures and paclitaxel pharmacokinetics, Pharmacogenetics and Genomics identified intronic CYP2C8 haplotype groups in 437 Japanese individuals where strong linkage disequilibrium throughout the gene meant that intronic tag SNPs could capture expression differences associated with the broader haplotype — including elevated paclitaxel metabolite levels, suggesting altered enzyme turnover.

The Evidence

The most compelling clinical signal comes from a 2008 genome-wide SNP study by Sarasquete et al.55 Sarasquete et al.
Blood, 2008 that examined 22 multiple myeloma patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) against 65 matched controls. Among four significant CYP2C8 variants, rs1934980 showed p = 4.2×10⁻⁶ between cases and controls. The biological plausibility rests on CYP2C8's role in metabolizing the bisphosphonate zoledronic acid and its production of EETs that protect bone vasculature. Follow-up evidence is mixed: Such et al. (2011)66 Such et al. (2011)
Haematologica, n=79 could not replicate the association for rs1934951, though a meta-analysis (2013)77 meta-analysis (2013)
Zhong et al., Acta Haematol recovered a significant signal for rs1934951 in multiple myeloma patients specifically (dominant model OR=5.77, p=0.028). Because rs1934980 is in strong LD with rs1934951, its effect likely tracks the same haplotype.

The clopidogrel connection emerged in a 2024 pharmacogenomic polygenic study of 935 Chinese CAD patients88 935 Chinese CAD patients
Zhang et al., Clinical Therapeutics where rs1934980 was nominally associated with recurrent ischemic events — consistent with CYP2C8 contributing to the metabolic conversion of clopidogrel's intermediate forms. The overall polygenic model (including rs1934980) predicted a hazard ratio of 1.87 for high risk-allele burden (p=0.04), though the individual variant contribution was not reported separately.

For the canonical CYP2C8 substrates, functional work on haplotype-defined alleles is clearest for CYP2C8*3 (which shares partial haplotype background with this variant cluster). Dawed et al. (2016)99 Dawed et al. (2016)
Diabetes Care, n=833 demonstrated that CYP2C8*3 carriers had a reduced HbA1c response to rosiglitazone (p=0.01), and Marcath et al. (2019)1010 Marcath et al. (2019)
Pharmacogenomics, n=58 found CYP2C8*3 carriers had shorter paclitaxel exposure (p=0.006).

Practical Actions

Carriers of one or two G alleles at rs1934980 should be aware of this variant's relevance to their medication history — particularly for paclitaxel-based chemotherapy regimens, thiazolidinediones (rosiglitazone, pioglitazone), and repaglinide. If ever receiving intravenous bisphosphonates (zoledronic acid, pamidronate) for cancer-related bone disease or osteoporosis, the association with BRONJ risk warrants heightened dental surveillance. The cardiovascular relevance — through both clopidogrel response and EET production — makes this variant one to flag for cardiologists managing antiplatelet therapy in homozygous G carriers.

Interactions

rs1934980 is in strong linkage disequilibrium with rs1934951, rs1341162, and rs17110453 — all four variants were co-identified in the Sarasquete BRONJ GWAS and likely travel together as a CYP2C8 intronic haplotype. The combined effect of carrying this CYP2C8 haplotype alongside impaired CYP2C19 function (rs4244285, rs4986893) could compound altered clopidogrel activation, since both enzymes contribute to the drug's bioactivation pathway. An interaction with CYP2C9 variants (rs1799853, rs1057910) is also plausible for shared NSAID substrates.

Drug Interactions

paclitaxel dose_adjustment literature
rosiglitazone dose_adjustment literature
repaglinide dose_adjustment literature
clopidogrel dose_adjustment literature
amodiaquine dose_adjustment literature
ibuprofen dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Normal Metabolizer Normal

Standard CYP2C8 activity — no intronic risk haplotype

The AA genotype places you on the reference haplotype background for this intronic CYP2C8 cluster. No altered expression signal has been associated with this genotype. Your CYP2C8-derived EET production from arachidonic acid metabolism is also expected to be unaffected, supporting normal vascular protective signaling. The overall risk of bisphosphonate- related osteonecrosis of the jaw attributable to this locus is not elevated.

AG Intermediate Metabolizer Intermediate

One copy of the CYP2C8 intronic risk haplotype

The AG genotype confers partial exposure to the intronic CYP2C8 haplotype that Sarasquete et al. (2008) identified at p=4.2×10⁻⁶ in association with BRONJ risk. The G allele likely tags a haplotype that reduces CYP2C8 transcriptional efficiency, consistent with the observation from Saito et al. (2007) that intronic haplotype groups elevate paclitaxel metabolite levels — suggesting altered drug clearance. In the clopidogrel polygenic study (Zhang et al. 2024), nominal association of this variant with ischemic recurrence in CAD patients on clopidogrel supports a modest impact on antiplatelet drug metabolism in heterozygotes.

GG Homozygous Risk Haplotype Reduced

Two copies of the CYP2C8 intronic risk haplotype — enhanced attention to specific drug regimens warranted

The GG genotype means all of your CYP2C8 expression comes from haplotype copies carrying the intronic variant cluster (rs1934951/rs1934980/rs1341162/ rs17110453). In the original GWAS by Sarasquete et al. (2008), allele distributions in BRONJ cases versus controls were highly significant (p=4.2×10⁻⁶), and a subsequent meta-analysis of the linked rs1934951 in multiple myeloma patients showed a 16-fold elevated BRONJ risk for homozygous carriers (OR=16.23, p=0.015). The intronic haplotype group described by Saito et al. (2007) showed approximately 2.5-fold higher paclitaxel hydroxylated metabolite AUC in heterozygotes, with homozygous effects potentially larger. Reduced EET synthesis from altered CYP2C8 activity may additionally impair vascular protection and alter inflammatory responses relevant to bone remodeling and cardiovascular outcomes.