rs1934967 — CYP2C9

Intronic CYP2C9 haplotype tag associated with altered warfarin sensitivity and NSAID metabolism in Asian populations

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CYP2C9 rs1934967 — An Intronic Haplotype Tag in the Warfarin Metabolism Gene

CYP2C9 is the liver enzyme responsible for metabolizing roughly 15% of all clinically used drugs, most notably warfarin (the world's most prescribed oral anticoagulant), phenytoin (an anticonvulsant), and a broad range of NSAIDs including ibuprofen, celecoxib, and meloxicam. Getting a warfarin dose wrong can be fatal — too little and blood clots form, too much and life-threatening bleeding follows. CYP2C9 genotype is now part of the FDA-approved warfarin labeling11 FDA-approved warfarin labeling
FDA Table of Pharmacogenomic Biomarkers in Drug Labeling and is used to guide individualized dosing in clinical practice.

rs1934967 (GRCh38 chr10:94,981,669, C>T) is an intronic variant 22 Intronic: located within a non-coding intron, 299 bases downstream of exon 9 in CYP2C9 transcript NM_000771.4 in CYP2C9 that does not directly alter the protein sequence. Instead, it acts as a haplotype tag33 haplotype tag
Haplotype tag: a variant in linkage disequilibrium with nearby functional variants, marking a specific chromosomal block for a broader CYP2C9 variant block. Multiple Chinese population studies have examined rs1934967 as one of a panel of CYP2C9 markers used in pharmacogenomically guided warfarin therapy.

The Mechanism

Unlike the well-characterized functional CYP2C9 alleles — *2 (rs1799853, p.Arg144Cys, ~50% residual activity) and *3 (rs1057910, p.Ile359Leu, ~5-15% residual activity) — rs1934967 carries no direct amino acid change. Its clinical significance derives from its position within a CYP2C9 haplotype block. The T allele (which occurs on the minus strand at c.1149+299) has been observed in linkage with CYP2C9 haplotypes that show modified enzymatic output. The precise functional mechanism — whether the variant tags a regulatory element affecting CYP2C9 expression, or is simply a surrogate marker for a nearby functional variant — has not been fully resolved by published studies.

CYP2C9 also hydroxylates arachidonic acid into epoxyeicosatrienoic acids44 epoxyeicosatrienoic acids
EETs: vasoactive lipid mediators with anti-inflammatory properties; CYP2C9 is a key EET synthase (EETs), which regulate vascular tone, platelet aggregation, and inflammation. Variation in EET production may contribute to the associations between CYP2C9 haplotypes and cardiovascular phenotypes observed in some studies.

The Evidence

Two pharmacogenomics studies from the same Chinese research group examined rs1934967 as part of multi-SNP CYP2C9 surveys in warfarin patients. A 2011 study by Liu et al.55 Liu et al.
Liu Y et al. Distribution of variant alleles for warfarin pharmacokinetics and pharmacodynamics in Han Chinese. Beijing Da Xue Xue Bao Yi Xue Ban, 2011 documented the T allele frequency at 19.18% in 400 Han Chinese warfarin recipients. A companion study by Liu et al.66 Liu et al.
Liu Y et al. Impact of CYP2C9 and VKORC1 polymorphism on warfarin response during initiation of therapy. Zhonghua Xin Xue Guan Bing Za Zhi, 2011 in 798 post-valve-replacement patients found that the multi-marker CYP2C9 genotype panel — including rs1934967 — was associated with warfarin anticoagulation response and bleeding risk during initial therapy.

A haplotype study by Fu et al.77 Fu et al.
Fu Z et al. Diplotypes of CYP2C9 gene is associated with coronary artery disease in Xinjiang Han population for women. Lipids Health Dis, 2014 among 301 CAD patients and 220 controls found that the protective CYP2C9 haplotype (C-T-A-C, where the T is the rs1934967 T allele) was underrepresented in women with coronary artery disease, while a risk haplotype (C-C-A-T, the C allele at rs1934967) was overrepresented. This suggests the T allele at rs1934967 may tag a cardioprotective haplotype in this population.

A 2025 ischemic stroke study by Zhang et al.88 Zhang et al.
Zhang J et al. CYP2C9 polymorphism is associated with susceptibility to ischemic stroke in a Chinese population. Ann Med, 2025 found that the four-SNP haplotype rs10509679-A|rs1934967-C|rs1934968-G|rs9332220-G was associated with elevated stroke risk (the complementary protective haplotype carries the T allele at rs1934967).

A lung cancer susceptibility study by Zhang et al.99 Zhang et al.
Zhang C et al. Variants in CYP2J2 and CYP2C9 Contribute to Susceptibility of Lung Cancer. Curr Cancer Drug Targets, 2025 in 507 lung cancer patients and 505 controls found that rs1934967 T allele carriers had decreased lung cancer risk in subgroup analyses (age ≤60, BMI >24, squamous carcinoma histology), potentially through altered CYP2C9-mediated carcinogen or eicosanoid metabolism.

All association data for rs1934967 comes from studies in East Asian (primarily Chinese Han) populations. The T allele frequency is substantially lower in African populations (~7%), and no large European pharmacogenomics trials have specifically genotyped this variant. Independent replication outside East Asian cohorts is needed.

Practical Actions

For individuals carrying the T allele at rs1934967, the clinical significance is primarily informational in the context of warfarin pharmacogenomics. The variant does not independently define a CPIC metabolizer class, as no CYP2C9 star allele is anchored to rs1934967 alone. Its value is as a component of multi-SNP CYP2C9 panels used for warfarin dose optimization, particularly in Asian populations where it was characterized. The more clinically actionable CYP2C9 variants are *2 (rs1799853) and *3 (rs1057910), which are directly referenced in CPIC and FDA labeling.

For NSAIDs (ibuprofen, celecoxib, meloxicam), CYP2C9 haplotype context matters because these drugs are cleared primarily by CYP2C9; individuals on haplotypes with reduced activity may have elevated NSAID plasma levels, increasing GI bleeding risk. The CPIC guideline for CYP2C9 and NSAIDs Theken et al.1010 Theken et al.
Theken KN et al. CPIC Guideline for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin Pharmacol Ther, 2020 recommends dose adjustment for confirmed poor metabolizers.

Interactions

rs1934967 has been studied in haplotype blocks alongside rs10509679, rs1934968, and rs9332220 in the same CYP2C9 gene region. The most clinically meaningful interactions involve the functional *2 variant (rs1799853) and *3 variant (rs1057910) — compound heterozygosity for *2/*3 or *3/*3 dramatically reduces CYP2C9 activity to near-zero and is the primary driver of warfarin sensitivity in European populations. VKORC1 rs9923231 (the warfarin target gene) interacts synergistically with CYP2C9 genotype to determine overall warfarin dose requirements. The combination of CYP2C9 reduced-function alleles with VKORC1 sensitive genotypes can require 80-90% dose reduction from population-average dosing.

Drug Interactions

warfarin dose_adjustment literature
ibuprofen increased_toxicity literature
celecoxib increased_toxicity literature
meloxicam increased_toxicity literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal Metabolizer Normal

Common CYP2C9 haplotype at this intronic position

rs1934967 C is the GRCh38 reference allele and the population-major allele globally. Because this is an intronic variant with no direct protein-coding effect, the CC genotype does not independently indicate either increased or decreased CYP2C9 enzymatic activity. Any clinical inference about CYP2C9 drug metabolism capacity requires assessment of the functional star alleles (*2, *3) alongside this intronic tag. The CC genotype at rs1934967 was found in the risk haplotype (C-C-A-T) associated with coronary artery disease in one Chinese female cohort, but the primary driver in that analysis was the rs2475376 variant, not rs1934967 alone.

CT Heterozygous T Carrier Intermediate

One copy of the CYP2C9 haplotype T allele

The T allele at rs1934967 appears to tag a specific CYP2C9 haplotype that has shown protective cardiovascular and cancer-susceptibility associations in East Asian cohorts. Whether this reflects a direct functional effect of rs1934967 itself (for example, altered CYP2C9 expression affecting eicosanoid production) or is a passenger marker for a nearby variant is unknown. The T allele frequency is ~21% in Europeans, ~19% in East Asians, and only ~7% in African populations — suggesting differential haplotype structure across ancestries.

Because rs1934967 has no CPIC star allele assignment, it does not independently modify warfarin or NSAID dosing algorithms. Its practical value lies in multi-SNP pharmacogenomics panels used in some Asian clinical settings.

TT Homozygous T Carrier Homozygous

Homozygous for the CYP2C9 haplotype T allele

Homozygous TT status maximizes the likelihood of being on the T-haplotype block in both CYP2C9 copies. The biological rationale includes the possibility that this haplotype influences CYP2C9 expression levels or alters the enzyme's metabolic balance between drug substrates and endogenous substrates like arachidonic acid (eicosanoid metabolism). EETs produced by CYP2C9 are vasodilatory and anti-inflammatory; haplotypes with altered EET output could plausibly affect cardiovascular risk independent of any drug metabolism effect.

It is important to note: because rs1934967 is intronic and carries no CPIC star allele designation, TT at this position alone does NOT define a poor metabolizer phenotype for warfarin or NSAID purposes. The functional *2 and *3 variants remain the primary pharmacogenomic determinants. TT here is not analogous to being *3/*3, which is a genuine no-function state.