rs3814637 — CYP2C19

Upstream CYP2C19 variant associated with altered R-warfarin clearance and increased exposure to CYP2C19 substrates

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CYP2C19 Upstream Variant — Warfarin Dose Sensitivity

CYP2C19 is one of the most important drug-metabolizing enzymes in the liver, responsible for processing a wide range of medications including anticoagulants, proton pump inhibitors, antidepressants, and antifungals. While much attention focuses on the well-characterized loss-of-function variants (*2, *3) and the gain-of-function *17 allele, rs3814637 is a separate upstream regulatory variant located approximately 1,400 bases before the CYP2C19 transcription start site. Carriers of the T allele show altered CYP2C19-mediated drug metabolism, with the most robust evidence coming from warfarin dosing studies.

The Mechanism

Rs3814637 sits in the regulatory region upstream of CYP2C1911 Located ~1,374–1,393 bp upstream of the CYP2C19 transcription start site per Ensembl VEP and is classified as an upstream gene variant. The precise molecular mechanism by which the T allele alters CYP2C19 activity has not been fully characterized in published literature, but the pharmacokinetic data consistently show that T-allele carriers have higher plasma concentrations of CYP2C19 substrates, suggesting either reduced enzyme activity or expression. Unlike the *2 allele's splice-site mutation, rs3814637 likely exerts its effect through altered transcription factor binding or promoter-region regulation.

Warfarin exists as two enantiomers22 Mirror-image forms of the same molecule with different metabolic fates: S-warfarin (more potent, metabolized mainly by CYP2C9) and R-warfarin (metabolized predominantly by CYP1A2, CYP3A4, and CYP2C19). The rs3814637 variant specifically affects R-warfarin clearance, meaning T-allele carriers clear this enantiomer more slowly, raising the effective anticoagulant exposure.

The Evidence

The strongest evidence for rs3814637 comes from a 2022 meta-analysis by Wang et al.33 2022 meta-analysis by Wang et al.
Wang D et al. Impact of CYP2C19 gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis. Pharmacogenomics, 2022 analyzing nine studies totaling 1,393 patients. Individuals with the TT genotype required 34% lower warfarin maintenance doses than CC carriers; CT heterozygotes required 18% less. A companion pharmacokinetic study by Lane et al. (2012)44 Lane et al. (2012)
Lane S et al. The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors. Br J Clin Pharmacol, 2012 independently identified rs3814637 as one of the key genetic determinants of R-warfarin clearance in a long-term anticoagulation cohort.

For other CYP2C19 substrates, a Chinese lung-cancer study by Tan et al. (2022)55 Tan et al. (2022)
Tan T et al. Genetic Polymorphisms in CYP2C19 Cause Changes in Plasma Levels and Adverse Reactions to Anlotinib in Chinese Patients With Lung Cancer. Front Pharmacol, 2022 found that TT+CT carriers showed significantly higher peak plasma concentrations of anlotinib — a multikinase inhibitor — and elevated rates of hypertension and hemoptysis compared to CC carriers. This is consistent with a broader pattern of reduced CYP2C19-mediated clearance in T-allele carriers.

Practical Actions

The most direct clinical implication is for warfarin dosing. Anyone prescribed warfarin who carries the T allele — particularly TT homozygotes — may need a lower starting dose and closer INR monitoring during initiation. The effect is modest for heterozygotes (CT, ~18% dose reduction) but more pronounced for homozygotes (TT, ~34% reduction). Standard warfarin dosing algorithms do not currently include rs3814637, so this information is supplementary to — not a replacement for — clinical INR monitoring and algorithmic dosing (e.g., IWPC or WarfarinDosing.org algorithms that already incorporate CYP2C9 and VKORC1).

The T allele is enriched in East Asian populations (15–17% in Japanese cohorts) compared to Europeans (~6%), which may partly explain observed population differences in warfarin sensitivity.

Interactions

Rs3814637 acts independently of the major CYP2C19 star alleles (*2 via rs4244285 and *17 via rs12248560). A person carrying both rs3814637 T and the *2 no-function allele (rs4244285 A) would have compounded reductions in CYP2C19-mediated warfarin metabolism. Conversely, carrying rs3814637 T alongside *17 (rs12248560 T) creates opposing effects in the CYP2C19 locus and could complicate pharmacokinetic prediction. The *2 and *17 alleles are already captured by separate GeneOps entries; this entry reflects the independent additive contribution of rs3814637.

Drug Interactions

warfarin dose_adjustment literature
anlotinib increased_toxicity literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal Metabolizer Normal

Normal CYP2C19 activity at rs3814637

You carry two copies of the common C allele at this upstream CYP2C19 position. Your CYP2C19 activity at this locus is normal, meaning standard dosing of CYP2C19 substrates such as warfarin applies. About 83% of people globally share this genotype; it is more common in Europeans (~88%) and less common in East Asians (~70%).

CT Intermediate Metabolizer Intermediate

Reduced CYP2C19 activity — warfarin dose may need adjustment

The ~18% warfarin dose reduction associated with the CT genotype is a population average from a meta-analysis of nine studies. Individual response will still vary based on other genetic factors (CYP2C9, VKORC1), age, body weight, and concomitant medications. This variant is not yet incorporated into the IWPC or WarfarinDosing.org algorithms, so it provides additive information beyond standard clinical dosing tools.

TT Poor Metabolizer Poor

Significantly reduced CYP2C19 clearance — warfarin dose reduction likely needed

The 34% dose reduction associated with TT homozygosity reflects substantially slower R-warfarin clearance through CYP2C19. Combined with CYP2C9 or VKORC1 variants, the cumulative dose reduction could be large enough to require clinical attention even at initiation. Evidence for non-warfarin substrates is limited to anlotinib so far, but the mechanism — reduced CYP2C19-mediated clearance — would theoretically affect other CYP2C19-dependent drugs as well. No CPIC or DPWG guideline currently incorporates rs3814637 specifically; the evidence level is moderate based on the published meta-analysis.