rs12248560 — CYP2C19 *17

CYP2C19*17 - The Rapid Metabolizer Variant

While most pharmacogenomic attention focuses on loss-of-function variants, the CYP2C19*17 allele¹¹ rs12248560 represents the opposite end of the spectrum: a gain-of-function variant that increases enzyme activity beyond normal levels. This variant sits in the promoter region and upregulates CYP2C19 gene expression.

The Mechanism

The rs12248560 variant²² C>T at position -806 in the promoter region alters a transcription factor binding site in the CYP2C19 promoter, increasing gene expression by approximately 2-fold. More enzyme means faster metabolism of all CYP2C19 substrates. Homozygous carriers (TT) are classified as ultrarapid metabolizers, while heterozygous carriers (CT) are rapid metabolizers. The variant was first characterized by Sim et al. in 2006³³ Sim et al. in 2006
Sim SC et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism. Clin Pharmacol Ther, 2006.

Clinical Implications

For proton pump inhibitors (PPIs), rapid and ultrarapid metabolizers break down the drug too quickly, potentially leading to inadequate acid suppression. Standard PPI doses may not effectively control acid reflux or heal ulcers. Higher doses or alternative medications may be needed. The CPIC guideline for PPIs⁴⁴ CPIC guideline for PPIs
Lima JJ et al. CPIC guideline for CYP2C19 and proton pump inhibitor dosing. Clin Pharmacol Ther, 2021 recommends increasing PPI doses by 50-100% for ultrarapid metabolizers.

For clopidogrel, increased CYP2C19 activity is actually beneficial because more prodrug gets converted to the active metabolite, enhancing the antiplatelet effect. However, this could theoretically increase bleeding risk.

The Diplotype Complexity

Your overall CYP2C19 status depends on the combination of both alleles. Someone carrying *2/*17 (one loss-of-function, one gain-of-function) presents a classification challenge - current guidelines generally classify this as intermediate metabolizer status, though the clinical impact may vary by medication.

Practical Considerations

If you are a rapid or ultrarapid metabolizer, pay attention to PPI effectiveness. If standard doses of omeprazole or pantoprazole do not adequately control your acid reflux symptoms, your CYP2C19 genotype may be the reason. Discuss with your doctor about dose adjustments or alternative acid-suppressing medications that are not CYP2C19 substrates.