Expressive

rs1057910 (CYP2C9 *3): Warfarin Dose Metabolism

Key takeaways

  • rs1057910 (CYP2C9 *3) is a non-synonymous variant in the gene encoding cytochrome P450 2C9, the primary enzyme that metabolizes the anticoagulant drug warfarin.
  • The CYP2C9 *2 and *3 alleles together explain roughly 12% of the 20-fold range in warfarin dose requirements seen across patients.
  • Combined with VKORC1 variants, CYP2C9 accounts for about 40% of warfarin dose variance, confirmed in a genome-wide study of 1,053 Swedish patients.
  • GTEx data show the alternate allele at rs1057910 is linked to increased expression of CYP2C9 and ACSM6 across several tissues.

Key takeaways

  • rs1057910 (CYP2C9 *3) is a non-synonymous variant in the gene encoding cytochrome P450 2C9, the primary enzyme that metabolizes the anticoagulant drug warfarin.
  • The CYP2C9 *2 and *3 alleles together explain roughly 12% of the 20-fold range in warfarin dose requirements seen across patients.
  • Combined with VKORC1 variants, CYP2C9 accounts for about 40% of warfarin dose variance, confirmed in a genome-wide study of 1,053 Swedish patients.
  • GTEx data show the alternate allele at rs1057910 is linked to increased expression of CYP2C9 and ACSM6 across several tissues.

What the research says rs1057910 marks the *3 allele of CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9), which encodes a key enzyme that metabolizes warfarin, the most widely prescribed anticoagulant. A genome-wide association study (GWAS) of 1,053 Swedish warfarin patients confirmed CYP2C9 as one of the principal genetic determinants of required dose, with univariate association p-values below 10^-31. The two non-synonymous CYP2C9 SNPs known as *2 and *3 account for approximately 12% of the variance in warfarin dose, and when combined with variants in VKORC1 (vitamin K epoxide reductase complex, subunit 1), the explained variance rises to approximately 40%.

Reported associations

  • Warfarin dose variance (CYP2C9 alone): The *2 and *3 alleles of this gene together explain approximately 12% of the interindividual variation in required warfarin dose, measured in a GWAS of 1,053 Swedish patients.
  • Warfarin dose variance (CYP2C9 combined with VKORC1): Variants in CYP2C9 paired with variants in VKORC1 explain approximately 40% of warfarin dose variance; non-genetic factors such as age and sex contribute an additional approximately 15%.

Evidence quality The primary evidence comes from a GWAS of 1,053 Swedish warfarin patients in which the CYP2C9 association reached p-values below 10^-31, far exceeding the genome-wide significance threshold applied in the study (p<1.5x10^-7). The same study included a replication cohort of 588 additional Swedish patients, used primarily to confirm a separate finding in CYP4F2. The study was designed with 80% statistical power to detect common variants explaining at least 1.5% of dose variance, meaning smaller effects could have been missed. The authors characterize the CYP2C9 and VKORC1 associations as "robust and now widely replicated" within the study text, though the available data are drawn from a single ethnically homogeneous population (Swedish), which limits generalizability. No conflicting findings regarding CYP2C9 and warfarin dose are reported in the provided materials.

Tissue-specific expression effects

  • ACSM6: The alternate allele at rs1057910 is associated with increased expression in subcutaneous adipose tissue, visceral adipose tissue, kidney cortex, esophageal junction, breast mammary tissue, coronary artery, and prostate. GTEx Portal
  • CYP2C9: The alternate allele is associated with increased expression in subcutaneous adipose tissue. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs1057910 and what does it affect?

rs1057910 is the identifier for the CYP2C9 *3 allele, a variant in the gene encoding cytochrome P450 2C9, the enzyme that breaks down the blood-thinning drug warfarin. Variation at this position influences how quickly the enzyme processes the drug.

How much of warfarin dose variation does CYP2C9 explain?

The two main CYP2C9 variants (*2 and *3) together account for approximately 12% of the interindividual variation in required warfarin dose, based on a genome-wide study of 1,053 patients. When combined with VKORC1 variants, the two genes together explain roughly 40% of dose variance.

What is the CYP2C9 gene?

CYP2C9 encodes the enzyme cytochrome P450 2C9, which breaks down several drugs in the body, including the anticoagulant warfarin. Variants in this gene can affect how quickly these drugs are processed.

Is rs1057910 the same as CYP2C9 *3?

Yes. rs1057910 is the SNP identifier for the CYP2C9 *3 allele, a non-synonymous variant that changes the amino acid sequence of the CYP2C9 enzyme and is known to influence warfarin metabolism.

What tissues show expression changes linked to rs1057910?

GTEx data show the alternate allele at rs1057910 is linked to increased CYP2C9 expression in subcutaneous adipose tissue, and to increased expression of the nearby ACSM6 gene across subcutaneous and visceral adipose tissue, kidney cortex, esophagus, breast, coronary artery, and prostate.