Wednesday, October 15, 2014

The genetics of warfarin dose: focus on African Americans

Warfarin has a narrow therapeutic window, therefore it is important to get the dosage for a patient correct - too low or too high a dose can have dangerous consequences. However, there is large interindividual variability in dose. Incorporation of a patient's genotypes at the polymorphisms CYP2C9*2 (C>T at rs1799853), CYP2C9*3 (A>C at rs1057910) and VKORC1 (G>A at rs9923231) into a dosing algorithm can help better predict the warfarin dose required by an individual (see the CPIC dosing guideline).

These three variants are rare in African American and African populations, and thus a larger percentage of variability in warfarin dosage remains unexplained in these patients compared to White individuals (see commentary below). There is therefore a need to identify genetic variants found in African Americans and Africans that could be used to enhance prediction of dosage in these patients.

A study in this month's issue of Blood outlines an exome sequencing project in African Americans that revealed a novel variant in the FPGS gene associated with warfarin dose. The G allele of rs7856096 was significantly associated with lower warfarin dose in both the discovery and independent replication cohorts of African American patients. This allele was shown to be most prevalent in populations on the African continent, and found at a frequency of around 0.2 in the discovery and replication cohorts. Adding this variant to the IWPC dosing algorithm helped to explain an additional 3.3% of dose variability in the combined cohort of African Americans. Preliminary functional analysis showed that the G allele may result in reduced FPGS expression. FPGS encodes an enzyme involved in folate homeostasis - though the biological mechanism behind the association with warfarin dose has yet to be investigated, the authors discuss that folate can affect warfarin metabolism and coagulation status.

Read the commentary:
Warfarin pharmacogenetics: it matters if you're black or white
Wadelius M. Blood. 2014 Oct 2;124(14):2171.

Read the article: 
Daneshjou R, Gamazon ER, Burkley B, Cavallari LH, Johnson JA, Klein TE, Limdi N, Hillenmeyer S, Percha B, Karczewski KJ, Langaee T, Patel SR, Bustamante CD, Altman RB, Perera MA. Blood. 2014 Oct 2;124(14):2298-305.