Monday, August 29, 2022

Study of vitamin K pathways presents potential new warfarin candidates

Almost two decades after the cloning of VKORC1 and association with warfarin dose, a new pathway of vitamin K cycling has been published. Mishima et al [PMID:35922516] report on the Ferroptosis suppressor protein 1 (FSP1), coded for by the AIFM2 gene, and its mechanism of maintaining vitamin K in the hydroquinone form. While not interacting directly with warfarin, AIFM2 may play a role in vitamin K-related branches in the warfarin PD pathway that warrant investigation for PGx. 

A review of several ferroptosis related proteins (Vabulas, 2021) discusses some variants of AIFM2. The review mentions a functional study of E156A in the FAD cofactor binding domain that found it impaired anti-ferroptotic activity. This variant is not found in dbSNP. A different amino acid change, E156D (rs1272224219C>A), has not been observed in the ALFA populations that dbSNP reports on, while yet another amino acid change, E156V (rs760393626T>A), is extremely rare (found in 1/121216 alleles). The review lists 2 other potential AIFM2 candidates for functional investigation which are more frequently observed: M135T (mapped by PharmGKB to rs10999147A>G) and D288N (mapped to rs2271694C>T).

(Edited 9/20/22) The Warfarin Pathway, Pharmacodynamics has been updated to include the new candidate gene.