9 December 2020
Some Saudi patients could require higher doses of the blood-thinning drug warfarin because of genetic variance, according to a KAIMRC study. Other factors also affect the correct dosage, highlighting the need for an algorithm to aid clinicians determine dosage.
Warfarin is used around the world to prevent dangerous blood clots. However, patient response to warfarin varies widely, and scientists believe that individual genetic variations influence the way the drug works in the body.
“Dosing and effectiveness of warfarin have been widely tested in patients, but most pharmacogenetic studies have been conducted in European-centred populations, not on Middle-Eastern patients,” says Jahad Alghamdi of KAIMRC’s Saudi Biobank. “There are several genotype-guided dosing algorithms available to determine the correct dose to offer, but their applicability to our population is questionable.”
Indeed, there may even be genotypic differences within the Arab population that affect warfarin effectiveness. Alghamdi, together with collaborators across Saudi Arabia, collated and studied the largest cohort of Saudi warfarin users to date – 936 people – to begin identifying the genetic factors that contribute to warfarin effectiveness in the Saudi population. The Saudi WArfarin Pharmacogenetic (SWAP) cohort will also form the basis for future warfarin studies in the Kingdom.
Warfarin works by blocking the production of vitamin K to make blood clot more slowly. Its target is a product of the VKORC1 gene, the VKORC1 enzyme, which is a key enzyme in the vitamin K cycle. People with a mutation in this gene might have reduced VKORC1 activity, meaning the required dose of warfarin will be lower, while in other patients the opposite might be the case.
Genetic variations in VKORC1 explain up between 40 and 50 per cent of dose variability. “We sought to determine the effect of one particular VKORC1 variant on warfarin responsiveness in our population. We found that patients with this variant required a higher warfarin dose and took a longer time to achieve a stable blood clotting ratio than other patients,” says Alghamdi.
The team also found that patient age, weight, and certain metrics of liver function were important factors to be considered when prescribing warfarin in the Saudi population.
“Our target goal is to translate these findings into clinical practice by developing a genotype-guided dosing algorithm that is specifically suited to the Saudi population,” says Alghamdi. “We are now working to identify further prevalent and rare variants that may explain more of the observed differences in warfarin responsiveness in the Saudi population to help us refine the algorithm and maximize its accuracy.”
- Al Ammari, M., AlBalwi, M., Sultana, K., Alabdulkareem, I.B., Almuzzaini, B., Almakhalifa, N.S., Aldrees, M., & Alghamdi, J. The effect of VKORC1 promoter variant on warfarin responsiveness in the Saudi Warfarin Pharmacogenetic (SWAP) cohort. Scientific Reports (2020) | article