Genomewide association analysis of warfarin dose requirements in Middle Eastern and North African populations

Abstract

To date, there has been no genomewide association study (GWAS) from the Middle East and North African (MENA) region to identify genetic variants associated with warfarin dose variability using this approach. In this study, we aimed to conduct the first GWAS of warfarin dose requirements in patients from the MENA region. A total of 132 Qatari (discovery) and 50 Egyptians (replication) were genotyped using Illumina Multi‐Ethnic Global BeadChip Array. A GWAS was performed on log‐transformed weekly warfarin dose in the studied population, adjusting for clinical characteristics and ancestry. The genomewide signals from the discovery cohort were tested in the Egyptian cohort. A GWAS meta‐analysis, including the Qatari and Egyptian cohorts, was also performed and the output from this analysis was used in a gene‐based analysis. The discovery analysis in Qatari identified five genomewide single‐nucleotide polymorphisms (SNPs) in chromosome 16. These signals were replicated in the Egyptian cohort. Combining the two data through a GWAS meta‐analysis strengthened the association in chromosome 16 with VKORC1 rs9934438 being the lead genomewide signal (β = −0.17, 6 × 10−15). Other SNPs were identified in chromosome 10 at a p value less than 1 × 10−5. The genetic variants within VKORC1 rs9934438 and CYP2C9 rs4086116 explained 39% and 27% of the variability in the weekly warfarin dose requirement in the Qatari and Egyptians, respectively. This is the first GWAS of warfarin dose variability in the MENA region. It confirms the importance of VKORC1 and CYP2C9 variants in warfarin dose variability among patients from the MENA region.

Forging the path to precision medicine in Qatar: a public health perspective on pharmacogenomics initiatives

“…The genetic variants within VKORC1 rs9934438 and CYP2C9 rs4086116 explained 39 and 27% of the variability in the weekly warfarin dose requirement in the Qatari and Egyptians, respectively. These results are consistent with previous studies that have shown that VKORC1 and CYP2C9 are the main genetic factors influencing warfarin dose response ( 34 ).…”

Ethnic Diversity and Warfarin Pharmacogenomics

“…Genome-wide association studies have confirmed that the most important warfarin pharmacogenomic variants are found in two genes, CYP2C9 and VKORC1 ( Cooper et al, 2008 ; Takeuchi et al, 2009 ; Cha et al, 2010 ; Perera et al, 2013 ; Parra et al, 2015 ; El Rouby et al, 2021 ). It is also known that the most important variants will differ between populations, which has been mainly attributed to differences in minor allele frequencies (MAFs) of these variants ( Cavallari and Perera, 2012 ; Johnson et al, 2017 ).…”

“…Whereas pharmacogenomic algorithms that incorporate both genetic and non-genetic factors can account for about half of the variability in warfarin daily dose requirements in Whites ( Table 1 ), they explain only about a third in Blacks, meaning that Blacks and other underrepresented populations could benefit from more studies to identify additional genetic variants. Although the majority of previous association studies used a candidate-gene approach, genome-wide association studies (GWASs) ( Cooper et al, 2008 ; Takeuchi et al, 2009 ; Cha et al, 2010 ; Perera et al, 2013 ; Parra et al, 2015 ; El Rouby et al, 2021 ) which systematically search the entire genome for new genetic factors have also been undertaken. One study in particular ( Perera et al, 2013 ) was able to identify a new genetic variant ( CYP2C rs12777823) that significantly altered dose requirements independent of the effects of CYP2C9*2 , CYP2C9*3 , and VKORC1 -1639G > A .…”

Genome-Wide Studies in Ischaemic Stroke: Are Genetics Only Useful for Finding Genes?

“…The effect of genetics on bleeding events in patients treated with this drug was also assessed. Four genetic variants increasing the expression of EPHA7 gene were found in the African American population, where the incidence of bleeding in patients treated with warfarin is higher [ 134 ].…”