Department of Pharmacy Practice and Administrative Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA.
Pfizer Global Research, Groton, Connecticut, USA.
Clin Transl Sci. 2022 Feb;15(2):558-566. doi: 10.1111/cts.13176. Epub 2021 Nov 2.
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 ). Other SNPs were identified in chromosome 10 at a p value less than 1 × 10 . 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.
迄今为止，中东和北非（MENA）地区尚未进行全基因组关联研究（GWAS），以使用这种方法鉴定与华法林剂量变异性相关的遗传变异。在这项研究中，我们旨在对 MENA 地区的患者进行华法林剂量需求的首次 GWAS。总共对 132 名卡塔尔人（发现队列）和 50 名埃及人（复制队列）进行了 Illumina 多民族全球珠芯片阵列基因分型。对研究人群中经对数转换的每周华法林剂量进行了 GWAS，调整了临床特征和祖源。在埃及队列中测试了发现队列中的全基因组信号。还对包括卡塔尔和埃及队列在内的 GWAS 进行了荟萃分析，并在基因分析中使用了该分析的结果。在卡塔尔的发现分析中，在 16 号染色体上鉴定出了五个全基因组单核苷酸多态性（SNP）。这些信号在埃及队列中得到了复制。通过 GWAS 荟萃分析结合这两个数据，加强了与 VKORC1 rs9934438 相关的染色体 16 上的关联，该基因是全基因组的主要信号（β=-0.17，6×10）。在染色体 10 上还鉴定出了其他 SNP，其 p 值小于 1×10。VKORC1 rs9934438 和 CYP2C9 rs4086116 内的遗传变异分别解释了卡塔尔人和埃及人每周华法林剂量需求变异性的 39%和 27%。这是 MENA 地区华法林剂量变异性的首次 GWAS。它证实了 VKORC1 和 CYP2C9 变异在 MENA 地区患者的华法林剂量变异性中的重要性。
