Siu Weng-Sam, Maruf Abdullah Al, Shaheen Sarker M, McCloud Ryden, Heintz Madison, McAusland Laina, Arnold Paul D, Bousman Chad A
Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Clin Pharmacol Ther. 2025 Apr 27. doi: 10.1002/cpt.3697.
Concerns about the applicability of pharmacogenetic (PGx) testing across diverse ancestry groups have risen from the underrepresentation of non-European populations in PGx research. Current PGx panels may fail to detect relevant variants in non-European populations, increasing the likelihood of false-negative results. To investigate this, we assessed reference allele (*1) and genotype (*1/*1) frequencies by self-reported ancestry in a cohort of 1086 youth aged 6-24 years who underwent PGx testing. Testing included 10 pharmacogenes (CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, NUDT15, SLCO1B1, TPMT, and VKORC1) using a panel covering all Association for Molecular Pathology Tier 1 alleles and 53% of Tier 2 alleles. Compared with Europeans (n = 727), non-Europeans (n = 359) had higher *1 allele frequencies for CYP2C9, CYP2D6, and CYP3A5 (all P < 0.01), while Europeans had higher frequencies for CYP2C19 and VKORC1 (all P < 0.01). Similarly, *1/*1 genotype frequencies were higher in non-Europeans for CYP2C9 and CYP3A4 (all P < 0.01), but higher in Europeans for VKORC1 (P < 0.01). False-negative estimates exceeded 1% for CYP2B6, CYP2D6, CYP2C9, CYP2C19, and SLCO1B1 in at least one ancestry group. These findings support the notion that *1 allele and *1/*1 genotype frequencies are more frequent in non-Europeans for specific genes, but Europeans are also at comparable risk for false-negative results. Expanded allele coverage on PGx panels could mitigate false-negative risks, improving equity in PGx testing across diverse populations.
由于非欧洲人群在药物遗传学（PGx）研究中的代表性不足，人们对PGx检测在不同血统群体中的适用性越来越担忧。当前的PGx检测 panel 可能无法检测出非欧洲人群中的相关变异，从而增加了假阴性结果的可能性。为了对此进行研究，我们在一个接受PGx检测的1086名6至24岁青少年队列中，根据自我报告的血统评估了参考等位基因（*1）和基因型（1/1）频率。检测包括10个药物代谢酶基因（CYP2B6、CYP2C19、CYP2C9、CYP2D6、CYP3A4、CYP3A5、NUDT15、SLCO1B1、TPMT和VKORC1），使用的检测 panel 涵盖了所有分子病理学协会一级等位基因以及53%的二级等位基因。与欧洲人（n = 727）相比，非欧洲人（n = 359）在CYP2C9、CYP2D6和CYP3A5基因上的1等位基因频率更高（所有P < 0.01），而欧洲人在CYP2C19和VKORC1基因上的频率更高（所有P < 0.01）。同样，非欧洲人在CYP2C9和CYP3A4基因上的1/*1基因型频率更高（所有P < 0.01），但欧洲人在VKORC1基因上的频率更高（P < 0.01）。在至少一个血统群体中，CYP2B6、CYP2D6、CYP2C9、CYP2C19和SLCO1B1的假阴性估计超过1%。这些发现支持了这样一种观点，即对于特定基因，1等位基因和1/*1基因型频率在非欧洲人中更为常见，但欧洲人也面临着相当的假阴性结果风险。扩大PGx检测 panel 上的等位基因覆盖范围可以降低假阴性风险，提高不同人群中PGx检测的公平性。
