The Identification of Novel CYP2D6 Variants in US Hmong: Results From Genome Sequencing and Clinical Genotyping

• Published in: Frontiers in pharmacology Vol. 13; p. 867331
• Main Authors: Wen, Ya Feng, Gaedigk, Andrea, Boone, Erin C, Wang, Wendy Y, Straka, Robert J
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 21-03-2022
• Subjects: CYP2D6; ethnic variability; minority health; pharmacogenetics; Pharmacology; population genetics; targeted exome sequencing; population genetics; CYP2D6; minority health; Hmong; ethnic variability; pharmacogenetics; targeted exome sequencing
• DOI: 10.3389/fphar.2022.867331
• EISSN: 1663-9812

Hmong individuals represent a unique East Asian subpopulation in whom limited information concerning pharmacogenetic variation exists. The objectives of this study were to comprehensively characterize the highly polymorphic
gene in Hmong, estimate allele and phenotype frequencies and to compare results between two testing platforms.
DNA from 48 self-identified Hmong participants were sequenced using a targeted next-generation sequencing (NGS) panel. Star allele calls were made using Astrolabe, manual inspection of NGS variant calls and confirmatory Sanger sequencing. Structural variation was determined by long-range (XL)-PCR and digital droplet PCR (ddPCR). The consensus diplotypes were subsequently translated into phenotype utilizing the activity score system. Clinical grade pharmacogenetic testing was obtained for 12 of the 48 samples enabling an assessment of concordance between the consensus calls and those determined by clinical testing platforms.
A total of 13
alleles were identified. The most common alleles were
and its structural arrangements (37.5%, 36/96) and the
gene deletion (13.5%, 13/96). Three novel suballeles (
,
, and
) were also identified. Phenotype frequencies were as follows: ultrarapid metabolizers (4.2%, 2/48), normal metabolizers (41.7%, 20/48) and intermediate metabolizers (52.1%, 25/48); none of the 48 participants were predicted to be poor metabolizers. Concordance of diplotype and phenotype calls between the consensus and clinical testing were 66.7 and 50%, respectively.
Our study to explore
genotypes in the Hmong population suggests that this subpopulation is unique regarding
allelic variants; also, a higher portion of Hmong participants (50%) are predicted to have an intermediate metabolizer phenotype for CYP2D6 compared to other East Asians which range between 27 and 44%. Results from different testing methods varied considerably. These preliminary findings underscore the importance of thoroughly interrogating unique subpopulations to accurately predict a patient's
metabolizer status.