TY - JOUR
T1 - Full-gene haplotypes refine CYP2D6 metabolizer phenotype inferences
AU - Wendt, Frank R.
AU - Sajantila, Antti
AU - Moura-Neto, Rodrigo S.
AU - Woerner, August E.
AU - Budowle, Bruce
N1 - Publisher Copyright:
© 2017, Springer-Verlag GmbH Germany.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - CYP2D6 is a critical pharmacogenetic target, and polymorphisms in the gene region are commonly used to infer enzyme activity score and predict resulting metabolizer phenotype: poor, intermediate, extensive/normal, or ultrarapid which can be useful in determining cause and/or manner of death in some autopsies. Current genotyping approaches are incapable of identifying novel and/or rare variants, so CYP2D6 star allele definitions are limited to polymorphisms known a priori. While useful for most predictions, recent studies using massively parallel sequencing data have identified additional polymorphisms in CYP2D6 that are predicted to alter enzyme function but are not considered in current star allele nomenclature. The 1000 Genomes Project data were used to produce full-gene haplotypes, describe their distribution in super-populations, and predict enzyme activity scores. Full-gene haplotypes generated lower activity scores than current approaches due to inclusion of additional damaging polymorphisms in the star allele. These findings are critical for clinical implementation of metabolizer phenotype prediction because a fraction of the population may be incorrectly considered normal metabolizers but actually may be poor or intermediate metabolizers.
AB - CYP2D6 is a critical pharmacogenetic target, and polymorphisms in the gene region are commonly used to infer enzyme activity score and predict resulting metabolizer phenotype: poor, intermediate, extensive/normal, or ultrarapid which can be useful in determining cause and/or manner of death in some autopsies. Current genotyping approaches are incapable of identifying novel and/or rare variants, so CYP2D6 star allele definitions are limited to polymorphisms known a priori. While useful for most predictions, recent studies using massively parallel sequencing data have identified additional polymorphisms in CYP2D6 that are predicted to alter enzyme function but are not considered in current star allele nomenclature. The 1000 Genomes Project data were used to produce full-gene haplotypes, describe their distribution in super-populations, and predict enzyme activity scores. Full-gene haplotypes generated lower activity scores than current approaches due to inclusion of additional damaging polymorphisms in the star allele. These findings are critical for clinical implementation of metabolizer phenotype prediction because a fraction of the population may be incorrectly considered normal metabolizers but actually may be poor or intermediate metabolizers.
KW - CYP2D6
KW - Full-gene haplotypes
KW - Massively parallel sequencing
KW - Metabolizer phenotype
UR - http://www.scopus.com/inward/record.url?scp=85032348251&partnerID=8YFLogxK
U2 - 10.1007/s00414-017-1709-0
DO - 10.1007/s00414-017-1709-0
M3 - Article
C2 - 29075918
AN - SCOPUS:85032348251
SN - 0937-9827
VL - 132
SP - 1007
EP - 1024
JO - International Journal of Legal Medicine
JF - International Journal of Legal Medicine
IS - 4
ER -