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Towards solving the missing heritability in pharmacogenomics
Medicine. By analyzing and interpreting one’s genetic profile dose and drug adjustments
can be made. In this way, one can strive to improve the safety and efficacy of drug
treatments. Nonetheless, not all genetic variability in drug response can be explained with
current PGx. In this thesis we explore the role of additional genetic factors which can explain this missing heritability. Firstly, rare and novel variants which are unaccounted for in routine PGx panels might play a role. Secondly, the complexity of pharmacogenes can result in an inability to
unravel the genetic make-up of these genes. Thirdly, haplotype phasing is generally not
taken into account in PGx. Fourthly, all genetic variants are currently summarized into
one of four metabolic categories: poor metabolizers (PM), intermediate metabolizers
(IM), normal metabolizers (NM) (previously EM)...Show morePharmacogenomics (PGx) is widely recognized as an important aspect in personalized
Medicine. By analyzing and interpreting one’s genetic profile dose and drug adjustments
can be made. In this way, one can strive to improve the safety and efficacy of drug
treatments. Nonetheless, not all genetic variability in drug response can be explained with
current PGx. In this thesis we explore the role of additional genetic factors which can explain this missing heritability. Firstly, rare and novel variants which are unaccounted for in routine PGx panels might play a role. Secondly, the complexity of pharmacogenes can result in an inability to
unravel the genetic make-up of these genes. Thirdly, haplotype phasing is generally not
taken into account in PGx. Fourthly, all genetic variants are currently summarized into
one of four metabolic categories: poor metabolizers (PM), intermediate metabolizers
(IM), normal metabolizers (NM) (previously EM) and ultra-rapid metabolizers (UM).
However, enzyme activity is not a matter of ‘on’ or ‘off ’, but is more of a continuous scale.
Finally, the effect of a genetic variant on drug metabolism shows substrate specific effects.
This substrate specificity can result in erroneous extrapolation of variant effects to the
entire range of substrates. The development of novel technologies to determine one’s
genetic make-up is evolving rapidly, thereby providing opportunities for the field of PGx
to address these issues. In this thesis we show that by using long-read sequencing or trio-based sequencing more information can be obtained which can lead to a better understanding of the (rare) variants and can help with haplotype phasing. Moreover, we have shown that by combining long-read sequencing with artificial intelligence a substantial increase in explained variability can be achieved.Show less
- All authors
- Lee, M. van der
- Supervisor
- Guchelaar, H.J.
- Co-supervisor
- Swen, J.J.; Kriek, M.
- Committee
- Baas, F.; Heijmans, B.T.; Lange, E.C.M. de; Schaik, R.H.N. van
- Qualification
- Doctor (dr.)
- Awarding Institution
- Faculty of Medicine, Leiden University Medical Center (LUMC) , Leiden University
- Date
- 2022-01-19
- ISBN (print)
- 9789490791995
Funding
- Sponsorship
- The research presented in this thesis was performed at the department of Clinical Pharmacy and Toxicology of Leiden University Medical Center, Leiden, The Netherlands. Financial support for the publication of this thesis was provided by Afdelingsfonds Klinische Farmacie & Toxicologie. The research leading to these results has received funding from the European Community’s Horizon 2020 Programme under grant agreement No.668353 (U-PGx) and from the ZonMw enabling Technologies Hotel grant under agreement No.435004018.