Genome-Wide Approaches in Pharmacogenomics: Heritability Estimation and Pharmacoethnicity as Primary challenges

Unravelling the transcriptomic landscape of the major phase II UDP-glucuronosyltransferase drug metabolizing pathway using targeted RNA sequencing

“…Undeniably, the high levels of sequence identity and dense genetic variability found within UGT loci represent the most important challenge. 19,20 Large-scale parallel pyrosequencing, a technology providing longer reads that encompass several exon-exon junctions, coupled to the use of two mapping softwares as well as a well-defined manual curation process have collectively greatly enhanced the precise assignment of reads to the appropriate UGT loci and transcript reconstruction. However, we cannot exclude that some of the less frequent exon-exon junctions arise from mapping errors.…”

“…However, investigating these pharmacogenes using nextgeneration sequencing technologies is challenging, 19,20 owing to the high polymorphic nature, 2 the high sequence identity reaching up to 97%, and the proximity of these genes within the UGT loci (Figures 1-2). We applied next-generation RNA sequencing (RNA-Seq) to collections of UGT mRNAs captured with UGT-specific designed probes from pools of drug metabolizing (DM) tissues including liver, kidney, intestine and colon, as well as hormone dependent (HD) tissues comprising prostate, breast and uterus.…”

Polymorphisms of ADME-related genes and their implications for drug safety and efficacy in Amazonian Amerindians

“…The discovery that the response to and tolerance of drugs may vary not only among individuals, but systematically among populations, in particular among different ethnic groups, had a fundamental impact on pharmacogenetic studies, leading to the development of the field of Pharmacoethnicity 4–6 . The principal determinant of this interethnic variability is the allelic frequencies of the polymorphisms found in pharmacogenes, which may vary considerably among different ethnic groups 7–9 .…”

Ethnic Identifiers are Not Necessarily Excellent Population Identifiers: A Commentary from the Turkana in North-Western Kenya

“…Since most medical and even evolutionary decisions are done on the basis of populations' ethnic labels, it is probable that the existing genetic diversity and structure are ignored (Risch et al, 2002;Race, Ethnicity, and Genetics Working Group, 2005;Dries, 2009;Campbell and Tishkoff, 2010;Gamazon and Perera, 2012). With such omissions, it is plausible that most of the reference populations used in evolutionary studies might not be representative enough and by extension the conclusions too end up being inaccurate (Reich et al, 2001;Risch et al, 2002).…”

“…From a medical perspective, it is likely that wrong therapeutic agents are administered onto populations following pharmacogenetic assumptions based on such 'faulty' ethnic identifiers which don't take the population's possible genetic diversity and structure into account. With the advent of personalised medicine, it is critical that populations are widely characterised using neutral genetic markers devoid of any ascertainment bias with respect to the populations studied and probably even the use of whole genome sequences might soon be feasible (Nebert and Menon, 2001;Foster and Sharp, 2004;Ma and Lu, 2011;Gamazon and Perera, 2012). This will possibly report on the true genetic heterogeneity and structure within populations before any further specific pharmacogenetic studies can be instituted (Daar and Singer, 2005).…”