Contrasting exome constancy and regulatory region variation in the gene encoding CYP3A4

Abstract

Ethiopia contained 60 CYP3A4 variants (26 novel) and more variants (>1%) than all non-African populations combined. No nonsynonymous mutation was found in the homozygous form or at more than 2.8% in any population. Seventy-nine per cent of haplotypes contained 3'UTR and/or regulatory region variation with striking pairwise population differentiation, highlighting the potential for interethnic variation in CYP3A4 expression. Conversely, coding region variation showed that significant interethnic variation is unlikely at the protein level. CYP3A7*1C was found at up to 17.5% in North African populations and in significant linkage disequilibrium with CYP3A5*3, indicating that adult expression of the foetal isoform is likely to be accompanied by reduced or null expression of CYP3A5.

Allele and genotype frequencies of CYP3A4, CYP3A5, CYP3A7, and GSTP1 gene polymorphisms among mainland Tibetan, Mongolian, Uyghur, and Han Chinese populations

“…The LD of the CYP3A4 and CYP3A5 alleles in Caucasian and American-African populations has been reported previously, and the LD of the CYP3A7 and CYP3A5 alleles in Ethiopia has also been identified. 4,12,45 However, to the best of our knowledge, the present study is the first to report the LD of the CYP3A4, CYP3A5, and CYP3A7 alleles in mainland Tibetan, Mongolian, and Uyghur populations.…”

The genetic landscape of Ethiopia: diversity, intermixing and the association with culture

“…More recently, the analysis of genomic variation in the peoples of Ethiopia has been used, together with information from other sources, to test hypotheses on possible migration routes at both 'Out of Africa' and more recent 'Migration into Africa' timescales (Pagani et al, 2015, Gallego-Llorente et al, 2015. The high genetic diversity in Ethiopians facilitates the identification of novel variants, and this has led to the inclusion of Ethiopian data in studies of the genetics of elite athletes (Rankinen et al, 2016, Ash et al, 2011, Scott et al, 2005, adaptation to living at high elevation (Huerta-Sanchez et al, 2013, Stobdan et al, 2015, Simonson, 2015, Ronen et al, 2014, Scheinfeldt et al 2012, milk drinking (Liebert et al, 2017, Jones et al, 2013, Ingram et al, 2009 and drug metabolising enzymes (Creemer et al, 2016, Browning et al, 2010, Sim et al, 2006.…”

Group-based pharmacogenetic prediction: is it feasible and do current NHS England ethnic classifications provide appropriate data?

“…There is well documented interethnic variation in allelic distribution of genes affecting drug metabolism, with metabolising enzymes, receptors and transporters all implicated [11][12][13] . Genetic variation in drug metabolising enzymes (DMEs) that occurs at significantly different frequencies 14 or is private to definable populations 12 may result in varying risk for a given ADR.…”

“…There is well documented interethnic variation in allelic distribution of genes affecting drug metabolism, with metabolising enzymes, receptors and transporters all implicated [11][12][13] . Genetic variation in drug metabolising enzymes (DMEs) that occurs at significantly different frequencies 14 or is private to definable populations 12 may result in varying risk for a given ADR. Ethnic identity has therefore been proposed as a source of information in medicinal intervention 15 , as a potentially useful indicator for assigning patients into groups at high and low risk of ADR, and has already been used to select patients for genetic testing to prevent ADRs prior to the administration of carbamazepine 16 .…”