CYP2D6 is one of the most studied enzymes in the field of pharmacogenetics. The CYP2D6 gene is highly polymorphic with over 100 catalogued star (*) alleles, and clinical CYP2D6 testing is increasingly accessible and supported by practice guidelines. However, the degree of variation at the CYP2D6 locus and homology with its pseudogenes make interrogating CYP2D6 by short-read sequencing challenging. Moreover, accurate prediction of CYP2D6 metabolizer status necessitates analysis of duplicated alleles when an increased copy number is detected. These challenges have recently been overcome by long-read CYP2D6 sequencing; however, such platforms are not widely available. This review highlights the genomic complexities of CYP2D6, current sequencing methods and the evolution of CYP2D6 from allele discovery to clinical pharmacogenetic testing.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden¹. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence². Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Warfarin is an oral anticoagulant widely used for thromboembolic disease prophylaxis. The pharmacokinetics and pharmacodynamics of this drug vary with environmental and genetic factors. Several algorithms including genetic and non‐genetic factors have been developed for different populations. These investigations have shown that polymorphisms in CYP2C9 and VKORC1 genes are related to warfarin dose variation. WHAT THIS STUDY ADDS • This study confirms that CYP2C9 and VKORC1 genes are the main predictors of warfarin dose, but there are other genes with smaller effects that can improve the algorithm for better dose prediction.• This study observed for the first time an effect of the F2 gene on warfarin dose prediction.• The inclusion for the first time of co‐medication with amlodipine, carbamazepine, β‐adrenoceptor blockers and diuretics refined the construction of an algorithm for dose prediction.AIMS To investigate the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2 and F2 genes on warfarin dose–response and develop a model including genetic and non‐genetic factors for warfarin dose prediction needed for each patient.METHODS A total of 279 patients of European ancestry on warfarin medication were investigated. Genotypes for −1639G>A, 1173C>T, and 3730G>A SNPs in the VKORC1 gene, CYP2C9*2 and CYP2C9*3, 1347C>T in the CYP4F2 gene and 494C>T in the F2 gene were determined by allelic discrimination with Taqman 5'‐nuclease assays.RESULTS The CYP2C9*2 and CYP2C9*3 polymorphisms in the CYP2C9 gene, −1639G>A and 1173C>T in the VKORC1 gene and 494C>T in the F2 gene are responsible for lower anticoagulant doses. In contrast, 1347C>T in the CYP4F2 gene and 3730G>A in the VKORC1 gene are responsible for higher doses of warfarin. An algorithm including genetic, biological and pharmacological factors that explains 63.3% of warfarin dose variation was developed.CONCLUSION The model suggested has one of the highest coefficients of determination among those described in the literature.

Aim: Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians. Methods: Patients receiving low (≤20 mg/week; n = 180) or high stable warfarin doses (≥42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom® Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project. Results: Genome-wide signals (p ≤ 5 × 10-8) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10-33) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 10-13) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study. Conclusion: We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015