The varying frequencies of pharmacogenetic alleles among populations have important implications for the impact of these alleles in different populations. Current population grouping methods to communicate these patterns are insufficient as they are inconsistent and fail to reflect the global distribution of genetic variability. To facilitate and standardize the reporting of variability in pharmacogenetic allele frequencies, we present seven geographically defined groups: American, Central/South Asian, East Asian, European, Near Eastern, Oceanian, and Sub‐Saharan African, and two admixed groups: African American/Afro‐Caribbean and Latino. These nine groups are defined by global autosomal genetic structure and based on data from large‐scale sequencing initiatives. We recognize that broadly grouping global populations is an oversimplification of human diversity and does not capture complex social and cultural identity. However, these groups meet a key need in pharmacogenetics research by enabling consistent communication of the scale of variability in global allele frequencies and are now used by Pharmacogenomics Knowledgebase (PharmGKB).

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10−17), arthritis (GDF5p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (updates on cpicpgx.org). The purpose of this guideline is to provide information for the interpretation of human leukocyte antigen B (HLA-B) and/or cytochrome P450 2C9 (CYP2C9) genotype test results to guide use and/or dosing of phenytoin. Guidelines for phenytoin use and cost-effectiveness of genetic testing are outside the scope of this report. This guideline updates the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing. 1 CPIC guidelines are periodically updated at www.cpicp gx.org. FOCUSED LITERATURE REVIEW We reviewed literature focused on CYP2C9 and HLA variation and phenytoin use (details in Supplementary Material). Evidence is summarized in Table S1 and Table S2. Genes: HLA-B and CYP2C9 Background. This guideline discusses HLA-B and the risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with phenytoin and CYP2C9 as it relates to phenytoin metabolism and dosing. Updated CYP2C9 allele function assignments are provided using the activity score system.