Methods

The allele frequency table was made by searching the PubMed® database (1995 to July 2019). The following criteria were used for CYP2C9: (CYP2C9 or 2C9 or cytochrome P4502C9) AND (genotype OR allele OR frequency OR minor allele OR variant OR ethnic OR race OR racial OR ethnicity OR population) with filter limits set to retrieve "full-text" and "English" literature. In addition, reports were also identified from citations by others or review articles. Studies were considered for inclusion in the CYP2C9 frequency table if: (1) the ethnicity of the population was clearly indicated, (2) either allele frequencies or genotype frequencies were reported, (3) the method by which the genes were genotyped was indicated, (4) the sample population consisted of at least 50 individuals with a few exceptions (e.g., smaller cohorts that were part of larger studies) and (5) the study represented an original publication (no reviews or meta-analyses). Allele frequencies reported in and gnomD browser and phase 3 1000 Genomes were also included (https://gnomad.broadinstitute.org/, http://browser.1000genomes.org/index.html) for alleles that contain single unique variant.

Diplotype and Phenotype Calculations. Diplotype and phenotype frequencies were estimated using the equation describing Hardy Weinberg equilibrium based on reported allele frequencies.

Caveats to estimated allele, diplotype and phenotype frequencies:

Sampling. Allele frequencies collected by CPIC for the supplemental tables are based on published literature reports which typically study small groups of people based on a geographic location (e.g. Malaysia, Berlin, Cairo). Almost no studies use genetic markers to estimate ancestry. Manuscripts are often focused on a specific phenotype (e.g. disease) or study only individuals taking a particular drug. Such samples would not be considered a random sample of the general population. Another consideration is that sample size is important, and PGx studies are typically not large. The frequencies collected from these studies are then used to estimate general estimates of entire ethnic population allele frequencies. Therefore, frequencies from larger groups of subjects and frequencies averaged from many sample populations probably result in better estimates.

Estimation of *1 frequency. In general, there are no population studies that test for all known variant alleles. Because *1 is not genotyped directly in many studies, all alleles that are negative for a sequence variation are defaulted to a *1 assignment. Because CYP2C9*1 is not genotyped directly, all alleles that are negative for a sequence variation are defaulted to a CYP2C9*1 assignment. Likewise, sequence variations of alleles that are not tested may default to a CYP2C9*1 assignment and hence contribute to the frequencies reported for this allele. Therefore, the inferred frequency for CYP2C9*1 was calculated as an average from studies describing allele frequencies for the most common alleles found in a particular biogeographical group.

Diplotype/Phenotype frequency estimates. When calculating diplotype frequencies from these allele frequencies, the margin of error is compounded based on the margin of error on each allele in the diplotype. So, the margin of error will necessarily increase for diplotype frequency estimates compared to allele frequency estimates. For allele frequencies with already large margins of error due to small and non-random sampling, the diplotype margin of error could potentially be quite large. On the other hand, for well-studied alleles, the margin of error is likely low.

Biogeographical groups. Biogeographical groups are derived from PMID 30506572. Further details can be found at https://www.pharmgkb.org/page/biogeographicalGroups. These tables group individuals from particular geographic locations into larger biogeographical groups. It is difficult to group populations with certainty, because some populations are often admixed, or at the least, a combination of different ethnicities. Therefore, the margin of error is increased when different subpopulations are grouped together.