A DPYD variant (Y186C) in individuals of african ancestry is associated with reduced DPD enzyme activity

Abstract

5-Fluorouracil (5-FU) is used to treat many aggressive cancers, such as those of the colon, breast, and head and neck. The responses to 5-FU, with respect to both toxicity and efficacy, vary among racial groups, potentially because of variability in the activity levels of the enzyme dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene). In this study, the genetic associations between DPYD variations and circulating mononuclear-cell DPD enzyme activity were evaluated in 94 African-American and 81 European-American volunteers. The DPYD-Y186C variant was unique to individuals of African ancestry, and DPD activity was 46% lower in carriers as compared with noncarriers (279 ± 35 vs. 514 ± 168 pmol 5-FU min(-1) mg(-1); P = 0.00029). In this study, 26% of the African Americans with reduced DPD activity were carriers of Y186C. In the African-American cohort, after excluding Y186C carriers, homozygous carriers of C29R showed 27% higher DPD activity as compared with noncarriers (609 ± 152 and 480 ± 152 pmol 5-FU min(-1) mg(-1), respectively; P = 0.013).

Figure 1

DPD enzyme activity for carriers and non-carriers of I560S (a), Y186C (b), V732I (c), I543V (d), IVS2-69 (e), and IVS15+75 (f) is reported for African American (AA) and European American (EA) populations. Boxplots presenting population means (filled dots), medians (dark black lines), 25–75% confidence intervals (boxes), 5–95% confidence intervals (dashed lines and whiskers), and outliers (open dots) are presented. If a single volunteer carried a given genotype, the value is presented as a single filled dot. P values are presented for significant differences (P<0.05) in enzyme activity within a population, and are not shown if P≥0.05. A full summary of enzyme activity by genotype is presented in Supplementary Table S3.

Figure 2

Boxplot histograms showing the distribution of DPD enzyme activity by C29R genotype in the African American (AA) population as a whole (left) and in the African American population not carrying Y186C (right) are shown. Significantly elevated DPD enzyme activity is noted for homozygous carriers of the C29R SNP (CC genotype) when individuals carrying Y186C are excluded from analysis. Boxplots depict variables as detailed for Figure 1.

Figure 3

The degree of LD among the DPYD SNPs in the African American population is presented. A D′ value of 1 indicates that no recombination was observed between the markers tested. Logarithm of odds (LOD) scores greater than or equal to 2 suggests that SNPs are inherited together. A high degree of LD between SNPs (D′=1, LOD≥2) is indicated in red and the lowest degree of LD (D′<1, LOD<2) in white. Recombination rates <1 are presented as a percentage. The LD block that includes Y186C is outlined in yellow. Asterisks are used to highlight the LD between Y186C and other SNPs associated with reduced DPD enzyme activity.