ePGA: A Web-Based Information System for Translational Pharmacogenomics

<div><p>One of the challenges that arise from the advent of personal genomics services is to efficiently couple individual data with state of the art Pharmacogenomics (PGx) knowledge. Existing services are limited to either providing static views of PGx variants or applying a simplistic match between individual genotypes and existing PGx variants. Moreover, there is a considerable amount of haplotype variation associated with drug metabolism that is currently insufficiently addressed. Here, we present a web-based electronic Pharmacogenomics Assistant (ePGA; <a href="http://www.epga.gr/" target="_blank">http://www.epga.gr/</a>) that provides personalized genotype-to-phenotype translation, linked to state of the art clinical guidelines. ePGA's translation service matches individual genotype-profiles with PGx gene haplotypes and infers the corresponding diplotype and phenotype profiles, accompanied with summary statistics. Additional features include i) the ability to customize translation based on subsets of variants of clinical interest, and ii) to update the knowledge base with novel PGx findings. We demonstrate ePGA's functionality on genetic variation data from the 1000 Genomes Project.</p></div

Chromosomal location and functional consequence distribution per chromosome of the PGx variants.

<p>The accompanied table shows the PGx variants and genes located in each chromosome.</p

Distribution of three phenotypes (WT/WT-green, WT/V-orange, V/V-red) for 5 highly covered genes with high phenotypic difference among 1kG populations.

<p>Distribution of three phenotypes (WT/WT-green, WT/V-orange, V/V-red) for 5 highly covered genes with high phenotypic difference among 1kG populations.</p

Translation process.

<p>(A) Haplotype table for the <i>UGT1A5</i> as downloaded from PharmGKB. (B) The modified <i>UGT1A5</i> haplotype table by completing Step 1 (i,ii,iii sub-steps). (C) Numerical form of the <i>UGT1A5</i> haplotype table. (D) <i>UGT1A5</i> diplotypes (all combinations of haplotypes) with their numerically coded values. (E) An example of PGx variant annotation table with major and minor alleles as stated by PharmGKB. (F) A sample genotype profile. (G) The transformed, numerically coded, sample genotype profile described in Step 3. (H) The numerically coded sample diplotype to be matched.</p

Minor Allele frequency distribution for the ten most differentiated PGx variants among 1kG ancestral groups.

<p>Minor Allele frequency distribution for the ten most differentiated PGx variants among 1kG ancestral groups.</p

Distribution of common (MAF≥0.1) possibly damaging (left) and benign (right) PGx variants across 1kG populations.

<p>These are African/AFR (GWD, MSL, ESN, YRI, LWK, ACB, ASW), Ad Mixed America/AMR (MXL, CLM, PEL, PUR), East Asian/EAS (CHS, KHV, CHB, JPT, CDX), European/EUR (TSI, IBS, GBR, CEU, FIN), South Asian/SAS (PJL, STU, ITU, BEB, GIH) ancestral groups.</p

Haplotype Frequency (HAF) heatmap for 53 PGx haplotype that are common (HAF> = 0.1) and rare (HAF< = 0.005) in at least one 1kG population.

<p>Haplotype Frequency (HAF) heatmap for 53 PGx haplotype that are common (HAF> = 0.1) and rare (HAF< = 0.005) in at least one 1kG population.</p

Individual haplotypes that did not match to any known haplotype per gene.

<p>Colours represent the five ancestral groups. Grey fills indicate haplotype matches.</p

A workflow of user-ePGA interaction.

<p>A workflow of user-ePGA interaction.</p

Matching distribution of individuals per ancestry group for the haplotypes with the highest variability and significant percentage match.

<p>Matching distribution of individuals per ancestry group for the haplotypes with the highest variability and significant percentage match.</p