Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine

Abstract

Pharmacogenetics is being used to develop personalized therapies specific to subjects from different ethnic or racial groups. To date, pharmacogenetic studies have been primarily performed in trial cohorts consisting of non-Hispanic white subjects of European descent. A "bottleneck" or collapse of genetic diversity associated with the first human colonization of Europe during the Upper Paleolithic period, followed by the recent mixing of African, European, and Native American ancestries, has resulted in different ethnic groups with varying degrees of genetic diversity. Differences in genetic ancestry might introduce genetic variation, which has the potential to alter the therapeutic efficacy of commonly used asthma therapies, such as β2-adrenergic receptor agonists (β-agonists). Pharmacogenetic studies of admixed ethnic groups have been limited to small candidate gene association studies, of which the best example is the gene coding for the receptor target of β-agonist therapy, the β2-adrenergic receptor (ADRB2). Large consortium-based sequencing studies are using next-generation whole-genome sequencing to provide a diverse genome map of different admixed populations, which can be used for future pharmacogenetic studies. These studies will include candidate gene studies, genome-wide association studies, and whole-genome admixture-based approaches that account for ancestral genetic structure, complex haplotypes, gene-gene interactions, and rare variants to detect and replicate novel pharmacogenetic loci.

Keywords: ADRB1; ADRB2; Asthma; BADGER; BARGE; Best Add-on Therapy Giving Effective Response Trial; Beta Agonist Response by Genotype Trial; CAAPA; Consortium on Asthma among African-ancestry Populations in the Americas; G protein receptor kinase 5; GALA; GLCCl1; GRK5; GWAS; Genetics of Asthma in Latino Americans; Genome-wide association study; Glucocorticoid-induced transcript 1 gene; ICS; Inhaled corticosteroid; LABA; LARGE; Long-acting Beta Agonist Response by Genotype; Long-acting β-agonist; NHLBI; NIH; National Heart, Lung, and Blood Institute; National Institutes of Health; PEFR; Peak expiratory flow rate; SABA; SMART; SNP; SPATS2L; Salmeterol Multicenter Asthma Research Trial; Short-acting β-agonist; Single nucleotide polymorphism; Spermatogenesis-associated, serine-rich 2-like gene; admixture mapping; ethnic group; genes; pharmacogenetics; response heterogeneity; single nucleotide polymorphism; β(1)-Adrenergic receptor; β(2)-Adrenergic receptor.

Figure 1. Common and Rare Genetic Variants in Human Disease

Based on the “common disease-common allele” hypothesis, multiple common genetic polymorphisms (alleles or variants) with small to modest effect sizes contribute additively to a common disease. Genome-wide association studies (GWAS) have detected multiple common variants associated with risk for common diseases such as hypertension or asthma. The “common disease-rare allele” hypothesis states that rare genetic variants with a large effect size contribute to risk for common diseases. Rare genetic variants cannot be detected with classic GWAS and have been evaluated with family-based genetic studies, admixture mapping, and DNA sequencing. Adapted from Tsuji S, et al. Hum Mol Genet 2010;19(R1):R65–70.

Figure 2. Ancestries of Recently Admixed Ethnic Groups in the United States

The first human colonization of Europe during the Upper Paleolithic period (purple arrow) was accompanied by a “bottleneck” or collapse of genetic diversity in the resulting European White ancestral population. Recent mixing between more genetically diverse, ancient African ancestral populations with European Whites, and Native Americans (blue arrow represents the first human colonization of the Americas) during the European colonization of the Americas (red arrows) and the African slave trade (green arrows) resulted in different, recently admixed ethnic groups with varying degrees of genetic diversity. The flow of genetic diversity is represented by the thickness of the arrows: thicker arrows reflect greater genetic diversity (i.e. resulting from a greater number of recombination events, shorter genomic regions of linkage disequilibrium, and a greater frequency of rare variants).

Figure 3. 3A and 3B: Relationship of Global African Ancestry with Lung Function in African Americans

Kumar and colleagues demonstrated an inverse relationship between percentage of global African ancestry and baseline forced expiratory volume in 1 second (FEV1 measured in liters) in self-identified African American men and women shown in Panels A and B, respectively. Global African ancestry was estimated using ancestry informative genetic markers. Reproduced from Kumar R, et al. NEJM 2010;363(4):321–330.

Figure 4. Illustration of Admixture Mapping

The hypothesis behind mapping by admixture linkage disequilibrium (MALD) or admixture mapping is that chromosomes from an admixed population (shown with red and blue genetic regions from a specific ancestry) contain a susceptibility allele for reduced therapeutic responsiveness which is more frequent in the red (ancestry A) ancestral region versus the blue (ancestry B). A hypothetical MALD for a pharmacogenetic study would identify an increased proportion of ancestry A at a susceptibility locus in individuals who are less likely to respond to a pharmacologic therapy (region intersected by thick black line). Reproduced from Montana G, et al. Am J Hum Genet 2004;75:771–789.