Population Pharmacogenomics for Precision Public Health in Colombia

Abstract

While genomic approaches to precision medicine hold great promise, they remain prohibitively expensive for developing countries. The precision public health paradigm, whereby healthcare decisions are made at the level of populations as opposed to individuals, provides one way for the genomics revolution to directly impact health outcomes in the developing world. Genomic approaches to precision public health require a deep understanding of local population genomics, which is still missing for many developing countries. We are investigating the population genomics of genetic variants that mediate drug response in an effort to inform healthcare decisions in Colombia. Our work focuses on two neighboring populations with distinct ancestry profiles: Antioquia and Chocó. Antioquia has primarily European genetic ancestry followed by Native American and African components, whereas Chocó shows mainly African ancestry with lower levels of Native American and European admixture. We performed a survey of the global distribution of pharmacogenomic variants followed by a more focused study of pharmacogenomic allele frequency differences between the two Colombian populations. Worldwide, we found pharmacogenomic variants to have both unusually high minor allele frequencies and high levels of population differentiation. A number of these pharmacogenomic variants also show anomalous effect allele frequencies within and between the two Colombian populations, and these differences were found to be associated with their distinct genetic ancestry profiles. For example, the C allele of the single nucleotide polymorphism (SNP) rs4149056 [Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) ∗ 5], which is associated with an increased risk of toxicity to a commonly prescribed statin, is found at relatively high frequency in Antioquia and is associated with European ancestry. In addition to pharmacogenomic alleles related to increased toxicity risk, we also have evidence that alleles related to dosage and metabolism have large frequency differences between the two populations, which are associated with their specific ancestries. Using these findings, we have developed and validated an inexpensive allele-specific PCR assay to test for the presence of such population-enriched pharmacogenomic SNPs in Colombia. These results serve as an example of how population-centered approaches to pharmacogenomics can help to realize the promise of precision medicine in resource-limited settings.

Heterogeneity in the distribution of 159 drug-response related SNPs in world populations and their genetic relatedness

“…Furthermore, even two neighboring populations living in the same country may have differences in drug response if they have different ancestry or different level of admixture. For example, there are differences in allele frequencies of drug response-related SNPs between two neighboring Colombian populations-Antioquia and Chocó-owing to their distinct ancestry profiles [118].…”

Precision, Equity, and Public Health and Epidemiology Informatics – A Scoping Review

“…The second distinction is that the role of genomic information is currently much more limited in PPH. However, the concept of PPH has been applied to population health genomics [8], for example pharmacogenomics [9,10], and some have proposed that polygenic risk scores may have application within a PPH context [11].…”

Population structure and pharmacogenomic risk stratification in the United States

“…The association between GA and PGx variant genotypes was measured using our previously described method 25 . To obtain the strength of association ( ) between continental ancestry proportions and genotypes, continental ancestry fractions were regressed against the observed PGx variant genotypes.…”

“…We posit that genetic ancestry provides a number of advantages over racial/ethnic categories for biomedical research: (i) it can be characterized independent of the social and environmental dimensions of race/ethnicity, (ii) it can be measured objectively and with precision, and (iii) it can be quantified as a continuous variable, as opposed to categorical racial/ethnic labels. Indeed, a number of recent studies have focused on PGx variation among populations defined by genetic ancestry rather than racial and ethnic groups [25][26][27][28][29][30] .…”