Inclisiran’s inclusion on the 2020 Cortellis Drugs to Watch list is an example of target discovery possibilities hiding in plain sight – if companies and institutions are willing to put effort into increasing sample diversity in genomic research.
Inclisiran lowers LDL cholesterol by inhibiting the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9). One of the key early publications demonstrating that very low LDL cholesterol levels caused by PCSK9 mutations lowered the risk of heart disease studied African Americans. About 2% of African Americans have mutations in PCSK9, a far higher rate than European ancestry populations. Several of the case studies that first linked PCSK9 mutations to extremely low LDL cholesterol levels were also of African ancestry families.
In the bigger picture, genomic variation is greatest in African populations and those of the African diaspora, that is, descendants of the more than 10 million Africans who were enslaved and forcibly transported to the Americas between 1500 and 1800. Prehistoric migrations out of the African continent caused repeated genetic bottlenecks, where a few individuals ended up being the ancestors of large populations and reduced genetic diversity in non-African populations.
That genomic variation means that risk variants are easier to identify in African populations. A paper published in the Jan. 31, 2020, issue of Science identified new risk variants in a genomewide association study (GWAS) in slightly more than 900 schizophrenics and age-, gender- and residence-matched controls from the South African Xhosa population.
The authors noted that they were able to gain new insights with what, by GWAS standards, were very few subjects due to “the depth of genetic variation in Africa.” African populations also have lower levels of linkage disequilibrium, which helps identify gene-trait associations.
Despite all those advantages, African and African diaspora populations, as well as non-European ancestry populations more broadly, remain poorly represented in most databases. In a 2018 commentary in Cell, researchers from the University of Pennsylvania and Case Western Reserve University reported that almost 80% of individuals in published studies of genomewide associations were of European ancestry, while only 2% were of African ancestry, and that the situation is no better in other subfields of genomics. For example, they wrote that “the Genotype-Tissue Expression (GTEx) project reflects the same bias that GWAS does, with more than 85% of samples being of European descent.”
There are, however, both academic and industrial efforts underway to take full advantage of genomic diversity.
The NIH’s All of Us program, whose goal is to collect genomic as well as health, environmental and family history data from a million individuals, is committed to enrolling participants of all ethnicities – and doing pretty well at it so far. On Jan. 1, 2020, All of Us deputy director Stephanie Devaney reported that of the 250,000 participants enrolled to date, “more than 51% belong to racial and ethnic minorities, more than 10% are sexual and gender minorities, and overall more than 80% represent a group that has been historically underrepresented in research data sets.”
The Human Health and Heredity in Africa (H3Africa) consortium, whose vision it is to build infrastructure to study “the complex interplay between environmental and genetic factors which determines disease susceptibility and drug responses in African populations,” includes a sequencing component.
And 2019 saw the founding of Gene54, which describes itself as “the world’s first and largest pan-African biobank.” With offices in Lagos and San Francisco, the company’s goal is to gather material from 200,000 individuals by the end of 2020 that samples Africa’s genetic subpopulations.
There are thousands of such subpopulations, and according to Gene54’s website, “the status quo is to collect samples from one subpopulation, in one country, in one major city, and assume it’s representative of the continent. We see things differently.”
Evidence suggests that their different view could prove to be a scientific goldmine – and a financial one as well.
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