Warfarin is a powerful blood thinner and a leading drug for cardiovascular disease worldwide. But in South Africa, it is among the top four drug varieties leading to hospitalisation from adverse drug reactions. It’s reasonable to suppose that the drug has similar problematic effects farther across sub-Saharan Africa, though the national data needed to show it are lacking.
The fact that warfarin is riskier in some populations than others isn’t a surprise. Different geographic regions tend to host people with slightly different genetic makeups, and sometimes those genetic differences lead to radically different reactions to drugs. For certain people, a higher dosage of warfarin is fine; for others, it’s dangerous. Researchers have known this for decades.
Focus on one subset
The problem is that the majority of medical research, including genetic research, is still done mainly on one subset of the world’s population: men of Northern European origin. This means that negative drug-gene interactions in other, less well-studied populations can fly beneath the radar. In the case of warfarin, one study concluded that using someone’s genetic information to help guide their drug dosing would benefit 18% to 24% of people categorised as white, but have no benefit for people identified as Black, Chinese or Japanese.
While that study is a decade old, the general point still holds true: A bias in our current understanding of the genetics of different populations means that some people would be helped far more than others by genetically informed personalised medicine.
As a bioinformatician, I am now focusing my attention on gathering the statistics to show just how biased medical research data are. There are problems across the board, ranging from which research questions get asked in the first place, to who participates in clinical trials, to who gets their genomes sequenced. The world is moving toward “precision medicine,” where any individual can have their DNA analysed and that information can be used to help prescribe the right drugs in the right dosages. But this won’t work if a person’s genetic variants have never been identified or studied in the first place.
Understudied populations
It’s astonishing how powerful our genetics can be in mediating medicines. Take the gene CYP2D6, which is known to play a vital role in how fast humans metabolise 25% of all the pharmaceuticals on the market. If you have a genetic variant of CYP2D6 that makes you metabolise drugs more quickly, or less quickly, it can have a huge impact on how well those drugs work and the dangers you face from taking them. Codeine was banned from all of Ethiopia in 2015, for example, because a high proportion of people in the country (perhaps 30%) have a genetic variant of CYP2D6 that makes them quickly metabolise that drug into morphine, making it more likely to cause respiratory distress and even death.
Researchers have identified over a hundred different CYP2D6 variants and there are likely many, many more out there that we don’t yet know the impacts of – especially in understudied populations.
Back in 2016, researchers published an important article looking at more than 2,500 genome-wide association studies done up to that time. These are studies that scan the genomes of thousands of people to find variants associated with disease traits. What the researchers found was disturbing: While there had been some improvement in diversity since 2009, still 81% of the nearly 35 million samples in those studies came from people of European descent.
Skew in sequencing services
You might expect that, since everyone knows this is a problem, it would have become much better over recent years. It hasn’t. In 2021, another study of genome-wide association studies showed that the European-origin proportion had increased, not decreased, from 81% to 86%.
It’s not just genome-wide studies that have this issue. Direct-to-consumer genetic sequencing services like 23andMe are also skewed: One analysis suggests that 95% of the participants have predicted European ancestry, compared to just 2% African. And in PharmGKB, one of the world’s leading databases of drug-gene interactions, 64% of the data come from people of European ancestry, though this group makes up only 16% of the global population. Indigenous Americans account for the smallest amount of the data (just 0.1%). But when taking the global population into account, it is Central and South Asian people who are least well represented, with only 2% of the data but 26% of the global population.
People of African descent have the greatest genetic diversity on the planet (because humanity originated in Africa), and so arguably they deserve the greatest amount of study. But this is hardly the situation. This population makes up just 4% of the PharmGKB dataset, for example.
Geographic ancestry isn’t the only factor that’s biased. Women make up only 38% of participants in studies of drug effectiveness and pharmacokinetics, for example. Because of gender bias all along the line, women experience adverse drug reactions nearly twice as often as men. And this doesn’t even scratch the surface of people with genetic conditions – like my son who has Down syndrome – or other disabilities.
There are some good efforts working to correct these problems. On October 18, 2023, researchers announced plans to create one of the largest-yet databases of genomes exclusively from people with African ancestry. The project aims to recruit at least 500,000 volunteers (for comparison, tens of millions of people globally have had their genomes sequenced to date). This is a great effort; more should follow suit.
Red herrings
Everyone stands to gain from more diverse work. Right now, one clue that researchers use to help determine whether a genetic mutation might be linked to disease (or not) is whether that mutation is rare (or not); if a variant is extremely uncommon, this is one hint that it might be pathogenic (since most people don’t have a given disease). But this could be sending researchers chasing after red herrings. One study published in March 2023, for example, performed whole-genome sequencing on 180 people from 12 indigenous African populations, and found that of 154 mutations labelled “pathogenic” or “likely pathogenic” in a well-known database, 44 were at least five times more frequent in at least one of these African populations. This suggests that those mutations might be benign after all.
The International Covenant on Economic, Social and Cultural Rights, adopted by the United Nations General Assembly on December 16, 1966, recognises everyone’s rights to enjoy the benefits of scientific progress. But that is not happening yet. We need to ramp up representation in genetic and medical studies to ensure fair treatment for all.
Manuel Corpas is a bioinformatician and genomics lecturer at the University of Westminster in London. He is chief scientist of Cambridge Precision Medicine. This article is republished from Knowable Magazine.
- Warfarin is a leading drug for cardiovascular disease worldwide but in South Africa, it is among the top four drug varieties leading to hospitalisation from adverse drug reactions
- Someone’s genetic information to help guide their drug dosing would benefit 18% to 24% of people categorised as white, but have no benefit for people identified as Black, Chinese or Japanese
- A bias in our current understanding of the genetics of different populations means that some people would be helped far more than others by genetically informed personalised medicine
