Precision Medicine

A trial of heart failure treatments among people

of different ethnic backgrounds even led to the development of BiDil, a heart disease drug aimed specifically at people who self-identified as black10. However, BiDil has not been as popular as hoped11. Physicians were sceptical of the bene- fits and some raised concerns that a drug was being marketed using the unscientific concept of perceived race rather than underlying genetic make-up12. For some drugs, the observed differences in effi-

cacies between ethnicities can be explained by pharmacogenetics. People with an Asian back- ground often require a lower dose of the blood thinner warfarin, for example, resulting from com- mon polymorphisms in two genes related to war- farin metabolism13. For example, our knowledge of the genetic basis

of cystic fibrosis is mostly based on the genetic variants that are commonly found in people of European background. This disease is often under- diagnosed in African Americans because the genet- ic variant that accounts for 70% of cystic fibrosis cases in people of European descent only occurs in 29% of African American patients14. As a result, cystic fibrosis is underdiagnosed in this population, disenfranchising them from access to specialty care and targeted treatments. Incomplete knowledge of genetic diversity also

leads to miscategorisation of pathological variants: a 2016 study showed that out of 192 genetic vari- ations that were supposed to be linked to a disease in western populations, just nine were genuinely disease-causing in South Asians15. Our own unpublished analysis of public genomic data has revealed that a supposedly pathological variant linked to epilepsy in those with European ancestry is present in 96% of Indians without causing any signs of the disease. The lack of information about the underlying

genetics of disease and drug response across differ- ent sections of the global population means that currently-available precision medicine treatments mainly benefit people who have a genetic profile that most resembles that of the most commonly studied genomes – those of a white European back- ground. Instead of developing solutions based on a small

proportion of the global population, the industry should be looking at disease profiles and genetics from a much more diverse set of individuals to identify drug targets and understand their effects in the body. Several groups and organisations are trying to broader participation in genetic studies by includ-

Drug DiscoveryWorld Summer 2019

ing groups that thus far have been under-represent- ed. But in order to do this, they have to address the issues that have led to the imbalance in genetic rep- resentation in the first place.

Reasons for the lack of global genome coverage One of the causes for the existing unequal distribu- tion of genomic data has been that many GWAS studies and other research projects have taken place in countries where the majority of the popu- lation has white European/Caucasian ancestry. Furthermore, a desire for statistical rigour has encouraged researchers to largely focus on well- controlled, homogenous cohorts, rather than risk including smaller segments which might not pro- vide the same statistical power16. Another reason for the lack of diversity is that

trial recruiters are finding it difficult to engage and involve under-represented groups. In the UK, researchers from the 100,000 Genomes Project noticed that cancer patients from Black and Caribbean communities were less likely to volun- teer to have their genome sequences researched than white patients. An internal report found sev- eral reasons for this, including pressure on medical staff to recruit patients in a timely manner, which discouraged themfromputting additional time and effort in reaching communities with possible lan- guage or cultural barriers17. The same study also looked at reasons why these

communities were reluctant to take part and found a persistent culture of distrust around genetic research. In recent years, the UK police force has been widely criticised for a biased method of DNA collecting, leading to black people being overrepre- sented in the police DNA database. This meant that the members of the black community were reluctant to share their DNA, even for a health cause. In the United States, meanwhile, the African American community has traditionally been less likely to trust doctors, partly as a result of the Tuskegee Syphilis Study18.

Increasing diversity in genetic databases Several new initiatives are now taking steps to include communities that have been reluctant to participate in genetic research and counter the lack of early recruitment of these groups. The NIH programme All Of Us has a specific

goal to build a research cohort of amillion ormore people representing the diverse backgrounds of the US population in order to advance precision medicine. It is encouraging anyone in the country

References 1 Davis,C et al.Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ 359, j4530 (2017). doi:10.1136/bmj.j4530. 2 Drug development innovations that work: Precision medicine (Part 3 in a series). BioPharma Dive Available at: m/news/drug-development- innovations-that-work- precision-medicine-part-3-in-a- ser/556187/ (Accessed: 16th June 2019). 3 Jiang,X, Li,W, Li,X, Bai,H and Zhang, Z.Current status and future prospects of PARP inhibitor clinical trials in ovarian cancer.Cancer Management and Research (2019). doi:10.2147/CMAR.S200524. 4 Sirugo,G,Williams, SM and Tishkoff, SA.The Missing Diversity in Human Genetic Studies.Cell 177, 26-31 (2019). doi: 10.1016/j.cell.2019.02.048. 5The International HapMap Consortium.The International HapMap Project.Nature 426, 789-796 (2003) doi: 10.1038/nature02168. 6Variety of life (editorial). Nature 526, 5-6 (2015) doi: 10.1038/526005b. 7 Sherman, RM et al.Assembly of a pan-genome from deep sequencing of 910 humans of African descent.Nature Genetics 51, 30-35 (2019) doi: 10.1038/s41588-018-0273-y. 8 Mak,ACY et al.Whole- genome sequencing of pharmacogenetic drug response in racially diverse children with asthma.Am J Respir Crit Care Med 197, 1552-1564 (2018). doi: 10.1164/rccm.201712- 2529OC. 9 Johnson, Julie A. Ethnic Differences in Cardiovascular Drug Response.Circulation 118, 1383-1393 (2008). doi: 10.1161/CIRCULATIONAHA. 107.704023.

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