The Apportionment of Pharmacogenomic Variation: Race, Ethnicity, and Adverse Drug Reactions
Main Article Content
Abstract
Fifty years ago, Richard Lewontin found that the vast majority of human genetic variation falls within (~85%) rather than between (~15%) racial groups. This result has been replicated numerous times since and is widely taken to support the notion that genetic differences between racial groups are trivial and thus irrelevant for clinical decision-making. The aim of this study was to consider how the apportionment of pharmacogenomic variation within and between racial and ethnic groups relates to risk disparities for adverse drug reactions. We confirmed that the majority of pharmacogenomic variation falls within (97.3%) rather than between (2.78%) the three largest racial and ethnic groups in the United States: Black, Hispanic, and White. Nevertheless, pharmacogenomic variants showing far greater within than between-group variation can have high predictive value for adverse drug reactions, particularly for minority racial and ethnic groups. We predicted excess adverse drug reactions for minority Black and Hispanic groups, compared to the majority White group, and considered these results in light of the apportionment of genetic variation within and between groups. For 85% within and 15% between group variation, there are 700 excess adverse drug reactions per 1,000 patients predicted for a recessive effect model and 300 for a dominant model. We found high numbers of predicted Black and Hispanic excess adverse drug reactions for widely prescribed platinum chemotherapy compounds, such as cisplatin and oxaliplatin, as well as controlled narcotics, including fentanyl and tramadol. Our results indicate that race and ethnicity, while imprecise proxies for genetic diversity, correlate with patterns of pharmacogenomic variation in a way that is clearly relevant to medical treatment decisions. The effects of this variation is particularly pronounced for Black and Hispanic minority groups, owing to genetic differences from the majority White group. Treatment decisions that are made based on (assumed) White pharmacogenomic variant frequencies can be harmful for minority groups. Ignoring clinically relevant genetic differences among racial and ethnic groups, however well-intentioned, will exacerbate rather than ameliorate health disparities.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Burchard EG, Ziv E, Coyle N, et al. The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med. Mar 20 2003;348(12):1170-5. doi:10.1056/NEJMsb025007
3. Oni-Orisan A, Mavura Y, Banda Y, Thornton TA, Sebro R. Embracing Genetic Diversity to Improve Black Health. N Engl J Med. Mar 25 2021;384(12):1163-1167. doi:10.1056/NEJMms2031080
4. Cerdena JP, Plaisime MV, Tsai J. From race-based to race-conscious medicine: how anti-racist uprisings call us to act. Lancet. Oct 10 2020;396(10257):1125-1128. doi:10.1016/S0140-6736(20)32076-6
5. Yudell M, Roberts D, DeSalle R, Tishkoff S, signatories. NIH must confront the use of race in science. Science. Sep 11 2020;369(6509):1313-1314. doi:10.1126/science.abd4842
6. Yudell M, Roberts D, DeSalle R, Tishkoff S. SCIENCE AND SOCIETY. Taking race out of human genetics. Science. Feb 5 2016;351(6273):564-5. doi:10.1126/science.aac4951
7. Vyas DA, Eisenstein LG, Jones DS. Hidden in Plain Sight - Reconsidering the Use of Race Correction in Clinical Algorithms. N Engl J Med. Aug 27 2020;383(9):874-882. doi:10.1056/NEJMms2004740
8. Lewontin RC. The apportionment of human diversity. Evolutionary biology. Springer; 1972:381-398.
9. Edge MD, Ramachandran S, Rosenberg NA. Celebrating 50 years since Lewontin's apportionment of human diversity. Philos Trans R Soc Lond B Biol Sci. Jun 6 2022;377(1852):20200405. doi:10.1098/rstb.2020.0405
10. Novembre J. The background and legacy of Lewontin's apportionment of human genetic diversity. Philos Trans R Soc Lond B Biol Sci. Jun 6 2022;377(1852):20200406. doi:10.1098/rstb.2020.0406
11. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. Oct 15 1999;286(5439):487-91. doi:10.1126/science.286.5439.487
12. Nagar SD, Conley AB, Jordan IK. Population structure and pharmacogenomic risk stratification in the United States. BMC Biol. Oct 13 2020;18(1):140. doi:10.1186/s12915-020-00875-4
13. Giacomini KM, Krauss RM, Roden DM, Eichelbaum M, Hayden MR, Nakamura Y. When good drugs go bad. Nature. Apr 26 2007;446(7139):975-7. doi:10.1038/446975a
14. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. Oct 7 2000;356(9237):1255-9. doi:10.1016/S0140-6736(00)02799-9
15. McDowell SE, Coleman JJ, Ferner RE. Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. BMJ. May 20 2006;332(7551):1177-81. doi:10.1136/bmj.38803.528113.55
16. Baehr A, Pena JC, Hu DJ. Racial and Ethnic Disparities in Adverse Drug Events: A Systematic Review of the Literature. J Racial Ethn Health Disparities. Dec 2015;2(4):527-36. doi:10.1007/s40615-015-0101-3
17. Barbarino JM, Whirl-Carrillo M, Altman RB, Klein TE. PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. Jul 2018;10(4):e1417. doi:10.1002/wsbm.1417
18. O'Brien TJ, Fenton K, Sidahmed A, Barbour A, Harralson AF. Race and Drug Toxicity: A Study of Three Cardiovascular Drugs with Strong Pharmacogenetic Recommendations. J Pers Med. Nov 18 2021;11(11)doi:10.3390/jpm11111226
19. Sonnega A, Faul JD, Ofstedal MB, Langa KM, Phillips JW, Weir DR. Cohort Profile: the Health and Retirement Study (HRS). Int J Epidemiol. Apr 2014;43(2):576-85. doi:10.1093/ije/dyu067
20. National Insitutes of Health. Office of Management and Budget (OMB) Standards. Accessed June 1, 2022, https://orwh.od.nih.gov/toolkit/other-relevant-federal-policies/OMB-standards
21. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7. doi:10.1186/s13742-015-0047-8
22. Hudson RR, Slatkin M, Maddison WP. Estimation of levels of gene flow from DNA sequence data. Genetics. Oct 1992;132(2):583-9. doi:10.1093/genetics/132.2.583
23. United States Census. QuickFacts: United States. Accessed June 1, 2022, https://www.census.gov/quickfacts/fact/table/US/PST045221
24. Wojcik GL, Graff M, Nishimura KK, et al. Genetic analyses of diverse populations improves discovery for complex traits. Nature. Jun 2019;570(7762):514-518. doi:10.1038/s41586-019-1310-4
25. Fang H, Hui Q, Lynch J, et al. Harmonizing Genetic Ancestry and Self-identified Race/Ethnicity in Genome-wide Association Studies. Am J Hum Genet. Oct 3 2019;105(4):763-772. doi:10.1016/j.ajhg.2019.08.012
26. Bryc K, Durand EY, Macpherson JM, Reich D, Mountain JL. The genetic ancestry of African Americans, Latinos, and European Americans across the United States. Am J Hum Genet. Jan 8 2015;96(1):37-53. doi:10.1016/j.ajhg.2014.11.010
27. Galanski M, Jakupec MA, Keppler BK. Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Curr Med Chem. 2005;12(18):2075-94. doi:10.2174/0929867054637626
28. Oun R, Moussa YE, Wheate NJ. The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans. May 15 2018;47(19):6645-6653. doi:10.1039/c8dt00838h
29. Oliveira L, Caquito JM, Jr., Rocha MS. Carboplatin as an alternative to Cisplatin in chemotherapies: New insights at single molecule level. Biophys Chem. Oct 2018;241:8-14. doi:10.1016/j.bpc.2018.07.004
30. Boulanger J, Boursiquot JN, Cournoyer G, et al. Management of hypersensitivity to platinum- and taxane-based chemotherapy: cepo review and clinical recommendations. Curr Oncol. Aug 2014;21(4):e630-41. doi:10.3747/co.21.1966
31. Lee SS, Mountain J, Koenig BA. The meanings of "race" in the new genomics: implications for health disparities research. Yale J Health Policy Law Ethics. Spring 2001;1:33-75.
32. Braun L. Reifying human difference: the debate on genetics, race, and health. Int J Health Serv. 2006;36(3):557-73. doi:10.2190/8JAF-D8ED-8WPD-J9WH
33. Gannett L. The Biological Reification of Race. British Journal for the Philosophy of Science. 2004;55(2)
34. Graves Jr JL. Biological theories of race beyond the millenium. In: Suzuki K, Von Vacano DA, eds. Reconsidering race: social science perspectives on racial categories in the age of genomics. Oxford University Press; 2018:21-31.
35. Graves Jr JL. 8. Evolutionary Versus Racial Medicine. Race and the Genetic Revolution. Columbia University Press; 2011:142-170.
36. Graves Jr JL. Great is their sin: Biological determinism in the age of genomics. The Annals of the American Academy of Political and Social Science. 2015;661(1):24-50.
37. Graves Jr JL. Why the nonexistence of biological races does not mean the nonexistence of racism. American Behavioral Scientist. 2015;59(11):1474-1495.
38. Hagen E. AAPA statement on biological aspects of race. Am J Phys Anthropol. 1996;101(4):569-70.
39. Bellon T, Raymond N. Bristol-Myers, Sanofi ordered to pay Hawaii $834 million over Plavix warning label. Accessed June 1, 2022, https://www.reuters.com/article/us-bristol-myers-sanofi-plavix/bristol-myers-sanofi-ordered-to-pay-hawaii-834-million-over-plavix-warning-label-idUSKBN2AF1YI
40. Nyakutira C, Roshammar D, Chigutsa E, et al. High prevalence of the CYP2B6 516G-->T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe. Eur J Clin Pharmacol. Apr 2008;64(4):357-65. doi:10.1007/s00228-007-0412-3
41. Nordling L. How the genomics revolution could finally help Africa. Nature. Apr 5 2017;544(7648):20-22. doi:10.1038/544020a
42. Nobles M. History counts: a comparative analysis of racial/color categorization in US and Brazilian censuses. Am J Public Health. Nov 2000;90(11):1738-45. doi:10.2105/ajph.90.11.1738
43. Genomes Project C, Auton A, Brooks LD, et al. A global reference for human genetic variation. Nature. Oct 1 2015;526(7571):68-74. doi:10.1038/nature15393
44. Li JZ, Absher DM, Tang H, et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science. Feb 22 2008;319(5866):1100-4. doi:10.1126/science.1153717
45. Krebs K, Milani L. Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good. Hum Genomics. Aug 27 2019;13(1):39. doi:10.1186/s40246-019-0229-z
46. Popejoy AB, Fullerton SM. Genomics is failing on diversity. Nature. Oct 13 2016;538(7624):161-164. doi:10.1038/538161a
47. Bustamante CD, Burchard EG, De la Vega FM. Genomics for the world. Nature. Jul 13 2011;475(7355):163-5. doi:10.1038/475163a
48. Petrovski S, Goldstein DB. Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine. Genome Biol. Jul 14 2016;17(1):157. doi:10.1186/s13059-016-1016-y
49. Need AC, Goldstein DB. Next generation disparities in human genomics: concerns and remedies. Trends in Genetics. 2009;25(11):489-494.
50. Genevieve LD, Martani A, Shaw D, Elger BS, Wangmo T. Structural racism in precision medicine: leaving no one behind. BMC Med Ethics. Feb 19 2020;21(1):17. doi:10.1186/s12910-020-0457-8
51. Sun S. Between personalized and racialized precision medicine: A relative resources perspective. International Sociology. 2020;35(1):90-110.