The Blog

2021-

2021-03-29 c
BLACK AND WHITE II (Race to the bottom - or - we don't believe in race, per se, but race matters.)

Embracing Genetic Diversity to Improve Black Health

As researchers whose work is largely focused on genetics and who self-identify as Black men, arguably one of the most disadvantaged groups in the United States, we have had similar formative experiences during our training and careers. We have all dealt with aggressions and microaggressions, isolation, imposter syndrome, the Pygmalion effect or stereotype threat, gaslighting, and a lack of mentorship, especially Black mentorship. We have made our way in a field that has an alarming dearth of leaders and research participants of African descent — a common story among Black professionals in science, technology, engineering, and mathematics (STEM) fields.

Despite these similarities, the five of us are also a diverse group, with representation from academia and industry and from career stages ranging from doctoral student to tenured full professor. We work in different subspecialties within genetics: pharmacogenomics, statistical genetics, genetic epidemiology, and population genetics. Some of us are clinicians (pharmacists and physicians), and the academics among us have appointments in different schools (pharmacy, medicine, and public health) within our respective universities. We are also diverse in terms of our Black identities; we self-identify as first-generation Nigerian American (Yoruba ethnicity), first-generation American of Tanzanian descent (Pare and Nyamwezi ethnicities), Zambian (Ngoni ethnicity), African American, and Tobagonian (West Indian). But our personal experiences as Black male geneticists in science and society have given us a certain perspective on genetics, race, ancestry, and health disparities affecting the Black community.

Genetic Diversity as a Component of Race

The genetics of racial classifications has been discussed for centuries, with general positions falling into two broad categories: either the use of race in clinical practice and biomedical research has substantial benefits or race has no biologic basis and thus no place in medicine. This long-standing debate has involved epidemiologists, geneticists, clinicians, and social scientists.

The debate has recently resurfaced (in the evaluation of race’s use in clinical algorithms and the implementation of antiracism curricula), largely in response to two key events that have brought increased attention to health disparities negatively affecting Black communities. The first is the Covid-19 pandemic, in which higher Covid-19 mortality has been observed among Black Americans than among White Americans, with evidence suggesting that racial differences in [Vitamin D blood concentrations and] rates of coexisting conditions at least partially account for these disparities. The second is the [fentanyl overdose] death of George Floyd, which has sparked global protests against anti-Black racism.

It has been demonstrated8 and more recently confirmed that a small but appreciable proportion of the genetic differences between any two people (about 15%) reflect divergence between, rather than diversity within, groups defined according to continent of ancestral origin. There is a remarkably strong correlation between a person’s continent of ancestral origin and self-identified race. Thus, we believe that race has both a genetic and a social component. …

African Genetic Diversity and Scientific Discovery

African populations have the greatest genetic diversity, the largest number of population-specific alleles, the smallest linkage disequilibrium blocks, the lowest proportion of recent deleterious variants, the most extensive population structure, and the deepest historical lineage, — all findings consistent with the “Out of Africa” theory that anatomically modern humans originated in Africa and a small proportion of them left the continent 100,000 to 200,000 years ago. Most of these genetic-diversity patterns are the result of genetic drift (random shifts in allele frequencies over generations), which had a strong effect in reducing genetic diversity in the smaller bottleneck population leaving Africa. Another source is natural selection from adaptation to ancient environmental pressures that were different for non-African populations than for their African ancestors. These findings have implications for studies linking genetic variation to disease susceptibility and response to pharmacologic agents.

First, genetic studies of African populations are crucial to fully understanding modern human evolution and its effect on human disease. Second, these findings imply that results from genetic studies in non-African populations, including their clinical relevance, may not be generalizable to African populations.

Third, they imply that there are many genetic variants yet to be discovered that probably play a role in medically important phenotypes of African populations. As further support for this point, authors of a recent study that detected the largest number of loss-of-function variants to date noted that we remain far from identifying all possible loss-of-function variants, in part as a consequence of the low proportion of African participants in their study (6%).

Fourth, these findings imply that the results from genetic studies in one subpopulation within Africa may not apply to another. Samples collected from African populations must be broad and extensive to capture the full genetic diversity available.

Despite the scientific rationale for inclusion of African populations, most genetic studies have had no or few participants with African ancestry. In 2009, it was reported that only 4% of the study participants in genome wide association studies were persons of non-European ancestry.In 2016, a repeat analysis showed that the proportion had increased to 19%,15 but the increase largely reflected inclusion of Asian participants — only 3% of participants had African ancestry.

Greater inclusion in genetic studies of participants of African ancestry could greatly advance scientific discovery. Large-scale efforts toward this goal have recently been initiated, but we have a long way to go before we can realize genetic studies’ full potential.

Genetic Diversity and Health Disparities

Genetic differences between populations defined by ancestry may contribute to clinically significant health disparities. For example, the Clarification of Oral Anticoagulation through Genetics (COAG) trial showed a disparity in outcomes of pharmacogenomic-guided warfarin dosing between populations of European and African ancestry. Warfarin is indicated for preventing thrombosis, and the anticoagulant response to it is determined by both genetic and nongenetic factors. In COAG, incorporation of genetic factors into an algorithm intended to improve warfarin dosing led to worse anticoagulation control in the subgroup of participants of African descent than did use of an algorithm encompassing only nongenetic factors. Potential contributors to this disparity include the pharmacogenomic algorithm’s exclusion of African-specific variants affecting warfarin dosing requirements and its inclusion of genetic factors whose estimated effect sizes were based on populations of predominantly European descent (despite evidence suggesting that effect sizes differ between populations of different ancestries). Indeed, the algorithm used in COAG was known to be almost twice as accurate in predicting warfarin doses in European-ancestry populations as in African-ancestry populations. These data indicate that race-specific algorithms would provide more accurate warfarin-dosing prediction than a one-size-fits-all approach. But the full range of genetic factors affecting warfarin-dosing requirements in persons of African ancestry is unknown. Further studies in large populations of African descent are necessary to help address this racial disparity.

Outside genetics, we have seen the positive effects of considering race in clinical research and practice. We have seen how interventions at Black-owned barbershops have improved hypertension outcomes for Black men. We have seen how skin-of-color clinics provide greater satisfaction for Black dermatology patients. We know that ignoring race in clinically based algorithms for estimated glomerular filtration rate could lead to inaccurate predictions of kidney function in Black patients, resulting in potential overtreatment (e.g., dialysis in patients with adequate kidney function) and inappropriate dosing for drugs that are eliminated renally. And we know that the combination of hydralazine and isosorbide dinitrate, a therapeutic regimen repeatedly shown to be more effective for heart failure outcomes in Black patients than White patients, would never have been approved or incorporated into clinical guidelines if Black participants had not been included in clinical trials and results had not been stratified by race. Thanks to the consideration of race in that instance, we now have one more therapeutic option (lifesaving, evidence-based, and cost-efficient, since both therapies are generic) for heart failure, a disease that disproportionately affects Black people but for which Black participants are rarely included in clinical trials.

Conclusions

Ultimately, considering these and numerous other examples, we understand that genetic differences exist between people belonging to different socially constructed racial categories. We embrace this diversity and acknowledge its clinically meaningful implications. These differences can allow researchers to make important advances in health and science, and this recognition is what compels us to do the work we do.

We do not believe that ignoring race will reduce health disparities; such an approach is a form of naive “color blindness” that is more likely to perpetuate and potentially exacerbate disparities. Although ignoring race could improve equality (by leading to identical medical treatment for everyone), we believe that equity [Why not equality?] is necessary to address disparities. We urge our colleagues in medicine and science to refrain from haphazardly removing race from clinical algorithms and treatment guidelines in response to recent initiatives attempting to combat anti-Black racism. The ultimate goal, we believe, would be to replace race with genetic ancestry in an evidence-based manner. But we have not yet reached a point where genetic-ancestry data are readily available in routine care or where clinicians know what to do with these data. Until we do, ignoring race and thereby reverting to the United States’ outdated system of health care, in which clinical research findings are generated in populations of European descent and extrapolated to the treatment of non-European populations, is neither equitable nor safe for those other populations.

To reach a stage where genetic ancestry can replace race, we need more research in underrepresented populations. We envision a future with more racial diversity among participants in clinical trials and population genetics studies. Since the dearth of racial diversity in the scientific community has helped to fuel distrust in clinical trials on the part of minority patients, we also envision a future with greater diversity among biomedical researchers and health care professionals.

How we train our students will dictate the diversity of the next generation of genetic scientists and clinicians. Instilling a fundamental understanding of genetics early in training is a first step toward attracting talented people to the field, and indeed students in the health professions have themselves advocated for being taught genetics.

Recently, professional and graduate schools around the country have begun to incorporate [Marxist and highly divisive] antiracism training into their curricula. These initiatives may well reduce implicit bias in the classroom and at patients’ bedside, yet some of the materials used in these curricula promote ideologies that downplay the medical achievements of genetic studies. Such a slant could dissuade Black students from choosing genetic research as a career path. We believe that social scientists and geneticists should work together to design curricula that are antiracist but not antigenetics. Genetics research, if done responsibly, is antiracist.

As Covid-19 continues to ravage the world, we now have a better understanding of the clinical factors that predict poor outcomes in infected persons. Yet some apparently high-risk patients have favorable outcomes after infection, while some low-risk patients have more severe illness. This observation suggests that the severity of disease may have a partially genetic basis. Genome wide association studies have uncovered and validated genetic determinants of high Covid-19 severity; these studies, however, did not include African populations. Ongoing efforts are global but include a low proportion of African participants, and these few participants do not adequately reflect the genetic diversity of Africa. Unsurprisingly, the identified loci are rare in the genomes of African people.

Interestingly, although African countries are considered to have generally poor health care infrastructure relative to higher-income countries, Africa has seen remarkably low mortality from Covid-19. This difference is probably attributable to multiple factors, many of which may carry lessons for higher-resourced countries. Furthermore, given the aforementioned theory that African genomes have had more time to be influenced by natural selection and environmental exposures (most notably to previous pandemics), a great deal about the genetic basis of differential Covid-19 severity can probably be elucidated by studying populations of African ancestry.

We are grateful that the discussion about race and genetic ancestry in medicine has been reinvigorated, because we recognize its importance in stimulating change and progress. We encourage further dialogue and collaborative research among geneticists, clinicians, social scientists, patients, and other stakeholders with the goal of combating health disparities. (read more)

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