Critical race theory: the newest foundational science
By: Natasha Edman
Tags: Health, Medical School, Genetics, Step 1, Critical Race Theory

In my second year of medical school, I took the grueling, high-stakes test known as the USMLE Step 1. This 7-hour multiple-choice test is designed to assess understanding of the “foundational” sciences, and I spent the first 18 months of medical school in preparation. One day, as I was reviewing genetic diseases in the 790-page reference book First Aid for the USMLE Step 1, I came across an entry for a genetic condition known as hereditary transthyretin amyloidosis. My first thought was, “Yet another disease they didn’t cover in class.” I read on and learned that transthyretin amyloidosis is caused by a mutation in the gene coding for the protein transthyretin. The protein misfolds and builds up inside cells, leading to a variety of symptoms: some patients develop heart failure, others suffer from debilitating nerve damage. Then I saw this sentence: “5% of African Americans are carriers of mutant allele.”

That short sentence raised 3 big red flags for me. Firstly, a cursory internet search revealed that First Aid was incorrect about the genetic mode of inheritance for transthyretin amyloidosis. Secondly, that same internet search also showed that transthyretin amyloidosis is drastically understudied given the number of people affected. The third and most concerning was the use of race — a social construct used to divide people into groups — to imply risk for a genetic disease. Each of these can be examined through the lens of critical race theory, which explores how powerful institutions create and perpetuate racist systems.

Transthyretin amyloidosis is autosomal dominant, meaning that a person needs only one copy of the mutation to develop the disease [1]. First Aid describes people with a transthyretin mutation as “carriers”, a term which is specifically used for autosomal recessive genetic conditions. Implying that the transthyretin amyloidosis mutation is recessive is not a trivial error: if a physician thinks their patient is a carrier, unaffected by the disease, they will not recommend any follow-up care. This misinformation could delay diagnosis and management for years.

Secondly, in my two years of medical school, I have never met a patient with transthyretin amyloidosis. If it were true that almost 1 in 20 African Americans have the mutation for the disease, odds are I would have seen it in clinic, or heard of it from a classmate or instructor. In fact, I do not know where First Aid even got their information on prevalence, because for the specific transthyretin mutation identified in African Americans, reported rates are actually between 3 and 3.4 percent — still a worryingly high number [1–3]. Compare this with Huntington’s disease, an infamous genetic illness with many similarities, including a fatal prognosis. There are currently 85 clinical trials for Huntington’s disease in the United States, but only 13 clinical trials for transthyretin amyloidosis. This is despite the fact that Huntington’s affects a far lower number of patients: 1–2 of every 100,000 people in the United States.

Why is transthyretin amyloidosis understudied? Racism, or systemic discrimination by powerful people and institutions against nonwhites, likely plays a significant role. While transthyretin amyloidosis is traditionally thought to be most prevalent in blacks, Huntington’s occurs at equal rates in blacks and whites [4]. Whites hold leadership positions in medical research at a disproportionately high level, and power players tend to promote causes with a concrete benefit to themselves, even if that benefit is not readily apparent (a phenomenon known as interest convergence). Some argue that transthyretin amyloidosis is a challenging diagnosis to make, with few hallmark features to distinguish it [5–7], which is possibly why I have never seen it in clinic. I would counter that diagnosis can become more accurate if we fund more research and increase awareness. Another argument is that patients often present at late stages of the disease, making it harder to study the course of illness and potential treatments. Here, critical race theory would remind us that black patients have multiple barriers to healthcare that delay their diagnosis and worsen their outcomes.

The third issue in First Aid’s statement on transthyretin amyloidosis is the term “African American”. The use of race in determining disease risk is pervasive in medicine, often without any supporting evidence. A prime example is glomerular filtration rate or GFR, which estimates kidney function and is calculated with a “correction” for African Americans, despite increasing evidence that this is unnecessary and even harmful to black patients [8,9]. Using race as a proxy for genetic disease risk is particularly problematic. Many recent studies have shown that race is not based in genetics and society’s definitions of race rarely reflect where a person’s ancestors came from [10,11]. In other words, the labels of “black” or “African American” may include people that actually have no African ancestry, while missing many people with African ancestry who have not been societally labeled as black or who self-report as two or more races.

Ancestry can be somewhat reliably determined through DNA [12], but as far as I know, medical research centers do not routinely collect DNA ancestry data. It is therefore almost impossible to estimate the true number of people with the transthyretin mutation. One is left asking, “5% of who? Does First Aid actually define who is an African American?” The answer is, they don’t. First Aid doesn’t even define race, or racism for that matter. To be fair, neither did the researchers who performed the original studies identifying the transthyretin mutation. By presenting information this way, without context or explanation, these groups perpetuate the myth that race is determined by genes.

This piece is not really about transthyretin amyloidosis, though I do think more clinicians should know about it. I sought to demonstrate the kinds of questions critical race theory leads us to ask in medical research. After learning that race is determined by society and not genes, I no longer accepted the argument that someone was at risk of a genetic disease because of their race. I wondered why transthyretin amyloidosis, which is (according to First Aid) 20 times more prevalent than Huntington’s, has one eighth the clinical trials and one tenth the research studies. The most troubling part of this exercise, however, was realizing that the premier reference material for medical students has absolutely no information about race. First Aid is not alone: none of my review materials attempted to define race. Why? Because they teach to the test, and the only material the USMLE Step 1 expects students to know in this area is “race/ethnicity health care disparities”, without any historical context of why those might exist.

Step 1 is meant to assess knowledge of the foundational scientific fields that underlie modern medicine. We have to learn biochemistry to understand the collagen in our skin, physics for the flow of blood through our arteries, and biomedical ethics for the complex circumstances in which we provide care. If race is considered an integral part of disease risk, then critical race theory should be an integral part of a physician’s education.

References

1. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-Sequence Transthyretin (Isoleucine 122) in Late-Onset Cardiac Amyloidosis in Black Americans. N Engl J Med. 1997;336(7):466–473. doi:10.1056/NEJM199702133360703

2. Buxbaum J, Alexander A, Koziol J, Tagoe C, Fox E, Kitzman D. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010;159(5):864–870. doi:10.1016/j.ahj.2010.02.006

3. Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African–Americans. Amyloid. 2015;22(3):171–174. doi:10.3109/13506129.2015.1051219

4. Bruzelius E, Scarpa J, Zhao Y, Basu S, Faghmous JH, Baum A. Huntington’s disease in the United States: Variation by demographic and socioeconomic factors. Mov Disord. March 2019. doi:10.1002/mds.27653

5. Kapoor P, Thenappan T, Singh E, Kumar S, Greipp PR. Cardiac Amyloidosis: A Practical Approach to Diagnosis and Management. Am J Med. 2011;124(11):1006–1015. doi:10.1016/J.AMJMED.2011.04.013

6. Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. J Am Coll Cardiol. 2015;66(21):2451–2466. doi:10.1016/j.jacc.2015.09.075

7. Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625–638. doi:10.3109/07853890.2015.1068949

8. Peralta CA, Lin F, Shlipak MG, et al. Race differences in prevalence of chronic kidney disease among young adults using creatinine-based glomerular filtration rate-estimating equations. Nephrol Dial Transplant. 2010;25(12):3934–3939. doi:10.1093/ndt/gfq299

9. Zanocco JA, Nishida SK, Passos MT, et al. Race adjustment for estimating glomerular filtration rate is not always necessary. Nephron Extra. 2012;2(1):293–302. doi:10.1159/000343899

10. Tishkoff SA, Kidd KK. Implications of biogeography of human populations for “race” and medicine. Nat Genet. 2004;36(11 Suppl):S21–7. doi:10.1038/ng1438

11. Fujimura JH, Rajagopalan R. Different differences: the use of “genetic ancestry” versus race in biomedical human genetic research. Soc Stud Sci. 2011;41(1):5–30. doi:10.1177/0306312710379170

12. Collins FS. What we do and don’t know about “race”, “ethnicity”, genetics and health at the dawn of the genome era. Nat Genet. 2004;36(S11):S13-S15. doi:10.1038/ng1436