Diversity of the patients we serve is no secret at Montefiore in the Bronx, where I practice. You see it in their faces, clothing, languages, and accents. The people present an extraordinary array of ancestries, making the borough a microcosm of the world.
As a healthcare provider, you may wonder about your treatments; maybe one size doesn’t fit all? Does something embedded in our genetic histories lead individuals toward different disease courses, therapeutic responses, and outcomes?
We should indeed be wondering about these issues. Research is showing that there is expanding evidence for ancestry influencing a number of diseases. Our patients’ genomes contribute to the health disparities they face due to failures to recognize these differences.
In modern healthcare, we want to meet the elusive quadruple aim of health-system performance: enhancing how patients experience our services, improving the health of the populations we serve, keeping our costs constrained, and making the job more enjoyable for our providers. Medical genomics is a field that can make inroads into population and costs—and nowhere more so than in the diverse population of the Bronx.
A Hidden Challenge for Puerto Ricans
One clinical situation vividly illustrated to me the value of understanding the genomics of the Bronx population. Puerto Rico was originally populated by the seafaring Taíno Indians. Those genes survive in the genomes of modern-day Puerto Ricans, where they reside with those of European and African ancestors. This is apparent in a mutation of a collagen gene on the end of the long arm of chromosome 9. This mutation was present in Taíno people and persists to this day, carried by one in every 50 Puerto Ricans. At its most severe, the mutation causes short stature and multiple skeletal problems, including hip dysplasia—a condition called Steel syndrome.
When we evaluate children presenting at Montefiore with hip dysplasia and other skeletal abnormalities, and the parents have Puerto Rican ancestry, we make certain to look for this ancient Taíno mutation. It’s important to check for it. When surgery is performed to fix a kid’s hip dysplasia, generally it goes well, but not in the kids with Steel syndrome. For these patients the outcomes have been described as dismal.
This vignette illustrates two important points: there are mutations, rare elsewhere, that are going to be relatively common in the Bronx, and when we find these DNA sequence changes, they will influence how we manage our patients.
Genomic Testing to Reduce Costs
The case for cost reduction is also easy to understand just by invoking the benefits of pharmacogenomics, or the prediction of adverse drug responses through genomic testing. Drugs as commonly used as warfarin (for blood clots) and carbamazepine (for seizures, nerve pain, and bipolar disorder) have known increased risks of adverse reactions in patients with specific DNA sequence changes. It has been estimated that by using pharmacogenomic guidance, the cost of managing a patient with depression can be reduced by about $4,000 per year. Adverse drug reactions account for over 6 percent of all U.K. hospital admissions, and rank somewhere between fourth and sixth in causes of mortality in U.S. hospitals. If we knew in advance who is genetically predisposed to adverse drug reactions, we could make significant improvements in both cost and quality of care.
In the biggest study of warfarin pharmacogenomics, while about a quarter of the study participants were black Americans, only the variants that occurred commonly in participants of Northern European ancestry were assessed. However, there are some variants that are more common in those with sub-Saharan African ancestry that also influence drug responses and are under-studied. Pharmacogenomics is therefore imperfect when used to help diverse populations. The Bronx population provides an opportunity for discovery of new pharmacogenomic variants.
Even common diseases show differences when ancestry is considered within the borough. If you have two men from the Bronx with the same degree of obesity and type 2 diabetes, one a black American and the other a Hispanic American, the sub-Saharan African ancestry of the former increases the chances of peripheral vascular disease as a complication. For the latter, the East Asian ancestry in many Hispanics predisposes him toward a very different complication: nonalcoholic fatty liver disease. Why, we do not know. The cause remains to be discovered within the array of DNA sequence differences distinguishing these populations.
Another Bronx feature is the very high proportion of individuals with severe asthma who have the generally less common, nonallergic form of the disease, which is much more difficult to treat, and likely to be due to our local population ancestries being distinctive compared with those in other urban communities. Again, a current challenge is a future opportunity: we can delve into the genomes of our non-allergic asthmatics and try to find treatments needed for our Bronx patients.
The Need for Diversity in Genomics Research
A major problem in genomics research has been the extreme skew toward studies of white people. Up to 2018, genome-wide association studies have focused on those of European ancestry (78 percent), with disproportionately few Asian (10 percent), African (2 percent), and Hispanic (1 percent) people studied. This is not even the good idea it appeared to be from the technical perspective that originally justified looking at homogeneous populations. We now appreciate that there are major advantages to studying diverse populations in making disease-gene discoveries. As a result of this awareness, NIH funding strategies are pivoting to focus on testing minority populations.
The world has brought its DNA to the Bronx; we do not need to travel to be exposed to the enormous genetic diversity of humankind. Instead, we’re challenged to learn how to identify and work with genetic variability when providing healthcare to our patients. We can also aim to make new discoveries, working in the Bronx while benefitting the countries at the source of our borough’s diaspora. It is not out of the question that the Bronx could be a center of discovery for medical genomics, driving everything from basic science research to clinical medical care while allowing us to become more attuned to each individual in the patient population we serve.