Dr. Wonkam’s research on sickle cell disease genetics

By Megan Sayles
AFRO Staff Writer
msayles@afro.com

When Dr. Ambroise Wonkam walked into a panel on medical genetics out of curiosity, he had no idea it would shape the course of his career. Born in Cameroon, Wonkam has dedicated his career to studying genetic and genomic variations in African populations and their impact on conditions, like sickle cell disease. 

Today, he is the director of the McKusick-Nathans Institute and Department of Genetic Medicine at the Johns Hopkins University School of Medicine. His father’s advice has been one of the guiding principles behind his work. 

“He always said you have to have three major objectives in your life. One was being useful to yourself, the second was being useful to your family and the third was being useful to your nation,” said Wonkam. “My nation is the African nation, and I did not remember seeing a single African at the time who was a geneticist. I thought if I did genetic medicine, I would certainly be useful to my nation.”

Dr. Ambroise Wonkam serves as the director of the McKusick-Nathans Institute and Department of Genetic Medicine at the Johns Hopkins University School of Medicine. (Photo courtesies of Johns Hopkins University School of Medicine)

This week, the AFRO connected with Wonkam to discuss the role of genetic modifiers in sickle cell disease and their impact on patient care. 

AFRO: Can you explain in simple terms what “genetic modifiers” of sickle cell are? 

Ambroise Wonkam: Sickle cell disease is a genetic condition that affects red blood cells. It is caused by a mutation in the gene that makes up the hemoglobin, which is the protein in red blood cells that transports oxygen in our body. It is a condition that evolved in Africa as a variant to confer resistance to malaria if you only have one copy of the mutation. If you inherit two copies of the mutation from your mother and father, you develop the disease. 

In Nigeria, it is known that without treatment, 50 percent of children will die before their fifth birthday. It’s also the case in Nigeria that without treatment, some children will still live up to 60, which is the life expectancy for sickle cell in America. 

The question is: how is it that one of two people in the same environment— even if that environment is very harsh in terms of health care provisions— will survive well above their 50s without appropriate treatment? That’s where genetic modifiers come in. If the environment is that bad and you still survive with a very severe condition that suggests that in some part of your body there is some other variant or mutation that improves the severity of the condition in you. 

Genetic modifiers are important because they allow us to understand why one kid is very sick and the other is not when they have the same mutation. When we understand those modifications, they can be amenable to therapeutic modifications for treating the condition. 

AFRO: What have you learned about these modifiers through your research?

AW:  In our research, we have revealed modifiers in many sickle cell disease complications. For example, kidney disease and sickle cell disease are modified by three genes: APOL1, alpha thalassemia and HMOX1. For APOL1, there were some clinical studies published last year showing that if you modify that gene by inhibiting it using genetic technology or a pill, you reduce the occurrence of kidney dysfunction. Importantly, this was in people without sickle cell, suggesting that knowledge we have from sickle cell can also help the general population. 

We’re also very interested in genetic modifiers of fetal hemoglobin. Fetal hemoglobin is the type of hemoglobin present in babies before they are born. It progressively reduces when we’re born and becomes nearly zero in all of us as adults. If you maintain the capacity to produce fetal hemoglobin at 8 percent, it positively modifies your disease. 

Earlier this year, we published a study about a fetal hemoglobin modifier that we call “FLT1,” which we strongly believe can be a target for therapeutics in the near future. 

AFRO: You’ve discussed how Africa is underrepresented in genetic research. Why does this matter for sickle cell patients?

AW: It matters for humanity as a whole. There are three reasons why African genomes, in general, are critical for all of us. The first reason is ancestry. We are all African. The first human being evolved in Africa about 300,000 years ago. Present-day Europeans and Asians moved out of Africa only about 50,000 to 70,000 years ago. Yet, 98 percent of the genomic data we currently have comes from people of European ancestry. If we only study those genomes, they only represent a small fraction of humanity variation. 

The second reason is the geography of Africa. Africa stretches north to south. If you look at Europe and Asia, they’re quite horizontal, extending east to west. Africa crosses many regions with different climates and environments. For example, in Cairo, you have the Mediterranean climate. In Central Africa, you have the rainforest. Different environments have different impacts on your genome. For example, skin color changes based on sun exposure.  

The third reason is if you have different environments, you also have different types of infection. For example, you don’t have mosquitos producing malaria in Europe, but you do have it in African rainforests. As a result, the sickle cell mutation evolved in Africa as a survival mechanism to resist malaria. 

AFRO: How could more inclusive genetic data change care for sickle cell patients globally? 

AW: This ties into genetic modifiers. In the study we published earlier this year, we found 14 new genes that modify fetal hemoglobin. One of which is the FLT1. The variant we discovered in FLT1 was African-specific, meaning that if we did the same research on one million Europeans we would not have found that variant. 

If you don’t study the African population, you refuse the opportunity of discovering new potential targets for sickle cell disease therapeutics. Additionally, studying African populations does not only improve the care for a condition, like sickle cell in Africans— it also helps us to understand the human genome, improving care for all of us and for many other conditions.