An exploration of large patient biobanks linked to clinical information has revealed new health conditions associated with sickle cell trait, the status of carrying just one beta globin gene with the sickle cell mutation. (People with two mutated copies get sickle cell disease.)
In new work published in The American Journal of Human Genetics, Fred Hutch Cancer Center genetic epidemiologists confirmed a link to chronic kidney disease, pulmonary embolism and anemia, and also highlighted new associations, as well as several sex-based differences in health associations.
“Our goal was to try to more comprehensively identify what are people with sickle cell trait at risk for: What are their clinical manifestations?” said Fred Hutch epidemiologist Alexander Reiner, MD. “In contrast to the thinking that sickle cell trait is completely benign, it can be associated with some clinical complications or laboratory alterations, particularly related to the kidney.”
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It’s too soon to say that sickle cell trait causes the newly linked health outcomes, but even non-causative associations could help providers tailor care for people with sickle cell trait, said Fred Hutch sickle cell expert Kleber Yotsumoto Fertrin, MD, PhD, who directs Fred Hutch’s Sickle Cell Disease and Iron Overload Program and was not involved with the study.
“We have to have an open mind as far as what the data is showing us,” Fertrin said. “I think the association helps us in health care find people at higher risk for issues. We're not saying that sickle cell trait necessarily causes all the things that they found, but maybe you're more likely to find certain health conditions among people who have sickle cell trait.”
“A lot is known about sickle cell disease and its clinical manifestations and complications,” Reiner said. “Traditionally, sickle cell trait, the carrier state, has been thought to be relatively benign.”
Most people with sickle cell disease have mutations in both copies of their beta globin gene. (Hemoglobin is made of two beta globin and two alpha globin proteins.) The sickle cell mutation creates a hemoglobin protein with a sticky patch. If all the hemoglobin is sticky, it is prone to forming stiff strands as it jettisons oxygen. Red blood cells full of these stiff strands switch from a flexible saucer shape to a cramped, “sickle” shape that’s too rigid to pass through minute capillaries.
Stressors that cause blood vessels to constrict, like dehydration, high altitude, changes in temperature and emotional stress, can trigger a sickle cell crisis. During these extraordinarily painful episodes, sickled red blood cells block blood flow to tiny vessels. People with sickle cell disease are at risk of strokes and organ damage all over the body, including to the kidneys, liver, lungs and eyes. And because sickled red blood cells don’t last as long as saucer-shaped red blood cells, people with sickle cell disease also get anemia.
A person with sickle cell trait carries only one mutated beta globin gene. Half of their hemoglobin is sticky, but this is almost never enough to trigger the hemoglobin polymerization and red cell sickling that’s so damaging.
Though people with sickle cell trait almost never have to worry about sickle cell crises, being a carrier is a risk factor for kidney disease. It’s also the biggest risk factor for renal medullary carcinoma, a very rare cancer of the kidney, and in very unusual conditions of extremely low oxygen people with sickle cell trait are at higher risk of losing blood flow to the spleen. Fertrin also noted that one of the extremely rare times that someone with sickle cell trait might experience red blood cell sickling is if physical trauma causes a bleed within the eye.
The association between kidney disease and sickle cell trait started with anecdotes that were then confirmed with larger studies. Reiner decided to explore whether other health conditions may also be associated with sickle cell trait by taking advantage of large biobanks of patient-donated tissue samples that are linked to clinical information, including diagnoses and lab results.
To explore health outcomes associated with sickle cell trait, Reiner and his team turned to three biobanks: Vanderbilt University Medical Center’s BioVU, the Penn Medicine Biobank and the National Institutes of Health’s All of US, all of which link genetic and molecular information to clinical information in electronic health records.
“This is the first comprehensive, cross-biobank analysis of medical conditions and laboratory abnormalities associated with sickle cell trait,” Reiner said.
The samples in these biobanks have been genetically sequenced, so Reiner and his collaborators knew which patients carry a sickle cell mutation. (This information is not always noted in someone’s medical chart. The investigators found that about 75% of sickle cell carriers in the study likely did not know their status.) They also worked to control for other mutations, like those that cause beta-thalassemia, which can combine with sickle cell trait to cause sickle cell disease. Out of 58,830 biobank donors with African genetic ancestry, 4,813 were sickle cell carriers.
Armed with this information, the researchers ran two types of meta-analyses. The first looked for associations between sickle cell trait and health complications like an enlarged spleen or anemia. These health outcomes are called phenotypes, and the group used billing codes for various diagnoses as phenotype proxies. Reiner’s team used a phenotype-wide association study (or PheWAS) to link billing codes to sickle cell trait status.
His group also looked at lab tests, using a clinical laboratory-wide association study (LabWAS) meta-analysis to see if sickle cell trait was associated with differences in test results like blood cell counts and kidney function. The biobank participants were about 60% female and 40% male, so Reiner’s team was also able to see if there are any associations differed based on sex.
The PheWAS study confirmed a previous association with chronic kidney disease. The analysis also confirmed associations between sickle cell trait and pulmonary embolism (a clot in the lungs) and anemia. Their LabWAS analysis confirmed prior associations with blood cell counts, red cell indices, kidney function and urinary concentrating ability.
The analyses also turned up associations not reported before, including with enlarged spleen, gout, acute kidney inflammation and anemia of pregnancy. In the LabWAS analysis, Reiner and his team saw new associations between sickle cell trait and higher serum electrolytes, bilirubin levels and immature red blood cell counts, as well as lower blood urea nitrogen and platelet counts.
Reiner’s group is also the first to see some sex-based differences in associations. In females, the researchers saw a stronger association between sickle cell trait and kidney-related disorders and kidney dysfunction. The studies showed a stronger association with lower platelets and certain immune cell counts in males.
“It does kind of dovetail with what’s known about sickle cell disease, in that there are some sex differences in terms of disease severity or particular complications,” he said.
The relationship between association and causation is not straightforward, and it’s too soon to know whether sickle cell trait causes any of the newly linked health conditions. If the new associations hold up in other studies, they could influence what other health conditions clinicians watch out for, and how they might read certain lab results.
It’s not unprecedented that sickle cell trait may alter lab tests. Certain assays for hemoglobin A1c, which is used to diagnose insulin resistance and diabetes, can be altered by having 50% sticky hemoglobin. (Luckily, most tests account for this.)
Reiner and his co-authors noted that other health conditions, such as the red blood cell disorder alpha-thalassemia, could underlie some of the new associations.
For example, people with sickle cell trait are more likely to have smaller red blood cells than normal, but that’s because they’re also more likely to have inherited alpha-thalassemia, which causes smaller red blood cells. Like sickle cell trait, alpha-thalassemia is more commonly (but not exclusively) found in people with African ancestry rooted in areas where malaria is endemic.
“Sickle cell trait did not cause their red cells to be smaller, it’s just associated and there is a known, geographical reason for that,” Fertrin said.
Both Reiner and Fertrin noted that using billing codes as stand-ins for diagnoses can complicate interpretation. Though billing codes are easy to use as diagnostic proxies, they are not always rigorously defined, Reiner said.
“Physicians may pick ‘splenomegaly’ as the code when they can’t find a more precise code to define what the patient was having; they may pick ‘sickle cell trait’ and ‘hemoglobin C trait’ instead of ‘hemoglobin SC disease,’” Fertrin said.
Further study is needed to understand whether these associations hold up in larger studies, or whether any of them represent causation.
For the associations confirmed by further work, the next step will be to try to predict who with sickle cell trait will go on to develop a health outcome like kidney disease or a lung clot, Reiner said. There may be other factors, genetic or environmental, that influence which sickle cell carriers are most at risk of health complications.
“For those modifying factors, you need even larger samples,” Reiner said. “In this study we had over 50,000 participants, but to really identify modifying factors, you probably need 10 times more.”
In the meantime, the work highlights the importance of knowing one’s sickle cell status, Fertrin said, and even non-causative associations could help guide patient care.
Sometimes people with sickle cell trait (or their physicians) will assume it is the cause of conditions like anemia or pain, which can lead to mistreatment, he said.
If a physician knows there is an association between sickle cell trait and certain health conditions or lab abnormalities, they may be more inclined to look for and investigate them, even if sickle cell trait is not the cause, Fertrin said.
“There is no treatment for trait, but knowledge is power … if you know you have an extra risk, you can take steps to mitigate the other risk factors,” he said. In the meantime, there’s plenty of reassurance for people with sickle cell trait, who are spared the pain and most organ damage risks faced by people with sickle cell disease.
“Sickle cell trait is something I think people should learn more about and should be aware of whether they carry it or not,” Fertrin said.
This work is part of the PRIMED Consortium and was supported by the National Institute of Health, the National Human Genome Research Institute, the National Cancer Institute and the Clinical and Translational Science Award Program.
Sabrina Richards, a senior editor and writer at Fred Hutch Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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