RASA3 may be novel candidate gene for PH in sickle cell disease
Changes in RASA3 gene activity seen in SCD-PH patients in new study
A gene called RASA3 may be a candidate gene — one suspected of playing a role in a specific trait or disorder — in the development of pulmonary hypertension (PH) among people with sickle cell disease (SCD), according to a new study.
Reduced activity of RASA3 was evident in SCD patients who also had PH, and was associated with mortality. A particular mutation in the gene also was found to be linked to measures of pulmonary hypertension susceptibility and severity in SCD-PH.
That same mutation also was associated with measures of disease severity among people with pulmonary arterial hypertension (PAH) of European ancestry.
Altogether, these findings suggest “RASA3 is a novel candidate gene in SCD-associated PH and PAH,” with greater gene activity “appearing to be protective,” according to researchers, who noted that ongoing studies are aimed at further clarifying this relationship.
The study, “RASA3 is a Candidate Gene in Sickle Cell Disease-Associated Pulmonary Hypertension and Pulmonary Arterial Hypertension,” was published in the journal Pulmonary Circulation.
Study names RASA3 a candidate gene in SCD-PH
People with sickle cell disease, known as SCD, produce an abnormal version of hemoglobin — the protein that helps red blood cells carry oxygen through the body. This causes red blood cells to take on the sickle-like shape that gives the rare disorder its name.
These cells are prone to clumping together, and thus can obstruct proper blood flow and oxygen delivery to the body’s tissues. Sickled red blood cells also are more vulnerable to breaking apart and dying off than their healthy counterparts, which causes a shortage of red blood cells, or anemia.
Among the many possible consequences of SCD is PH, in which the pressure in the arteries supplying blood from the heart to the lungs — the pulmonary arteries — is too high. About 10% of SCD patients are thought to have this disorder.
The treatment of SCD-associated PH is usually similar to that of PAH, but new insights into the disease’s mechanisms are still needed to optimize therapeutic approaches for these patients, according to researchers.
RASA3 is a protein that’s involved in blood vessel formation and the function of the endothelial cells that line blood vessels. While it’s possible that RASA3 dysfunction may be a driver of PH, its potential role in the disease has not been explored.
Now, a team of researchers aimed to determine whether changes to the activity or DNA sequence of the gene encoding production of RASA3 might play a role in driving SCD-associated PH.
To that end, they utilized genetic data obtained from SCD patients to look for changes in the RASA3 gene.
RASA3 gene activity, or expression, in the blood was found to be decreased among SCD patients who also had signs of PH. Lower gene activity also was linked to indicators of higher PH severity and a worse prognosis.
Specifically, the gene’s activity was lower among patients who had higher pulmonary vascular resistance — a measure of resistance to blood flow in the pulmonary arteries — and in those who died over the course of follow-up.
Our results suggest that RASA3 may be a novel biomarker and potential candidate gene for pulmonary vascular disease.
In lung tissue samples, the researchers also identified particular mutations in RASA3 that were associated with the definitive presence of PH or signs of its existence among SCD patients. One in particular, called rs9525228, was significantly associated with markers of PH susceptibility and severity, and was linked to lower RASA3 gene activity.
Among a group of PAH patients without SCD, the rs9525228 mutation was associated with higher pulmonary artery pressure and pulmonary vascular resistance, but only among people of European ancestry, and not those of African ancestry.
That discrepancy warrants further analyses, according to the researchers.
Interestingly, the rs9525228 variant resides in a part of the gene called an intron. These regions don’t directly encode the production of a protein, but serve a variety of regulatory roles that influence gene activity.
“Further work is needed to elucidate the role of rs9525228, particularly within the context of the lung,” the researchers wrote.
“Additional studies are ongoing to decipher whether rs9525228 is the culprit or bystander of” the observed relationship with disease severity, the team added.
Specifically, these studies are seeking to better understand how RASA3 plays into the development of PH and how rs9525228 might contribute to more severe disease.
Overall, “our results suggest that RASA3 may be a novel biomarker and potential candidate gene for pulmonary vascular disease,” the researchers wrote.