Genetic Contribution to Asthma Informs Acute Chest Syndrome Pathophysiology and Risk Stratification

ABSTRACT Acute chest syndrome (ACS) is a severe complication of sickle cell disease (SCD) occurring in ~50% of patients, some presenting frequent episodes. We lack tools to identify patients at high risk of ACS occurrence or frequent episodes. Epidemiological studies have found an association between asthma and ACS, but whether this link is causal is unclear. We used polygenic scores (PGS) to analyze whether the genetic propensity for asthma was associated with ACS and could be used to stratify the risk of ACS. We identified that PGS for asthma (PGS asthma ) was associated with ACS rate (number of episodes per year), but not ACS occurrence, in both the CSSCD ( n = 1278) and the GEN‐MOD ( n = 406) prospective SCD cohorts, independently of fetal hemoglobin (HbF) ( β = 0.17, standard error = 0.06, p = 0.006). This effect was most pronounced in patients with low HbF levels. Combining PGS asthma and HbF identified a population at high risk of frequent ACS after a first episode: individuals within the highest PGS asthma quintile and the lowest HbF quintile. Finally, we found that the genetic correlation between these two conditions only partially overlapped. This suggests that genetically determined asthma is not the unique contributor to the genetic propensity for ACS and that other genetic determinants may also play a role. In sum, our results suggest that patients with a high genetic propensity for asthma are prone to frequent ACS if not protected by high HbF levels. Combining PGS asthma and HbF may allow identifying patients at high risk of frequent ACS after a first episode for personalized management.