Genetic contribution to asthma informs acute chest syndrome pathophysiology and risk stratification

Acute chest syndrome (ACS) is a severe complication of sickle cell disease (SCD), but we lack tool to identify patients at high risk of ACS. Epidemiological studies have found an association between asthma and ACS but whether this link is causal is unclear. We used polygenic score (PGS) to analyze whether the genetic susceptibility to asthma was associated with ACS and could be used to stratify the risk of ACS. We identified that a PGS for asthma (PGS _asthma ) was associated with ACS rate, but not ACS occurrence, in both the CSSCD and the GEN-MOD cohorts, independently of fetal hemoglobin (HbF) (β=0.17, standard error=0.06, p=0.006). This effect was mainly found in patients with HbF <5%. Combining PGS _asthma and HbF allowed to identify a population at high risk of ACS recurrence: individuals within the highest PGS _asthma quintile and the lowest HbF quintile. Partitioned PGS suggested that lymphocytes were the main driver of the genetically mediated risk of ACS by asthma. Finally, we assessed asthma and ACS overall genetic correlation. We found that these two conditions only partially overlap distinct, suggesting that asthma is not the main determinant of genetic propensity to ACS. In sum, our result suggests that patients with high genetic propensity to asthma are prone to recurrent ACS if not protected by high HbF levels. Combining PGS _asthma and HbF may allow identifying high risk patients for personalize ACS management. Apart from this population at high risk of ACS, additional genetic determinants independent from asthma contribute to ACS.