Inflammatory Polymorphisms Link the Risk of Acute Chest Syndrome with Asthma in Adults with Sickle Cell Disease
Authors: Barber Latorya A. , Soldano Karen , Garrett Melanie , Orringer Eugene P. , Eckman James R. , Telen Marilyn J. , Ashley-Koch Allison E 
Published: October 2019

Abstract
Abstract 1072
Acute chest syndrome (ACS) is a common cause of death among patients with sickle cell disease (SCD). There is increasing evidence that asthma may represent a significant risk factor for the development of ACS in children with SCD and it is associated with increased mortality (Newaskar, et al. 2010; Poulter, et al. 2011).The incidence of ACS in adolescent SCD patients is associated with the occurrence of asthma and genetic polymorphisms in NOS1 and NOS3 (Duckworth, et al. 2007). Polymorphisms in inflammatory genes, including IL-12A, IL-12B, and IL-4 receptor have been previously associated with the incidence and severity of asthma in non-SCD cohorts (Chen, et al. 2011; Mannino, et al. 2002; Caggana, et al. 1999). These data imply that the association of asthma with increased risk for ACS in adolescent SCD patients has a genetic component. However, the clinical and genetic associations among ACS, asthma, and inflammation have not been evaluated in adults with SCD. Our goals were (1) to identify clinical risk factors for ACS and (2) to identify single nucleotide polymorphisms (SNPs) in inflammatory genes associated with asthma and ACS in our population of adult SCD patients. All clinical data were collected using standardized report forms. Use of bronchodilators served as a surrogate for the occurrence of asthma. We analyzed 94 SNPs within 14 inflammatory genes in 675 DNA samples from SCD patients ascertained from Duke University, University of North Carolina-Chapel Hill, and Emory University. In order to achieve greater coverage in our genes of interest, SNP genotyping data was derived from two methods, Taqman genotyping assays from Applied Biosystems and genome-wide association studies (GWAS) using the Illumina-610 SNP array. Clinical and genetic associations with ACS and use of bronchodilators were examined using regression analysis (PROC LOGISTIC or GLM in SAS version 9.2, Cary, NC). The incidence of ACS in our population was 73%. Six percent of our population used bronchodilators, similar to the overall incidence of asthma in the US population (Newaskar et al., 2011). We observed a significant association between the use of bronchodilators and the incidence of ACS in our dataset, such that the percentage of patients with a history of ACS among bronchodilator users was 90% versus 73% in non-users (p=0.028). ACS was also associated with an increase in pain episodes (OR=1.6, p<0.0001), narcotics use (OR=1.5, p=0.0002), WBC counts (p=0.04), platelet counts (p=0.007), and higher mean hemoglobin (Hb) levels (p=0.003). ACS was also associated with decreased Hb F levels (p=0.05). After controlling for age, gender, and use of hydroxyurea, SNPs in IL-12A (rs568408; p=0.007), IL-12B (rs2195940; p=0.022), and IL-4R (rs3024537; p=0.049) were significantly associated with ACS. In addition, IL-12A (rs568408; p=0.037), IL-12B (rs2853694; p=0.009), and IL-4R (rs2283563; p=0.031) were significantly associated with the use of bronchodilators in our adult SCD cohort. None of the SNPs in IL=12B or IL-4R were found to be in linkage disequilibrium (LD) with each other. After multiple regression analysis, SNPs in IL-12A (rs568408; p=0.013), IL-12B (rs2195940; p=0.01), and IL-4R (rs3024537; p=0.02) remained significantly associated with ACS, and SNPs in IL-12A (rs568408; p=0.048), IL-12B (rs2853694; p=0.005), and IL-4R (rs2283563; p=0.01) remained significantly associated with use of bronchodilators. The functional significance of these SNPs is presently unknown. All of the polymorphisms are intronic except for rs568408, located in the 3'untranslated region of IL-12A. In summary, our findings in adult SCD patients support previous data in children demonstrating associations among inflammatory markers and asthma with the occurrence of ACS. Our data also support the association between asthma and increased risk of ACS. Finally, we have identified potential genetic risk factors for both asthma and ACS in adults with SCD. Our findings suggest that further investigation into the role of these inflammatory mediators in pulmonary dysfunction in SCD is warranted.

Disclosures:
No relevant conflicts of interest to declare.