Mapping the 17q12–21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans

Abstract

Rationale: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants.Objectives: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals.Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant. Measurements and Main Results:The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.

17q12‐q21 variants interact with early‐life exposures to modify asthma risk in Black children

“…In summary, our study suggests that variants in GSDMA modify the effects of early-life exposure to colds on the risk of developing asthma at age 7 among Black children. These findings, together with studies in African ancestry cohorts which focused on GSDMB, [3][4][5] suggest that the gasdermin genes at the 17q12-q21 locus are important determinants of childhood-onset asthma risk in chil-…”

“…Recent studies used the reduced LD on African American chromosomes to identify SNPs that regulate the expression of GSDMB as the main drivers of the 17q12-q21 locus-associated asthma risk. 3,5 Here, we demonstrate that the number of colds in early life increases the risk of asthma in Black children with GSDMA variants (rs8069202-A or rs3859192-T), which are associated with reduced expression of GSDMA in NECs.…”

“…In summary, our study suggests that variants in GSDMA modify the effects of early‐life exposure to colds on the risk of developing asthma at age 7 among Black children. These findings, together with studies in African ancestry cohorts which focused on GSDMB , 3–5 suggest that the gasdermin genes at the 17q12‐q21 locus are important determinants of childhood‐onset asthma risk in children with African ancestry. Understanding the mechanisms that underlie these GEI effects may lead to improved identification of children at risk and novel intervention strategies.…”

“…Fine‐mapping at this locus has been difficult in populations of European ancestry because of extensive linkage disequilibrium (LD) in this region. Taking advantage of the reduced LD in African ancestry populations, we 3 and others 4,5 have shown that single nucleotide polymorphisms (SNPs) in GSDMB are likely causal for childhood‐onset asthma at this locus. However, it remains unclear whether the same variants underlie the many genotype‐exposure interaction (GEI) effects.…”

Respiratory Viral and Bacterial Factors That Influence Early Childhood Asthma

“…There were also genes associated with eosinophil identity, IKZF2 and also genes associated with epithelial mesenchymal communication in asthma such as FGFR2. Interestingly, some of these genes (IKZF3, PGAP3, GSDMA, GSDMB, ERBB2, and ORMDL3) fall within 17q21 locus which is linked with high risk of children developing early wheezing episodes due to viral and fungal exposure ( 63 ). The subsequent study that focused on ORMDL3 proposed that its mechanism is related to the regulation of ICAM1 and epithelial response to stress due to detection of unfolded proteins, which could explain higher vulnerability toward RV infections and an important mediator of AHR induced by fungal allergens ( 64 ).…”