학술논문
Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans.
Document Type
article
Author
Gui, Hongsheng; Levin, Albert M; Hu, Donglei; Sleiman, Patrick; Xiao, Shujie; Mak, Angel CY; Yang, Mao; Barczak, Andrea J; Huntsman, Scott; Eng, Celeste; Hochstadt, Samantha; Zhang, Ellen; Whitehouse, Kyle; Simons, Samantha; Cabral, Whitney; Takriti, Sami; Abecasis, Gonçalo; Blackwell, Thomas W; Kang, Hyun Min; Nickerson, Deborah A; Germer, Soren; Lanfear, David E; Gilliland, Frank; Gauderman, W James; Kumar, Rajesh; Erle, David J; Martinez, Fernando D; Hakonarson, Hakon; Burchard, Esteban G; Williams, L Keoki
Source
American Journal of Respiratory and Critical Care Medicine. 203(4)
Subject
Language
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.Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.