Multi-ancestry genome-wide association study of asthma exacerbations.
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Herrera-Luis Esther, Ortega Victor E, Ampleford Elizabeth J, Sio Yang Yie, Granell Raquel, de Roos Emmely, Terzikhan Natalie, Vergara Ernesto Elorduy, Hernandez-Pacheco Natalia, Perez-Garcia Javier, Martin-Gonzalez Elena, Lorenzo-Diaz Fabian, Hashimoto Simone, Brinkman Paul, U-BIOPRED Study Group, Jorgensen Andrea L, Yan Qi, Forno Erick, Vijverberg Susanne J, Lethem Ryan, Espuela-Ortiz Antonio, Gorenjak Mario, Eng Celeste, González-Pérez Ruperto, Hernández-Pérez José M, Poza-Guedes Paloma, Sardón Olaia, Corcuera Paula, Hawkins Greg A, Marsico Annalisa, Bahmer Thomas, Rabe Klaus F, Hansen Gesine, Kopp Matthias Volkmar, Rios Raimon, Cruz Maria Jesus, González-Barcala Francisco-Javier, Olaguibel José María, Plaza Vicente, Quirce Santiago, Canino Glorisa, Cloutier Michelle, Del Pozo Victoria, Rodriguez-Santana Jose R, Korta-Murua Javier, Villar Jesús, Potočnik Uroš, Figueiredo Camila, Kabesch Michael, Mukhopadhyay Somnath, Pirmohamed Munir, Hawcutt Daniel B, Melén Erik, Palmer Colin N, Turner Steve, Maitland-van der Zee Anke H, von Mutius Erika, Celedón Juan C, Brusselle Guy, Chew Fook Tim, Bleecker Eugene, Meyers Deborah, Burchard Esteban G, Pino-Yanes Maria
Аннотация
METHODS: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico.
RESULTS: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10-5 and replication: ORC allele = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood.
CONCLUSIONS: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.