Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth.

Background: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations.
Objective: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles.
Methods: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases.
Results: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 ( C5orf46 ) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels.
Conclusions: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2 .
Competing Interests: Competing interests: EH-L, and M.P.-Y. report funding from the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and by “ESF Investing in your future” by the European Union. JP-G reports funding from the Spanish Ministry of Universities. M.P.-Y. and F.L.D. report grants from MCIN/AEI/10.13039/501100011033 and the European Regional Development Fund “ERDF A way of making Europe” by the European Union. MP-Y reports grant support from GlaxoSmithKline, Spain paid to Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC) for a project outside the submitted work. MP-Y and JV reports grants from Instituto de Salud Carlos III, Madrid, Spain. JV also reports funding by ISCIII and the European Regional Development Fund “ERDF A way of making Europe”. JMH-P has received fees from CSL Behring, GSK, Astra-Zeneca, Laboratorios Menarini, Boehringer Ingelheim, FAES, Laboratorios Esteve, Laboratorios Ferrer, Mundipharma, Laboratorios Rovi, Roche, Novartis, GRIFOLS, Pfizer, Acthelion-Jansen, Chiesi y Laboratorios Bial for the realization of courses, talks, consultancies, and other activities related to his professional activity. FTC has received research support from the Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network (SIgN), National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore). F.T.C. has received consulting fees from Sime Darby Technology Centre; First Resources Ltd; Genting Plantation, and Olam International, outside the submitted work. YYS has received research support from the NUS Resilience & Growth Postdoctoral Fellowships. The other authors declare no conflict of interest.
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