PT  - JOURNAL ARTICLE
AU  - Herrera-Luis, Esther
AU  - Mak, Angel C Y
AU  - Perez-Garcia, Javier
AU  - Martin-Gonzalez, Elena
AU  - Eng, Celeste
AU  - Beckman, Kenneth B
AU  - Huntsman, Scott
AU  - Hu, Donglei
AU  - González-Pérez, Ruperto
AU  - Hernández-Pérez, José M
AU  - Mederos-Luis, Elena
AU  - Sio, Yang Yie
AU  - Poza-Guedes, Paloma
AU  - Sardón, Olaia
AU  - Corcuera, Paula
AU  - Sánchez-Machín, Inmaculada
AU  - Korta-Murua, Javier
AU  - Martínez-Rivera, Carlos
AU  - Mullol, Joaquim
AU  - Muñoz, Xavier
AU  - Valero, Antonio
AU  - Sastre, Joaquin
AU  - Garcia-Aymerich, Judith
AU  - Llop, Sabrina
AU  - Torrent, Maties
AU  - Casas, Maribel
AU  - Rodríguez-Santana, José R
AU  - Villar, Jesús
AU  - del Pozo, Victoria
AU  - Lorenzo-Diaz, Fabian
AU  - Williams, L Keoki
AU  - Melén, Erik
AU  - Chew, Fook Tim
AU  - Borrell, Luisa N
AU  - Burchard, Esteban G
AU  - Pino-Yanes, Maria
TI  - Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth
AID  - 10.1136/thorax-2022-218755
DP  - 2023 Mar 01
TA  - Thorax
PG  - 233--241
VI  - 78
IP  - 3
4099  - http://thorax.bmj.com/content/78/3/233.short
4100  - http://thorax.bmj.com/content/78/3/233.full
SO  - Thorax2023 Mar 01; 78
AB  - 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.All data relevant to the study are included in the article or uploaded as supplementary information. TOPMed WGS and RNA-seq data from GALA II are available on dbGaP under accession number phs000920.v4.p2. TOPMed WGS data from SAGE is available on dbGaP under accession number phs000921.v4.p1.