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

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• dc.contributor.author Herrera-Luis, Esther
• dc.contributor.author García Aymerich, Judith
• dc.contributor.author Casas Sanahuja, Maribel
• dc.contributor.author Pino-Yanes, Maria
• dc.date.accessioned 2023-04-03T06:16:43Z
• dc.date.available 2023-04-03T06:16:43Z
• dc.date.issued 2023
• dc.description.abstract 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.
• dc.description.sponsorship This work was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033 and the European Regional Development Fund 'ERDF A way of making Europe' by the European Union grant [SAF2017-83417R], and by MCIN/AEI/10.13039/501100011033 [grant PID2020-116274RB-I00]. Whole-genome sequencing for the TOPMed (Trans-Omics in Precision Medicine) program was supported by the NHLBI. Whole-genome sequencing for GALA II (NHLBI TOPMed: Genes-environments and Admixture in Latino Americans) Study (phs000920) was performed at the New York Genome Center [3R01HL117004-01S3]. Centralised read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center [3R01HL-117626-02S1]. Phenotype harmonization, data management, sample-identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center [3R01HL-120393-02S1]. WGS of part of GALA II was performed by New York Genome Center under The Centers for Common Disease Genomics of the Genome Sequencing Program (GSP) Grant [UM1 HG008901]. The GSP Coordinating Center [U24 HG008956] contributed to cross-program scientific initiatives and provided logistical and general study coordination. GSP is funded by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and the National Eye Institute [NA]. This work was also supported by the Sandler Family Foundation[NA], the American Asthma Foundation [NA], the RWJF Amos Medical Faculty Development Program [NA], Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II [NA], the National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL117004, R01HL128439, R01HL135156, X01HL134589, R01HL155024, R01AI079139, R01HL141845, R01HL118267 and R01DK113003], the National Institute of Health and Environmental Health Sciences [R01ES015794 and R21ES24844], the National Institute on Minority Health and Health Disparities [R01MD010443 and R56MD013312], the Tobacco-Related Disease Research Program [Award Number 24RT-0025 and 27IR-0030]. The BAMSE study was funded by the Swedish Heart-Lung Foundation and the Swedish Research Council and Region Stockholm (ALF project and database maintenance). The INMA study was funded by the Instituto de Salud Carlos III [Red INMA G03/176, CB06/02/0041], Spanish Ministry of Health [FIS-FEDER PI16/1288, FIS-FEDER PI19/1338; Miguel Servet FEDER 15/0025 and 20/0006], Generalitat Valenciana [BEST/2020/ 059]. This work was also partially funded by Fundación Canaria Instituto de Investigación Sanitaria de Canarias [PIFIISC19/17]. JV was funded by ISCIII and the European Regional Development Fund 'ERDF A way of making Europe' by the European Union [PI16/00049 and PI19/00141]. MP-Y was funded by the Ramón y Cajal Program [RYC-2015-17205] by MCIN/AEI/10.13039/501100011033 and by the European Social Fund 'ESF Investing in your future' and by the EAACI Allergopharma Award 2021. JV and M.P.-Y were funded Instituto de Salud Carlos III (ISCIII) [CB06/06/1088]. EH-L was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by 'ESF Investing in your future' [PRE2018-083837]. JP-G was supported by a fellowship awarded by the Spanish Ministry of Universities [FPU19/02175].
• dc.format.mimetype application/pdf
• dc.identifier.citation Herrera-Luis E, Mak ACY, Perez-Garcia J, Martin-Gonzalez E, Eng C, Beckman KB et al. Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth. Thorax. 2023 Mar;78(3):233-41. DOI: 10.1136/thorax-2022-218755
• dc.identifier.doi http://dx.doi.org/10.1136/thorax-2022-218755
• dc.identifier.issn 0040-6376
• dc.identifier.uri http://hdl.handle.net/10230/56394
• dc.language.iso eng
• dc.publisher BMJ Publishing Group
• dc.relation.ispartof Thorax. 2023 Mar;78(3):233-41
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-83417R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-116274RB-I00
• dc.rights © BMJ Publishing Group http://dx.doi.org/10.1136/thorax-2022-218755
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Asthma
• dc.subject.keyword Asthma genetics
• dc.subject.keyword Paediatric lung disaese
• dc.subject.keyword Paediatric asthma
• dc.title Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion