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Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth
  1. Esther Herrera-Luis1,
  2. Angel C Y Mak2,
  3. Javier Perez-Garcia1,
  4. Elena Martin-Gonzalez1,
  5. Celeste Eng2,
  6. Kenneth B Beckman3,
  7. Scott Huntsman2,
  8. Donglei Hu2,
  9. Ruperto González-Pérez4,5,
  10. José M Hernández-Pérez6,7,
  11. Elena Mederos-Luis4,
  12. Yang Yie Sio8,
  13. Paloma Poza-Guedes4,5,
  14. Olaia Sardón9,10,
  15. Paula Corcuera9,
  16. Inmaculada Sánchez-Machín4,
  17. Javier Korta-Murua9,10,
  18. Carlos Martínez-Rivera11,12,
  19. Joaquim Mullol12,13,
  20. Xavier Muñoz12,14,
  21. Antonio Valero12,15,
  22. Joaquin Sastre12,16,
  23. Judith Garcia-Aymerich17,18,19,
  24. Sabrina Llop17,20,
  25. Maties Torrent21,
  26. Maribel Casas18,19,
  27. José R Rodríguez-Santana22,
  28. Jesús Villar12,23,
  29. Victoria del Pozo12,24,
  30. Fabian Lorenzo-Diaz1,25,
  31. L Keoki Williams26,
  32. Erik Melén27,28,
  33. Fook Tim Chew8,
  34. Luisa N Borrell29,
  35. Esteban G Burchard2,30,
  36. Maria Pino-Yanes1,12,31
  1. 1Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain
  2. 2Department of Medicine, University of California San Francisco, San Francisco, California, USA
  3. 3University of Minnesota Genomics Center, Minneapolis, Minnesota, USA
  4. 4Allergy Department, Hospital Universitario de Canarias, La Laguna, Spain
  5. 5Severe Asthma Unit, Allergy Department, Hospital Universitario de Canarias, La Laguna, Spain
  6. 6Pulmonary Medicine, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain
  7. 7Pulmonary Medicine, Hospital Universitario de La Palma, Breña alta, Spain
  8. 8Department of Biological Sciences, National University of Singapore, Singapore
  9. 9Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain
  10. 10Department of Pediatrics, University of the Basque Country (UPV/EHU), San Sebastián, Spain
  11. 11Servicio de Neumología, Hospital Universitario Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
  12. 12CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
  13. 13Rhinology Unit & Smell Clinic, ENT Department; Clinical & Experimental Respiratory Immunoallergy (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
  14. 14Servicio de Neumología, Hospital Vall d’Hebron, Barcelona, Spain
  15. 15Allergy Unit & Severe Asthma Unit, Pneumonology and Allergy Department, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
  16. 16Allergy Department, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
  17. 17Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain
  18. 18ISGlobal, Barcelona, Spain
  19. 19Universitat Pompeu Fabra, Barcelona, Spain
  20. 20Epidemiology and Environmental Health Joint Research Unit, FISABIO, Universitat Jaume I, Universitat de Valencia, Valencia, Spain
  21. 21Ib-salut, Area de Salut de Menorca, Menorca, Spain
  22. 22Centro de Neumología Pediátrica, San Juan, Puerto Rico
  23. 23Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
  24. 24Immunology Department, Instituto de Investigación Sanitaria Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
  25. 25Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC), Universidad de La Laguna (ULL), La Laguna, Spain
  26. 26Center for Individualized and Genomic Medicine Research, Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan, USA
  27. 27Department of Clinical Sciences and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
  28. 28Sachs’ Children’s Hospital, South General Hospital, Stockholm, Sweden
  29. 29Department of Epidemiology & Biostatistics, Graduate School of Public Health & Health Policy, City University of New York, New York, New York, USA
  30. 30Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
  31. 31Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna (ULL), La Laguna, Spain
  1. Correspondence to Dr Maria Pino-Yanes, Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna 38200, Spain; mdelpino{at}ull.edu.es

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.

  • Asthma
  • Asthma Genetics
  • Paediatric asthma
  • Paediatric Lung Disaese

Data availability statement

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.

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Data availability statement

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.

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Footnotes

  • EGB and MP-Y are joint senior authors.

  • Twitter @EstherHL5, @Javier_pg96, @JoseMariaAlfa1, @FabLorenzo6, @Maria_PinoYanes

  • Contributors EH-L: Conceptualisation (supporting), data curation (equal), formal analysis (lead), methodology (equal), writing original draft (lead), writing review and editing (equal); ACYM: data curation (equal), formal analysis (supporting), writing review and editing (supporting); JP-G: investigation (supporting), formal analysis (supporting), writing review and editing (equal); EM-G: investigation (supporting), writing review and editing (supporting); CE: investigation (supporting), writing review and editing (supporting); KBB: investigation (supporting), writing review and editing (supporting); SH: data curation (equal), methodology (supporting), writing review and editing (supporting); DH: data curation (equal), writing review and editing (supporting); RG-P: resources (equal), investigation (supporting), writing review and editing (supporting); JMH-P: resources (equal), investigation (supporting), writing review and editing (supporting); EM-L: resources (equal), investigation (supporting), writing review and editing (supporting); YYS: resources (equal), investigation (supporting), data curation (equal), formal analysis (equal), writing review and editing (supporting); PP-G: resources (equal), investigation (supporting), writing—review and editing (supporting); OS: resources (equal), investigation (supporting), writing review and editing (supporting); PC: resources (equal), investigation (supporting), writing—review and editing (supporting); IS-M: resources (equal), investigation (supporting), writing—review and editing (supporting); JK-M: resources (equal), investigation (supporting), writing review and editing (supporting); CMR: investigation (supporting), writing review and editing (supporting); JM: investigation (supporting), writing review and editing (supporting); XM: investigation (supporting), writing review and editing (supporting); AV: investigation (supporting), writing review and editing (supporting); JS: investigation (supporting), writing review and editing (supporting); JG-A: investigation (supporting); formal analysis (supporting), writing review and editing (supporting); SL: investigation (supporting); formal analysis (supporting), writing review and editing (supporting); MT: investigation (supporting), formal analysis (supporting); MC: investigation (supporting), formal analysis (supporting), writing review and editing (supporting); JRR-S: investigation (supporting), writing review and editing (supporting); JV: conceptualisation (supporting), resources (supporting), writing review and editing (equal); VP: resources (supporting), investigation (supporting), writing review and editing (supporting); FL-D: resources (equal), conceptualisation (supporting), funding acquisition (supporting), writing review and editing (equal); funding acquisition (lead), writing review and editing (supporting); LKW: resources (equal), funding acquisition (lead), writing review and editing (supporting); EM: resources (equal), writing review and editing (supporting); FTC: resources (equal), writing review and editing (supporting); LNB: funding acquisition (equal), writing review and editing (supporting); EGB: garantor of the content (equal), resources (equal), conceptualisation (lead), funding acquisition (lead), supervision (supporting), writing review and editing (supporting); MP-Y: garantor of the content (equal); resources (equal), conceptualisation (lead), supervision (lead), funding acquisition (lead); methodology (equal), writing original draft (supporting), writing review and editing (lead).

  • Funding 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].

  • Disclaimer The funders of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the report for publication.

  • 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.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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