Nicolas Vince1, Sophie Limou2, Michelle Daya3, Wataru Morii4, Nicholas Rafaels3, Estelle Geffard1, Venceslas Douillard1, Alexandre Walencik1, Meher Preethi Boorgula3, Sameer Chavan3, Candelaria Vergara5, Victor E Ortega6, James G Wilson7, Leslie A Lange3, Harold Watson8, Dan L Nicolae9, Deborah A Meyers10, Nadia N Hansel5, Jean G Ford11, Mezbah U Faruque12, Eugene R Bleecker10, Monica Campbell3, Terri H Beaty13, Ingo Ruczinski14, Rasika A Mathias15, Margaret A Taub14, Carole Ober16, Emiko Noguchi4, Kathleen C Barnes3, Dara Torgerson17, Pierre-Antoine Gourraud18. 1. Université de Nantes, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France. 2. Université de Nantes, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France; Ecole Centrale de Nantes, Nantes, France. 3. Department of Medicine, University of Colorado Denver, Aurora, Colo. 4. Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan. 5. Department of Medicine, Johns Hopkins University, Baltimore, Md. 6. Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC. 7. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss. 8. Faculty of Medical Sciences Cave Hill Campus, The University of the West Indies, Bridgetown, Barbados. 9. Department of Medicine, University of Chicago, Chicago, Ill. 10. Department of Medicine, University of Arizona College of Medicine, Tucson, Ariz. 11. Department of Medicine, Einstein Medical Center, Philadelphia, Pa. 12. National Human Genome Center, Howard University College of Medicine, Washington, DC. 13. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md. 14. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md. 15. Department of Medicine, Johns Hopkins University, Baltimore, Md; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md. 16. Department of Human Genetics, University of Chicago, Chicago, Ill. 17. McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. 18. Université de Nantes, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France. Electronic address: pierre-antoine.gourraud@univ-nantes.fr.
Abstract
BACKGROUND: Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (single nucleotide polymorphisms) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis. OBJECTIVE: To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African-ancestry individuals. METHODS: We collected high-density genomics data for the Consortium on Asthma among African-ancestry Populations in the Americas (N = 4993) participants. Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE (tIgE) levels in subjects with and without asthma. RESULTS: Among the 1607 individuals with asthma, 972 had available tIgE levels, with a mean tIgE level of 198.7 IU/mL. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1∗09:01 was associated with increased tIgE levels (P = 8.5 × 10-4; weighted effect size, 0.51 [0.15-0.87]). CONCLUSIONS: We identified for the first time an HLA allele associated with tIgE levels in African-ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations.
BACKGROUND:Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (single nucleotide polymorphisms) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis. OBJECTIVE: To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African-ancestry individuals. METHODS: We collected high-density genomics data for the Consortium on Asthma among African-ancestry Populations in the Americas (N = 4993) participants. Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE (tIgE) levels in subjects with and without asthma. RESULTS: Among the 1607 individuals with asthma, 972 had available tIgE levels, with a mean tIgE level of 198.7 IU/mL. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1∗09:01 was associated with increased tIgE levels (P = 8.5 × 10-4; weighted effect size, 0.51 [0.15-0.87]). CONCLUSIONS: We identified for the first time an HLA allele associated with tIgE levels in African-ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations.
Authors: Ana Valencia; Candelaria Vergara; Chloe L Thio; Nicolas Vince; Venceslas Douillard; Alba Grifoni; Andrea L Cox; Eric O Johnson; Alex H Kral; James J Goedert; Alessandra Mangia; Valeria Piazzolla; Shruti H Mehta; Gregory D Kirk; Arthur Y Kim; Georg M Lauer; Raymond T Chung; Jennifer C Price; Salim I Khakoo; Laurent Alric; Matthew E Cramp; Sharyne M Donfield; Brian R Edlin; Michael P Busch; Graeme Alexander; Hugo R Rosen; Edward L Murphy; Genevieve L Wojcik; Mary Carrington; Pierre-Antoine Gourraud; Alessandro Sette; David L Thomas; Priya Duggal Journal: Am J Hum Genet Date: 2022-01-31 Impact factor: 11.043
Authors: Katherine A Fawcett; German Demidov; Nick Shrine; Megan L Paynton; Stephan Ossowski; Ian Sayers; Louise V Wain; Edward J Hollox Journal: BMC Med Genomics Date: 2022-05-21 Impact factor: 3.622
Authors: Venceslas Douillard; Erick C Castelli; Steven J Mack; Jill A Hollenbach; Pierre-Antoine Gourraud; Nicolas Vince; Sophie Limou Journal: Front Genet Date: 2021-12-02 Impact factor: 4.599