Association of HLA-DRB1*09:01 with tIgE levels among African ancestry individuals with asthma

Nicolas Vince (1) , Sophie Limou (1) , Michelle Daya (2) , Wataru Morii (3) , Nicholas Rafaels (2) , Estelle Geffard (1) , Venceslas Douillard (1) , Alexandre Walencik (1) , Meher Preethi Boorgula (2) , Sameer Chavan (2) , Candelaria Vergara (4) , Victor Ortega (5) , James Wilson (6) , Leslie Lange (2) , Harold Watson (7) , Dan Nicolae (8) , Deborah A. Meyers (9) , Nadia Hansel (4) , Jean Ford (10) , Mezbah Faruque (11) , Eugene R. Bleecker (12) , Monica Campbell (2) , Terri Beaty (4) , Ingo Ruczinski (4) , Rasika Mathias (4) , Margaret Taub (4) , Carole C. Ober (13) , Emiko Noguchi (3) , Kathleen Barnes (2) , Dara Torgerson (14) , Pierre-Antoine Gourraud (1)

1 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
2 Department of Medicine [Aurora, CO, USA]
3 Université de Tsukuba = University of Tsukuba
4 JHU - Johns Hopkins University
5 Wake Forest School of Medicine [Winston-Salem]
6 UMMC - University of Mississippi Medical Center
7 The University of the West Indies
8 Titu Maiorescu University Bucharest
9 Center for Human Genomics
10 Einstein Medical Center [Philadelphia, PA, USA]
11 Howard University College of Medicine [Washington, DC, USA]
12 University of Arizona
13 UIC - University of Illinois [Chicago]
14 UC San Francisco - University of California [San Francisco]

BACKGROUND:Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970's, 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 (SNPs) 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 CAAPA participants (Consortium on Asthma among African-ancestry Populations in the Americas, N=4,993). 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 levels (tIgE) in subjects with and without asthma.RESULTS:Among the 1,607 individuals with asthma, 972 had available tIgE levels with a mean tIgE level of 198.7 IU.ml-1. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1*09:01 was associated with increased tIgE levels (P=8.5x10-4, 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.

Mots clés: Admixture; Asthma; Atopy; CAAPA; HLA; Imputation; tIgE levels

Domaines: Sciences du Vivant [q-bio]

Nicolas Vince, Sophie Limou, Michelle Daya, Wataru Morii, Nicholas Rafaels, et al.. Association of HLA-DRB1*09:01 with tIgE levels among African ancestry individuals with asthma. Journal of Allergy and Clinical Immunology, 2020, pp.S0091-6749(20)30098-1. ⟨10.1016/j.jaci.2020.01.011⟩. ⟨inserm-02490604⟩