Association of HLA-DRB1?09:01 with tIgE levels among African-ancestry individuals with asthma - 22/07/20

Doi : 10.1016/j.jaci.2020.01.011

Nicolas Vince, PhD ^a, Sophie Limou, PhD ^a,^p, Michelle Daya, PhD ^b, Wataru Morii, PhD ^c, Nicholas Rafaels, MS ^b, Estelle Geffard, MS ^a, Venceslas Douillard, MS ^a, Alexandre Walencik, PharmD ^a, Meher Preethi Boorgula, MS ^b, Sameer Chavan, MS ^b, Candelaria Vergara, MD, PhD ^d, Victor E. Ortega, MD, PhD ^e, James G. Wilson, MD ^f, Leslie A. Lange, PhD ^b, Harold Watson, MD ^g, Dan L. Nicolae, PhD ^h, Deborah A. Meyers, PhD ⁱ, Nadia N. Hansel, MD, MPH ^d, Jean G. Ford, MD ^j, Mezbah U. Faruque, MD, PhD ^k, Eugene R. Bleecker, MD ⁱ, Monica Campbell, MS ^b, Terri H. Beaty, PhD ^l, Ingo Ruczinski, PhD ^m, Rasika A. Mathias, ScD ^d,^l, Margaret A. Taub, PhD ^m, Carole Ober, PhD ⁿ, Emiko Noguchi, MD, PhD ^c, Kathleen C. Barnes, PhD ^b, on behalf of
CAAPA
Dara Torgerson, PhD ^o, Pierre-Antoine Gourraud, PhD, MPH ^a,^⁎
^a Université de Nantes, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France
^b Department of Medicine, University of Colorado Denver, Aurora, Colo
^c Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
^d Department of Medicine, Johns Hopkins University, Baltimore, Md
^e 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
^f Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss
^g Faculty of Medical Sciences Cave Hill Campus, The University of the West Indies, Bridgetown, Barbados
^h Department of Medicine, University of Chicago, Chicago, Ill
ⁱ Department of Medicine, University of Arizona College of Medicine, Tucson, Ariz
^j Department of Medicine, Einstein Medical Center, Philadelphia, Pa
^k National Human Genome Center, Howard University College of Medicine, Washington, DC
^l Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md
^m Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md
ⁿ Department of Human Genetics, University of Chicago, Chicago, Ill
^o McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
^p Ecole Centrale de Nantes, Nantes, France

^∗Corresponding author: Pierre-Antoine Gourraud, PhD, MPH, ATIP-Avenir Team 5, CRTI UMR1064 - ITUN, CHU Nantes Hôtel Dieu, 30 Bld Jean Monnet, 44093 Nantes Cedex 01, France.ATIP-Avenir Team 5, CRTI UMR1064 - ITUN, CHU Nantes Hôtel Dieu30 Bld Jean Monnet2eme étageNantes Cedex 0144093France

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.

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Key words : Asthma, HLA, tIgE levels, atopy, CAAPA, imputation, admixture

Abbreviations used : CAAPA, GWAS, tIgE

Mappa

Methods

CAAPA

Genotyping and SNP imputation

HLA allele SNP-based imputation and haplotyping

Ancestry estimation

Statistical analysis

Results

Description of the study population

Admixture in the MHC region

HLA alleles’ imputation

Asthma susceptibility

Total IgE levels in individuals with asthma

Discussion

	N.V. has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement number 846520. Funding for this study was provided in part by the National Institutes of Health (grant nos. R01-HL129239 and R01HL104608 to K.C.B.).
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

Esportazione

Vol 146 - N° 1

P. 147-155 - Luglio 2020 Ritorno al numero

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Association of HLA-DRB1?09:01 with tIgE levels among African-ancestry individuals with asthma - 22/07/20

Abstract

Background

Objective

Methods

Results

Conclusions

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