Association of HLA-DRB1∗09:01 with tIgE levels among African-ancestry individuals with asthma.,Journal of Allergy and Clinical Immunology

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Association of HLA-DRB1∗09:01 with tIgE levels among African-ancestry individuals with asthma.
Journal of Allergy and Clinical Immunology ( IF 14.2 ) Pub Date : 2020-01-22 , DOI: 10.1016/j.jaci.2020.01.011
Nicolas Vince ₁ , Sophie Limou ₂ , Michelle Daya ₃ , Wataru Morii ₄ , Nicholas Rafaels ₃ , Estelle Geffard ₁ , Venceslas Douillard ₁ , Alexandre Walencik ₁ , Meher Preethi Boorgula ₃ , Sameer Chavan ₃ , Candelaria Vergara ₅ , Victor E Ortega ₆ , James G Wilson ₇ , Leslie A Lange ₃ , Harold Watson ₈ , Dan L Nicolae ₉ , Deborah A Meyers ₁₀ , Nadia N Hansel ₅ , Jean G Ford ₁₁ , Mezbah U Faruque ₁₂ , Eugene R Bleecker ₁₀ , Monica Campbell ₃ , Terri H Beaty ₁₃ , Ingo Ruczinski ₁₄ , Rasika A Mathias ₁₅ , Margaret A Taub ₁₄ , Carole Ober ₁₆ , Emiko Noguchi ₄ , Kathleen C Barnes ₃ , , Dara Torgerson ₁₇ , Pierre-Antoine Gourraud ₁

Affiliation

Université de Nantes, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France.
Université de Nantes, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France; Ecole Centrale de Nantes, Nantes, France.
Department of Medicine, University of Colorado Denver, Aurora, Colo.
Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
Department of Medicine, Johns Hopkins University, Baltimore, Md.
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.
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss.
Faculty of Medical Sciences Cave Hill Campus, The University of the West Indies, Bridgetown, Barbados.
Department of Medicine, University of Chicago, Chicago, Ill.
Department of Medicine, University of Arizona College of Medicine, Tucson, Ariz.
Department of Medicine, Einstein Medical Center, Philadelphia, Pa.
National Human Genome Center, Howard University College of Medicine, Washington, DC.
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md.
Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md.
Department of Medicine, Johns Hopkins University, Baltimore, Md; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md.
Department of Human Genetics, University of Chicago, Chicago, Ill.
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.

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.

中文翻译：

非洲裔哮喘个体中HLA-DRB1 * 09：01与tIgE水平的关联。

背景

哮喘是一种复杂的气道慢性炎症性疾病。HLA与哮喘之间的关联性研究最早是在1970年代报道的，但尚未完全了解HLA等位基因在哮喘中的确切作用。最近对哮喘进行了许多全基因组关联研究，但始终仅限于简单的遗传标记（单核苷酸多态性），而不是复杂的HLA基因多态性（等位基因/单倍型），因此未捕获此复杂基因位与哮喘发病机制的生物学相关性。