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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:146

Article

Vince, Nicolas¹  Limou, Sophie^1,17  Daya, Michelle²  Morii, Wataru³  Rafaels, Nicholas²  Geffard, Estelle¹  Douillard, Venceslas¹  Walencik, Alexandre¹  Boorgula, Meher Preethi²  Chavan, Sameer²  Vergara, Candelaria⁴  Ortega, Victor E.⁵  Wilson, James G.⁶  Lange, Leslie A.²  Watson, Harold⁷  Nicolae, Dan L.⁸  Meyers, Deborah A.⁹  Hansel, Nadia N.⁴  Ford, Jean G.¹⁰  Faruque, Mezbah U.¹¹  Bleecker, Eugene R.⁹  Campbell, Monica²  Beaty, Terri H.¹²  Ruczinski, Ingo¹³  Mathias, Rasika A.^4,12  Taub, Margaret A.¹³  Ober, Carole¹⁴  Noguchi, Emiko³  Barnes, Kathleen C.²  Torgerson, Dara^15,16  Gourraud, Pierre-Antoine¹ 

[1] Univ Nantes, CHU Nantes, Cent Nantes, Inserm,Ctr Rech Transplantat & Immunol, Nantes, France

[2] Univ Colorado Denver, Dept Med, Aurora, CO USA

[3] Univ Tsukuba, Fac Med, Dept Med Genet, Ibaraki, Japan

[4] Johns Hopkins Univ, Dept Med, Baltimore, MD USA

[5] Wake Forest Sch Med, Ctr Precis Med, Dept Internal Med, Sect Pulm Crit Care Allergy & Immunol Dis, Winston Salem, NC 27101 USA

[6] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA

[7] Univ West Indies, Fac Med Sci, Cave Hill Campus, Bridgetown, Barbados

[8] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA

[9] Univ Arizona, Coll Med, Dept Med, Tucson, AZ USA

[10] Einstein Med Ctr, Dept Med, Philadelphia, PA USA

[11] Howard Univ, Coll Med, Natl Human Genome Ctr, Washington, DC USA

[12] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[13] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA

[14] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[15] McGill Univ, Montreal, PQ, Canada

[16] Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[17] Ecole Cent Nantes, Nantes, France

关键词: Asthma;    HLA;    tIgE levels;    atopy;    CAAPA;    imputation;    admixture;   

DOI  :  10.1016/j.jaci.2020.01.011

来源: Elsevier

【 摘 要 】

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 x 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.

【 授权许可】

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