Asthma and lower airway disease
Association of HLA-DRB1∗09:01 with tIgE levels among African-ancestry individuals with asthma

https://doi.org/10.1016/j.jaci.2020.01.011Get rights and content

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.

Section snippets

CAAPA

The CAAPA multicenter participants were previously described.31 A total of 1607 cases with asthma and 3365 controls of African ancestry (the United States and Barbados) were recruited (for a full description, see Table E1 in this article’s Online Repository at www.jacionline.org and Daya et al31). Briefly, 8 of the 17 CAAPA investigators contributed data to this study. The distributions of age, sex, and age of asthma onset for each cohort are summarized in Table E1. Participants in these

Description of the study population

In our study, we had access to a total of 4993 individuals of African ancestry (the United States and Barbados) from 8 CAAPA studies (Table E1). Overall, our patients were 39.3% males and were recruited at age 38.7 years on average (for a description of the demographic characteristics in each cohort, see Table E1). Our analyses only focused on unrelated individuals, with a total of 1607 subjects with asthma and 3365 controls (BAGS and HUFS cohorts included some family members, and these

Discussion

Our study focused for the first time on HLA allele associations with asthma susceptibility and atopy in a large African ancestry cohort of individuals with asthma (CAAPA, N = 4993). We identified the HLA-DRB1∗09:01 allele associated with elevated tIgE levels in individuals with asthma.

Thus far, most HLA studies in asthma either had small sample sizes or assessed associations only at the SNP level, therefore not fully capturing the complexity and biological relevance of the HLA genes in the MHC

References (60)

  • P.-A. Gourraud et al.

    Inferred HLA haplotype information for donors from hematopoietic stem cells donor registries

    Hum Immunol

    (2005)
  • B.K. Maples et al.

    RFMix: a discriminative modeling approach for rapid and robust local-ancestry inference

    Am J Hum Genet

    (2013)
  • M. Naqvi et al.

    Association between IgE levels and asthma severity among African American, Mexican, and Puerto Rican patients with asthma

    J Allergy Clin Immunol

    (2007)
  • M. Maiers et al.

    High-resolution HLA alleles and haplotypes in the United States population

    Hum Immunol

    (2007)
  • W. Morii et al.

    Association of Japanese cedar pollinosis and sensitization with HLA-DPB1 in the Japanese adolescent

    Allergol Int

    (2018)
  • J.-M. Anaya

    Common mechanisms of autoimmune diseases (the autoimmune tautology)

    Autoimmun Rev

    (2012)
  • E. Wambre et al.

    Characterization of CD4+ T cell subsets in allergy

    Curr Opin Immunol

    (2012)
  • S.E. Wenzel

    Asthma phenotypes: the evolution from clinical to molecular approaches

    Nat Med

    (2012)
  • T.H. Hansen et al.

    MHC class I antigen presentation: learning from viral evasion strategies

    Nat Rev Immunol

    (2009)
  • E.Y. Jones et al.

    MHC class II proteins and disease: a structural perspective

    Nat Rev Immunol

    (2006)
  • D. Welter et al.

    The NHGRI GWAS Catalog, a curated resource of SNP-trait associations

    Nucleic Acids Res

    (2014)
  • J. Trowsdale et al.

    Major histocompatibility complex genomics and human disease

    Annu Rev Genomics Hum Genet

    (2013)
  • C.A. Bruce et al.

    Studies of HLA antigen frequencies, IgE levels, and specific allergic sensitivities in patients having ragweed hayfever, with and without asthma

    Clin Exp Immunol

    (1976)
  • M.L. Lara-Marquez et al.

    Immunogenetics of atopic asthma: association of DRB1∗1101 DQA1∗0501 DQB1∗0301 haplotype with Dermatophagoides spp.-sensitive asthma in a sample of the Venezuelan population

    Clin Exp Allergy

    (1999)
  • J. Robinson et al.

    The IPD and IMGT/HLA database: allele variant databases

    Nucleic Acids Res

    (2015)
  • T. Hirota et al.

    Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population

    Nat Genet

    (2011)
  • M.F. Moffatt et al.

    A large-scale, consortium-based genomewide association study of asthma

    N Engl J Med

    (2010)
  • I. Ivković-Jureković et al.

    The distribution of HLA alleles among children with atopic asthma in Croatia

    Coll Antropol

    (2011)
  • M.C. Munthe-Kaas et al.

    HLA Dr-Dq haplotypes and the TNFA-308 polymorphism: associations with asthma and allergy

    Allergy

    (2007)
  • F. Demenais et al.

    Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

    Nat Genet

    (2018)

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    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.

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