HLA-G Haplotypes Are Differentially Associated with Asthmatic Features

Camille Ribeyre, Federico Carlini, Céline René, François Jordier, Christophe Picard, Jacques Chiaroni, Laurent Abi-Rached, Philippe Gouret, Grégory Marin, Nicolas Molinari, Pascal Chanez, Julien Paganini, Delphine Gras, Julie Di Cristofaro

Human leukocyte antigen (HLA)-G, a HLA class Ib molecule, interacts with receptors on lymphocytes such as T cells, B cells, and natural killer cells to influence immune responses. Unlike classical HLA molecules, HLA-G expression is not found on all somatic cells, but restricted to tissue sites, including human bronchial epithelium cells (HBEC). Individual variation in HLA-G expression is linked to its genetic polymorphism and has been associated with many pathological situations such as asthma, which is characterized by epithelium abnormalities and inflammatory cell activation. Studies reported both higher and equivalent soluble HLA-G (sHLA-G) expression in different cohorts of asthmatic patients. In particular, we recently described impaired local expression of HLA-G and abnormal profiles for alternatively spliced isoforms in HBEC from asthmatic patients. sHLA-G dosage is challenging because of its many levels of polymorphism (dimerization, association with β2-microglobulin, and alternative splicing), thus many clinical studies focused onHLA-Gsingle-nucleotide polymorphisms as predictive biomarkers, but few analyzedHLA-Ghaplotypes. Here, we aimed to characterizeHLA-Ghaplotypes and describe their association with asthmatic clinical features and sHLA-G peripheral expression and to describe variations in transcription factor (TF) binding sites and alternative splicing sites.HLA-Ghaplotypes were differentially distributed in 330 healthy and 580 asthmatic individuals. Furthermore,HLA-Ghaplotypes were associated with asthmatic clinical features showed. However, we did not confirm an association between sHLA-G and genetic, biological, or clinical parameters.HLA-Ghaplotypes were phylogenetically split into distinct groups, with each group displaying particular variations in TF binding or RNA splicing sites that could reflect differential HLA-G qualitative or quantitative expression, with tissue-dependent specificities. Our results, based on a multicenter cohort, thus support the pertinence ofHLA-Ghaplotypes as predictive genetic markers for asthma.