HLA-G Haplotypes Are Differentially Associated with Asthmatic Features

HLA-G, a HLAclass Ib molecule, interacts with receptors on lymphocytes such as T cells, B cells and NK cells to influence immune responses. Unlike classical HLAmolecules, HLA-G expression is not found on all somatic cells, but restricted to tissue sites, including human bronchial epithelial cells (HBEC). Individual variation of 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 expression in different cohorts of asthmatic patients. In particular, we recently described impaired local expression of HLA-G and abnormal profiles for alternatively splicedisoforms 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 on HLA-G SNPs as predictive biomarkers, but few analyzed HLA-G haplotypes. Here, we aimed to characterize HLA-G haplotypesand describe their association with asthmatic clinical features and sHLA-G peripheral expression, and to describe variations in transcription factor binding sites and alternative splicingsites. HLA-G haplotypeswere differentially distributed in 330 healthy and 580 asthmatic individuals. Furthermore, HLA-G haplotypeswere associated with asthmatic clinical features showed. We did not however confirm an association between sHLA-G and genetic, biological or clinical parameters. HLA-G haplotypeswere phylogenetically split into distinct groups, with each group displaying particular variations in transcription factor binding or RNA splicingsites 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 of HLA-G haplotypesas predictive genetic markers for asthma.