Identification of MICA as a Susceptibility Gene for Pulmonary Mycobacterium avium Complex Infection

Host genetic susceptibility to adult pulmonary Mycobacterium avium complex disease remains unknown. To identify genetic loci for the disease, we prepared 3 sets of pooled DNA samples from 300 patients and 300 sex- matched control subjects and genotyped 19,651 microsatellite markers in a case-control manner. D6S00091― located in the MICA (major histocompatibility complex class I chain-related A) gene, which encodes a ligand of the NKG2D receptor―had the lowest P value in pooled and individual DNA typing. The A6 allele of the micro- satellite was significantly associated with female patients (P <.001), whereas the classical HLA-B and HLA-DRB1 alleles did not show significant association. Functional analysis of allelic expression imbalance revealed that A6-derived messenger RNA was more highly expressed than non-A6-derived messenger RNA in human bronchial epithelial cells. MICA was expressed in bronchiolar epithelium, alveolar macrophages, and granulomatous lesions. These findings suggest that MICA might be one of the immune molecules affecting the pathogenesis of the disease.