The strongest association with FEV1/FVC was at 6p21, a gene-rich region of the major histocompatibility complex (MHC). The extended LD in this region of the MHC prevented accurate localization of the association signal. However, we observed the peak of association for a nonsynonymous coding SNP in AGER (rs2070600, P = 3.07 × 10−15; Table 2 and Fig. 2e), which is a plausible candidate for causal association. AGER, also known as RAGE, is a multiligand receptor of the immunoglobulin superfamily23. AGER is highly expressed in the lung, in particular alveolar epithelial cells24, with a potential role in epithelium–extracellular matrix interactions. Reduced AGER expression has been identified in individuals with idiopathic pulmonary fibrosis25, and Ager-/- mice develop age-related pulmonary fibrosis26. Another candidate in this region is the nearby gene NOTCH4, a member of the family of transmembrane receptors involved in cell fate decisions27. Notch4 is expressed in endothelial cells of the adult mouse lung, where it is believed to regulate angiogenesis28.
