Enho Mutations Causing Low Adropin: A Possible Pathomechanism of MPO-ANCA Associated Lung Injury

BACKGROUND Myeloperoxidase (MPO) anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis commonly causes life-threatening pulmonary alveolar hemorrhage or fibrosis. Only a limited number of candidate gene variants have been explored, but hitherto, are not widely confirmed. In the present study, we investigated the importance of energy homeostasis associated gene (Enho) mutations and adropin deficiency in the development of MPO-ANCA associated lung injury. METHODS We analyzed the peripheral blood mononuclear cells from 152 unrelated patients and 220 population-matched healthy individuals for genetic variations in Enho. Functional studies with adropin knockout (AdrKO) on C57BL/6J mice were also performed. FINDINGS Sequencing revealed six patients with p.Ser43Thr and that five patients shared Cys56Trp amino acid substitution in Enho. Serum concentration of adropin was significantly lower in patients than that of the healthy subjects (P<0.0001), especially those with Enho mutations. In vivo, homo- and heterozygous carriers of the null adropin allele exhibited MPO-ANCA associated pulmonary alveolar hemorrhage as compared to wild-type mice. AdrKO mice exhibit reduced eNOS (Ser1177) and Akt1 (Ser473) phosphorylation and loss of Treg cells. INTERPRETATION Our findings indicate that the presence of Enho mutations or adropin-deficiency is a probable molecular basis for the initial events triggered in MPO-ANCA associated lung injury.