Genome-wide association study identifies kallikrein 5 in type 2 inflammation-low asthma

• DOI: 10.1016/j.jaci.2022.03.033
• Publication Date: 2022-04-26T15:20:34Z
• Authors: Janet K. Jackman; Amy Stockwell; David F. Choy; Markus M. Xie; Peipei Lu; Guiquan Jia; Hong Li; Alexander R. Abbas; Paola G. Bronson; Wei-Yu Lin; Cecilia P.C. Chiu; Henry R. Maun; Merone Roose-Girma; Lucinda Tam; Juan Zhang; Zora Modrusan; Robert R. Graham; Timothy W. Behrens; Steven R. White; Ted Naureckas; Carole Ober; Manuel Ferreira; Radislav Sedlacek; Jiansheng Wu; Wyne P. Lee; Robert A. Lazarus; James T. Koerber; Joseph R. Arron; Brian L. Yaspan; Tangsheng Yi
• Keywords: Inflammation; Interleukin-13; 06 humanities and the arts; Antibodies, Neutralizing; Asthma; 3. Good health; Cytokines; Humans; Kallikreins; 0601 history and archaeology; Interleukin-4; Chemokines; Genome-Wide Association Study

Clinical studies of type 2 (T2) cytokine-related neutralizing antibodies in asthma have identified a substantial subset patients with low levels T2 inflammation who do not benefit from cytokine antibody treatment. Non-T2 mechanisms are poorly understood but represent redefined unmet medical need.We sought to gain better understanding genetic contributions T2-low asthma.We utilized an unbiased genome-wide association study moderate severe stratified by serum biomarker periostin. We also performed additional expression and biological analysis for the top hits.We novel protective single nucleotide polymorphism at chr19q13.41, which is selectively associated establishes Kallikrein-related peptidase 5 (KLK5) as causal gene mediating this association. Heterozygous carriers polymorphisms reduced KLK5 expression. secreted human bronchial epithelial cells elevated alveolar lavage. cytokines IL-4 IL-13 downregulate cells. KLK5, dependent on its catalytic function, induces chemokine/cytokine Finally, overexpression airway or lack endogenous inhibitor, SPINK5, leads spontaneous neutrophilic inflammation.Our data identify be locus chr19q13.41 asthma.