Genome-wide association study identifies kallikrein 5 in type 2 inflammation-low asthma - 04/10/22
, Tangsheng Yi, PhD a, ⁎ Abstract |
Background |
Clinical studies of type 2 (T2) cytokine-related neutralizing antibodies in asthma have identified a substantial subset of patients with low levels of T2 inflammation who do not benefit from T2 cytokine neutralizing antibody treatment. Non-T2 mechanisms are poorly understood in asthma but represent a redefined unmet medical need.
Objective |
We sought to gain a better understanding of genetic contributions to T2-low asthma.
Methods |
We utilized an unbiased genome-wide association study of patients with moderate to severe asthma stratified by T2 serum biomarker periostin. We also performed additional expression and biological analysis for the top genetic hits.
Results |
We identified a novel protective single nucleotide polymorphism at chr19q13.41, which is selectively associated with T2-low asthma and establishes Kallikrein-related peptidase 5 (KLK5) as the causal gene mediating this association. Heterozygous carriers of the single nucleotide polymorphisms have reduced KLK5 expression. KLK5 is secreted by human bronchial epithelial cells and elevated in asthma bronchial alveolar lavage. T2 cytokines IL-4 and IL-13 downregulate KLK5 in human bronchial epithelial cells. KLK5, dependent on its catalytic function, induces epithelial chemokine/cytokine expression. Finally, overexpression of KLK5 in airway or lack of an endogenous KLK5 inhibitor, SPINK5, leads to spontaneous airway neutrophilic inflammation.
Conclusion |
Our data identify KLK5 to be the causal gene at a novel locus at chr19q13.41 associated with T2-low asthma.
Le texte complet de cet article est disponible en PDF.Key words : T2-low asthma, genome-wide association, KLK5, SPINK5
Abbreviations used : BAL, KLK5, LEKTI, PAR2, SNP, SPINK5, T2
Plan
| The first 2 authors contributed equally to this article, and both should be considered first author. The last 2 authors contributed equally to this article, and both should be considered senior author. |
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| The University of Chicago cohort was funded by U19 AI095230 (to C.O. and S.R.W.). |
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| Disclosure of potential conflict of interest: All authors affiliated with Genentech are current or past employees of Genentech Inc, a member of the Roche group, and may hold Roche stock or stock options. Genentech Inc has patent applications for anti-KLK inhibitors for asthma and other inflammatory diseases. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 150 - N° 4
P. 972 - octobre 2022 Retour au numéro
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