An Association of the Arginase 1 Gene with Preschool Wheezing Phenotypes

An Association of the Arginase 1 Gene with Preschool Wheezing PhenotypesHartmut Grasemann and Fernando HolguinArginases are enzymes that metabolize L-arginine to form urea and L-ornithine. The two arginase isoforms, arginase I and arginase II, which are encoded by two different genes (ARG1 and ARG 2), are expressed in various cell types throughout the human body, including the lungs and airways. Arginase competes with nitric oxide synthase (NOS) for L-arginine as substrate, and increased arginase expression and activity in asthma reduces nitric oxide (NO) bioavailability, causing airways obstruction and contributing to reactive oxygen species production (1). Arginase also plays a role in allergen-induced airway remodeling in chronic asthma, presumably due to increased formation of L-ornithine, the precursor of L-proline and the polyamines (2). Proline is further metabolized to collagen and the polyamines putrescine, spermidine and spermine, which among other functions, also inhibit NOS. Increased production of endogenous NOS inhibitors including the polyamines as well as asymmetric dimethylarginine (ADMA), further contribute to the imbalance of NOS and arginases in asthma (figure 1).Previous studies of genetic variations or single nucleotide polymorphisms (SNPs) in arginase genes had shown associations with atopy and asthma. For example, SNPs in both arginase genes were associated with atopy and asthma in children and with risk for asthma in adults (3,4,5). Interestingly, ARG1 and ARG2 were also found to be associated with bronchodilator response in children and adults with asthma, and ARG1 with long term outcome on inhaled corticosteroid (ICS) therapy in adult asthma (5,6,7,8,9).Preschool wheeze is a common phenomenon, usually benign and mostly self-limited (10,11). Different phenotypes of preschool wheeze have been described, including early transient wheeze, late onset wheeze and persistent wheeze (12). A more recent classifications distinguishes multiple trigger wheeze (MTW) from episodic wheeze (EW), which is mainly caused by viral respiratory tract infections. The clinical usefulness of phenotype driven classifications has been questioned for a number of reasons including the longitudinal instability of phenotypes. However, some evidence suggests that MTW may be linked to later onset allergic asthma and MTW may therefore be more likely to respond to asthma treatment as compared to EW (13,14,15,16,17,18). Interestingly, a more recent analysis of the natural history of MTW and EW in two large independent birth cohorts demonstrated that phenotypes may track over time (19), suggesting that the two indeed represent different disease entities and not just differences in severity of the same disease.In a study by Gokmirza Ozdemir et al., published in this issue of theJournal , the authors report an association between arginase 1 gene polymorphisms and preschool wheezing phenotypes (20). In a cohort of 83 well characterized preschool wheezers with either multi trigger wheeze (MTW) or episodic wheeze (EW) phenotype of Turkish origin and matched controls, there was a difference in homozygous frequency of the ARG1 rs2781667T>C SNP between wheezing phenotypes and between patients with vs without allergic rhinitis. The homozygous frequency of this SNP in ARG1 was significantly higher in MTW vs EW, and in allergic rhinitis vs no allergic rhinitis. There were no associations of other tested SNPs in either ARG1 or ARG2 with preschool wheezing, allergic rhinitis, presence of aeroallergen sensitivity or tobacco exposure. Further analyses also showed significant differences in a number of haplotype frequencies in ARG1 between all wheezers and controls, and also between wheezing phenotypes. No associations were found with ARG2 in this study (20). Thus, these results show that in the population studied, variants in ARG1 but not ARG2 were associated with wheezing phenotypes in pre-school age.This observation is exiting as the genotype-phenotype association implies that arginase I could be involved in the development of preschool wheeze and wheezing phenotypes, possibly through an effect on L-arginine availability for nitric oxide synthase (NOS) or by affecting airway remodelling. However, the population studied here was relatively small and the findings have not yet been confirmed by others. Therefore, the results need to be interpreted with caution and additional studies are needed for confirmation. Similarly, it is unclear at this point, whether the SNPs and haplotypes found to be different in frequency between groups, alter arginase expression or activity, and what the biological or molecular explanation could be for the observed associations. Nevertheless, these observations by Gokmirza Ozdemir et al. are promising, and once confirmed in larger and independent cohorts, also have the potential to help develop a genetic test for wheezing pre-schoolers that may predict future asthma risk and response to asthma therapies.References1) North ML, Grasemann H, Khanna N, Inman MD, Gauvreau GM, Scott JA. Increased ornithine-derived polyamines cause airway hyperresponsiveness in a mouse model of asthma. Am J Respir Cell Mol Biol. 2013 Jun;48(6):694-702.2) Maarsingh H, Dekkers BG, Zuidhof AB, Bos IS, Menzen MH, Klein T, Flik G, Zaagsma J, Meurs H. Increased arginase activity contributes to airway remodelling in chronic allergic asthma. Eur Respir J. 2011 Aug;38(2):318-28.3) Donthi S, Neela VSK, Gaddam S, Mohammed HH, Ansari SS, Valluri VL, Sivasai KSR. Association of increased risk of asthma with elevated arginase & interleukin-13 levels in serum & rs2781666 G/T genotype of arginase I. Indian J Med Res. 2018 Aug;148(2):159-168.4) Li H, Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M, Estela Del Rio-Navarro B, Kistner EO, Gjessing HK, Lara-Sanchez Idel C, Chiu GY, London SJ. Genetic polymorphisms in arginase I and II and childhood asthma and atopy. J Allergy Clin Immunol. 2006 Jan;117(1):119-26.5) Vonk JM, Postma DS, Maarsingh H, Bruinenberg M, Koppelman GH, Meurs H. Arginase 1 and arginase 2 variations associate with asthma, asthma severity and beta2 agonist and steroid response. 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