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\begin{document}

\title{An Association of the Arginase 1 Gene with Preschool Wheezing Phenotypes}



\author[1]{Hartmut Grasemann}%
\author[2]{Fernando Holguin}%
\affil[1]{The Hospital for Sick Children}%
\affil[2]{University of Colorado Denver School of Medicine}%


\vspace{-1em}



  
  \date{May 08, 2024}


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\textbf{An Association of the Arginase 1 Gene with Preschool Wheezing
Phenotypes}

Hartmut Grasemann and Fernando Holguin

Arginases 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
the\emph{Journal} , 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\textgreater{}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.

References

1) 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
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3) Donthi S, Neela VSK, Gaddam S, Mohammed HH, Ansari SS, Valluri VL,
Sivasai KSR. Association of increased risk of asthma with elevated
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13) Schultz A, Devadason SG, Savenije OE, Sly PD, Le Sou\selectlanguage{ngerman}ëf PN, Brand PL.
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18) van Wonderen KE, Geskus RB, van Aalderen WM, Mohrs J, Bindels PJ,
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19) Spycher BD, Cochrane C, Granell R, Sterne JAC, Silverman M, Pedersen
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20) Gokmirza Ozdemir, P, Eker D, Celik V, Beken B, Gurkan H, Yazicioglu
M, Sut N. The relationship between arginase genes polymorphisms and
preschool wheezing phenotypes. Pediatr Pulmonol. 2020 \ldots{}.\selectlanguage{english}
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