DISCUSSION
To our knowledge, this is the first study to look at PSW phenotypes andARG gene polymorphisms. We hypothesized that there would be
relationships between a PSW phenotype and polymorphisms of theARG1 and ARG2 genes. Our study revealed that the frequency
of the homozygote C-allele rs2781667 in ARG1 was significantly
higher in the MW and asthma groups than in the EW group. Li et
al.13 reported that four SNPs in ARG1(rs2781659, rs2781665, rs2781667, rs2246012) and rs 3742880 inARG2 were associated with the number of positive skin tests, and
carrying two copies of the minor allele for rs3759757 and rs6573788 SNPs
in ARG2 were found to be associated with the presence and
severity of asthma. Litonjua et al.14 reported that
rs2781659 in ARG1 was significantly associated with BDR in
asthmatic children. In another study15, each variant
allele of rs3742879 in ARG2 was found to be associated with
increased asthma risk. Vonk et al.16 reported that two
polymorphisms in ARG2 (rs17249437 and rs3742879) were associated
with both asthma and more severe airway obstruction, and increased
airway hyperreactivity (AHR) and lower beta-2-agonist reversibility were
reported as associated with both ARG1 and ARG2. Hing Yee
et al.20 reported that rs7216389 in ORMDL3 and
rs3756780 in ARG1 interactions might be associated with a risk of
asthma, and rs2749935 in ARG1 and rs2190242 in CRHR2interactions might be associated with BDR. A recent study from India
showed that high arginase activity and IL-13 concentration in serum and
the ARG1 rs2781666 G/T genotype might increase the risk of
asthma21. Vonk et al.16 reported
that the protective effect of inhaled corticosteroids (ICS) against
annual FEV1 decline was significantly lower in homozygote carriers of
the C-allele of rs2781667 in ARG1 in a longitudinal cohort of 200
adult asthma patients. Based on this, our finding of a higher frequency
of homozygote C-allele rs2781667 in ARG1 in the MW and asthma
groups may be important for the management of patients with PSW. We
think it might be a useful marker for the differentiation of the PSW
phenotype. In addition, the association between this SNP and ICS or BDR
could be addressed in future studies.
We also found that the homozygote CC genotype of the ARG1rs2781667T>C SNP was more frequent in patients with
allergic rhinitis than in those without allergic rhinitis (p =
0.004). While it is known that the arginase-NOS pathway is associated
with allergic rhinitis 23,24, we were unable to find
any study related to the association of allergic rhinitis and ARGgenes until now. Furthermore, we have no data for whether ARG1rs2781667 is a functional polymorphism and associated with changes in
arginase expression in the nasal mucosa.
Our haplotype analyses revealed that the frequencies of the ARG1haplotype 2 and haplotype 5 were significantly higher in the EW group
than in the control group. Two recent studies suggest an interaction
between arginase expression and viral airway
infections25,26. Santiago-Olivares et
al.25 investigated the impact of Respiratory Syncytial
Virus (RSV) infection on nitric oxide production in an experimental
model and found that ARG1 overexpression contributes to the
maintenance of the RSV genome in the host in persistent infection.
Wieczfinska et al.26 found that the expression of
TGF-β1 and arginase was increased due to rhinovirus infection. To date,
we have no data for viral-induced wheezing and genetic variations inARG genes, but new studies could advance this. The ARG1haplotype 4 was more frequent in the MW group than in the EW group.
Interestingly, ARG1 haplotype 4 carried the variant C-allele for
rs2781667 in ARG1 , so it may be useful for differentiating
between EW and MW. Salam et al.15 reported that the
association between arginase variants and childhood asthma may be
related with haplotypes rather than SNPs. Duan et
al.19 studied haplotypes were identified according to
the SNPs (rs2781659, rs2781663, rs2781665, and rs60389358) in theARG1 and they have reported that two haplotypes may alter BDR and
differentially regulate gene expression. The haplotypes that we
estimated according to the studied SNPs were different from those used
in these studies, so it is impossible to make a comparison between
haplotype-based results.
The diagnoses of asthma cases and the classification of patients
according to a PSW phenotype were performed by pediatric allergists at a
tertiary pediatric allergy specialty clinic, these were strengths of the
our study. However, there were some limitations. First, the sample size
was smaller than previous studies have referred to; additionally, it
does not represent all Turkish children. Second, this was a case-control
study; thus, we have no longitudinal data about the progress and
bronchodilator or ICS responses of patients with a homozygote CC
genotype of the ARG1 rs2781667T>C and/or ARG1haplotype 4. Third, we included no information about the functionality
of the homozygote CC genotype of the ARG1rs2781667T>C and/or ARG 1 haplotype 4 in lung and
nasal mucosa.
In conclusion, our study revealed that ARG1rs2781667T>C and/or ARG 1 haplotype 4 were more
frequent in patients with MW and asthma than in the EW group. The
frequencies of the ARG1 haplotype 2 and haplotype 5 were
significantly higher in the EW group, while haplotype 9 was more
frequent in the healthy controls. Taken together, we conclude that
variations in ARG1 gene may be potentially important for
differentiating PSW phenotypes. Our findings need to be confirmed in
larger, different PSW populations, preferably with different ethnic
backgrounds.