INTRODUCTION

Preschool wheeze (PSW) is a highly prevalent clinical problem1 that presents within a wide spectrum of severity and is associated with considerable healthcare costs2. Asthma has its origins in early childhood; however, different patterns of childhood wheezing vary in their association with subsequent asthma, atopy, and bronchial hyper-responsiveness. Wheezing phenotypes used in epidemiological studies are frequently defined retrospectively and are therefore not usable in clinical practice3. In 2008, the European Respiratory Society’s preschool study group divided wheezing phenotypes into episodic (viral) wheeze (EW) and multiple-trigger wheeze (MW)4. According to this classification, wheezing attacks triggered only by viral respiratory tract infections with no complaints between attacks are classified as EW. Wheezing attacks triggered by allergens, exercise, cold weather conditions, or smoke, in addition to viral respiratory tract infections, with complaints between attacks are classified as MW4. However, wheeze patterns in young children vary over time and with treatment, rendering the distinction between EW and MW unclear in many patients5. Therefore, we need predictive markers that are useful for differentiating between wheezing phenotypes and predicting asthma development in children with PSW as a guide for clinicians in early treatment decision-making.
There has been increasing interest among researchers to find a relationship between different genes and wheezing phenotypes and persistence and the development of childhood asthma6,7. Arginase (ARG ) genes have been investigated in this context. Arginase, an essential enzyme in the hepatic urea cycle, is involved in L-arginine homeostasis by catalyzing the reaction in which L-arginine is converted to L-ornithine and urea. Arginase is also expressed in nonhepatic tissues, including in the airways. In humans, two arginase isoenzymes have been identified, arginase 1 and arginase 2, and both are constitutively expressed in the airways. Arginase and nitric oxide synthases (NOS) compete for their common substrate, L-arginine. Increased arginase expression and low L-arginine levels have been found to be associated with asthma and airway remodeling8-12. After defining the important contributions of arginase in asthma, genetic studies have attempted to identify an association between genetic variation in ARG genes and susceptibility for asthma, atopic sensitization, and bronchodilator response (BDR) in different populations13-21. These studies have reported many associations between different single nucleotide polymorphisms (SNPs) in ARG1 or ARG2 genes and atopic sensitization13, 15, risk of asthma13, 16,21, asthma severity16, bronchodilator/steroid response in asthma14, 16, 19,20, and the arginase-NOS pathway 17,18, although some of these results have not been replicated.
To date, associations between polymorphisms in ARG genes and PSW phenotypes are unknown. Therefore, this study aimed to investigate whether there is any relationship between polymorphisms in ARGgenes and PSW phenotypes among Turkish children and compare these results with those of asthmatic children over five years old.