Nitric Oxide Synthase 2 Promoter Polymorphism Is a Risk Factor for Allergic Asthma in Children
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Hardy–Weinberg Equilibrium Test
3.2. Single Marker Association Results
3.3. Gene × Gene Interaction Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
- Hering, T. [Update of the GINA-Recommendations]. MMW Fortschr. Med. 2017, 159, 63–64. [Google Scholar] [CrossRef] [PubMed]
- Nettis, E.; Ortoncelli, M.; Pellacani, G.; Foti, C.; di Leo, E.; Patruno, C.; Rongioletti, F.; Argenziano, G.; Ferrucci, S.M.; Macchia, L.; et al. A Multicenter Study on the Prevalence of Clinical Patterns and Clinical Phenotypes in Adult Atopic Dermatitis. J. Investig. Allergol. Clin. Immunol. 2020, 30, 448–450. [Google Scholar] [CrossRef] [PubMed]
- Dattola, A.; Bennardo, L.; Silvestri, M.; Nisticò, S.P. What’s new in the treatment of atopic dermatitis? Dermatol. Ther. 2019, 32, e12787. [Google Scholar] [CrossRef] [PubMed]
- Kharitonov, S.A.; Barnes, P.J. Exhaled Markers of Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2001, 163, 1693–1722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alving, K.; Weitzberg, E.; Lundberg, J.M. Increased amount of nitric oxide in exhaled air of asthmatics. Eur. Respir. J. 1993, 6, 1368–1370. [Google Scholar] [PubMed]
- Deykin, A.; Massaro, A.F.; Drazen, J.M.; Israel, E. Exhaled nitric oxide as a diagnostic test for asthma: Online versus offline techniques and effect of flow rate. Am. J. Respir. Crit. Care Med. 2002, 165, 1597–1601. [Google Scholar] [CrossRef] [PubMed]
- van der Valk, R.J.P.; Baraldi, E.; Stern, G.; Frey, U.; de Jongste, J.C. Daily exhaled nitric oxide measurements and asthma exacerbations in children. Allergy 2012, 67, 265–271. [Google Scholar] [CrossRef] [PubMed]
- Avital, A.; Uwyyed, K.; Berkman, N.; Godfrey, S.; Bar-Yishay, E.; Springer, C. Exhaled nitric oxide and asthma in young children. Pediatr. Pulmonol. 2001, 32, 308–313. [Google Scholar] [CrossRef]
- Malmberg, L.P.; Pelkonen, A.S.; Haahtela, T.; Turpeinen, M. Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma. Thorax 2003, 58, 494–499. [Google Scholar] [CrossRef] [Green Version]
- Stern, G.; de Jongste, J.; van der Valk, R.; Baraldi, E.; Carraro, S.; Thamrin, C.; Frey, U. Fluctuation phenotyping based on daily fraction of exhaled nitric oxide values in asthmatic children. J. Allergy Clin. Immunol. 2011, 128, 293–300. [Google Scholar] [CrossRef]
- Franklin, P.J.; Turner, S.W.; Le Souëf, P.N.; Stick, S.M. Exhaled nitric oxide and asthma: Complex interactions between atopy, airway responsiveness, and symptoms in a community population of children. Thorax 2003, 58, 1048–1052. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bastain, T.M.; Islam, T.; Berhane, K.T.; McConnell, R.S.; Rappaport, E.B.; Salam, M.T.; Linn, W.S.; Avol, E.L.; Zhang, Y.; Gilliland, F.D. Exhaled nitric oxide, susceptibility and new-onset asthma in the Children’s Health Study. Eur. Respir J. 2011, 37, 523–531. [Google Scholar] [CrossRef] [Green Version]
- di Palmo, E.; Cantarelli, E.; Catelli, A.; Ricci, G.; Gallucci, M.; Miniaci, A.; Pession, A. The Predictive Role of Biomarkers and Genetics in Childhood Asthma Exacerbations. Int. J. Mol. Sci. 2021, 22, 4651. [Google Scholar] [CrossRef] [PubMed]
- Anderson, J.T.; Zeng, M.; Li, Q.; Stapley, R.; Moore, D.R., 2nd; Chenna, B.; Fineberg, N.; Zmijewski, J.; Eltoum, I.E.; Siegal, G.P.; et al. Elevated levels of NO are localized to distal airways in asthma. Free Radic. Biol. Med. 2011, 50, 1679–1688. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fischer, A.; Folkerts, G.; Geppetti, P.; Groneberg, D.A. Mediators of asthma: Nitric oxide. Pulm. Pharmacol. Ther. 2002, 15, 73–81. [Google Scholar] [CrossRef]
- Ricciardolo, F.L.M.; Sterk, P.J.; Gaston, B.; Folkerts, G. Nitric oxide in health and disease of the respiratory system. Physiol. Rev. 2004, 84, 731–765. [Google Scholar] [CrossRef] [PubMed]
- Salam, M.T.; Bastain, T.M.; Rappaport, E.B.; Islam, T.; Berhane, K.; Gauderman, W.J.; Gilliland, F.D. Genetic variations in nitric oxide synthase and arginase influence exhaled nitric oxide levels in children. Allergy 2010, 66, 412–419. [Google Scholar] [CrossRef] [Green Version]
- Szczepankiewicz, A.; Sobkowiak, P.; Rachel, M.; Breborowicz, A.; Schoneich, N.; Bruce, K.; Kycler, Z.; Wojsyk-Banaszak, I.; Dmitrzak-Weglarz, M. Multilocus Analysis of Candidate Genes Involved in Neurogenic Inflammation in Pediatric Asthma and Related Phenotypes: A Case–Control Study. J. Asthma 2012, 49, 329–335. [Google Scholar] [CrossRef]
- Miller, S.A.; Dykes, D.D.; Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988, 16, 1215. [Google Scholar] [CrossRef] [Green Version]
- Ritchie, M.D.; Hahn, L.W.; Roodi, N.; Bailey, L.R.; Dupont, W.D.; Parl, F.F.; Moore, J.H. Multifactor-Dimensionality Reduction Reveals High-Order Interactions among Estrogen-Metabolism Genes in Sporadic Breast Cancer. Am. J. Hum. Genet. 2001, 69, 138–147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wigner, P.; Czarny, P.; Synowiec, E.; Bijak, M.; Białek, K.; Talarowska, M.; Galecki, P.; Szemraj, J.; Sliwinski, T. Variation of genes involved in oxidative and nitrosative stresses in depression. Eur. Psychiatry 2018, 48, 38–48. [Google Scholar] [CrossRef]
- Yoo, K.H.; Kim, S.K.; Chung, J.-H.; Chang, S.-G. Nitric oxide synthase 2 gene polymorphisms are associated with prostatic volume in Korean men with benign prostatic hyperplasia. Asian J. Androl. 2010, 12, 690–696. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, F.; Li, Y.-M.; Yang, L.-Q.; Zhong, C.-G.; Zhuang, Z.-X. Association of NOS2 and NOS3 gene polymorphisms with susceptibility to type 2 diabetes mellitus and diabetic nephropathy in the Chinese Han population. IUBMB Life 2016, 68, 516–525. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yan, L.; Guo, W.; Wu, S.; Liu, J.; Zhang, S.; Shi, L.; Ji, G.; Gu, A. Genetic variants in nitric oxide synthase genes and the risk of male infertility in a Chinese population: A case-control study. PLoS ONE 2014, 9, e115190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Synowiec, E.; Wigner, P.; Cichon, N.; Watala, C.; Czarny, P.; Saluk-Bijak, J.; Miller, E.; Sliwinski, T.; Zielinska-Nowak, E.; Bijak, M. Single-Nucleotide Polymorphisms in Oxidative Stress-Related Genes and the Risk of a Stroke in a Polish Population-A Preliminary Study. Brain Sci. 2021, 11, 391. [Google Scholar] [CrossRef] [PubMed]
- Bouzigon, E.; Monier, F.; Boussaha, M.; Le Moual, N.; Huyvaert, H.; Matran, R.; Letort, S.; Bousquet, J.; Pin, I.; Lathrop, M.; et al. Associations between Nitric Oxide Synthase Genes and Exhaled NO-Related Phenotypes according to Asthma Status. PLOS ONE 2012, 7, e36672. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sato, S.; Wang, X.; Saito, J.; Fukuhara, A.; Uematsu, M.; Suzuki, Y.; Sato, Y.; Misa, K.; Nikaido, T.; Fukuhara, N.; et al. Exhaled nitric oxide and inducible nitric oxide synthase gene polymorphism in Japanese asthmatics. Allergol. Int. 2016, 65, 300–330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dahgam, S.; Nyberg, F.; Modig, L.; Naluai, Å.T.; Olin, A.-C. Single nucleotide polymorphisms in theNOS2andNOS3genes are associated with exhaled nitric oxide. J. Med. Genet. 2012, 49, 200–205. [Google Scholar] [CrossRef]
- Sample, P.J.; Wang, B.; Reid, D.W.; Presnyak, V.; McFadyen, I.J.; Morris, D.R.; Seelig, G. Human 5’ UTR design and variant effect prediction from a massively parallel translation assay. Nat. Biotechnol. 2019, 37, 803–809. [Google Scholar] [CrossRef]
- Wechsler, M.E.; Grasemann, H.; Deykin, A.; Silverman, E.K.; Yandava, C.N.; Israel, E.; Wand, M.; Drazen, J.M. Exhaled nitric oxide in patients with asthma: Association with NOS1 genotype. Am. J. Respir. Crit. Care Med. 2000, 162, 2043–2047. [Google Scholar] [CrossRef] [PubMed]
- Grasemann, H.; Gravesande, K.S.V.; Büscher, R.; Drazen, J.M.; Ratjen, F. Effects of Sex and of Gene Variants in Constitutive Nitric Oxide Synthases on Exhaled Nitric Oxide. Am. J. Respir. Crit. Care Med. 2003, 167, 1113–1116. [Google Scholar] [CrossRef] [PubMed]
- Ali, M.; Khoo, S.-K.; Turner, S.; Stick, S.; Le Souëf, P.; Franklin, P. NOS1 polymorphism is associated with atopy but not exhaled nitric oxide levels in healthy children. Pediatr. Allergy Immunol. 2003, 14, 261–265. [Google Scholar] [CrossRef]
- Holla, L.I.; Schuller, M.; Buckova, D.; Vacha, J. Neuronal nitric oxide synthase gene polymorphism and IgE-mediated allergy in the Central European population. Allergy 2004, 59, 548–552. [Google Scholar] [CrossRef]
- Leung, T.F.; Liu, E.K.H.; Tang, N.L.S.; Ko, F.W.S.; Li, C.Y.; Lam, C.W.K.; Wong, G.W.K. Nitric oxide synthase polymorphisms and asthma phenotypes in Chinese children. Clin. Exp. Allergy 2005, 35, 1288–1294. [Google Scholar] [CrossRef]
- Martínez, B.; Barrios, K.; Vergara, C.; Mercado, D.; Jiménez, S.; Gusmão, L.; Caraballo, L. A NOS1 Gene Polymorphism Associated with Asthma and Specific Immunoglobulin E Response to Mite Allergens in a Colombian Population. Int. Arch. Allergy Immunol. 2007, 144, 105–113. [Google Scholar] [CrossRef] [PubMed]
- Duckworth, L.; Hsu, L.; Feng, H.; Wang, J.; Sylvester, J.E.; Kissoon, N.; Sandler, E.; Lima, J.J. Physician-diagnosed asthma and acute chest syndrome: Associations with NOS Polymorphisms. Pediatr. Pulmonol. 2007, 42, 332–338. [Google Scholar] [CrossRef]
- Diamant, Z.; Vijverberg, S.; Alving, K.; Bakirtas, A.; Bjermer, L.; Custovic, A.; Dahlen, S.; Gaga, M.; Van Wijk, R.G.; Del Giacco, S.; et al. Toward clinically applicable biomarkers for asthma: An EAACI position paper. Allergy 2019, 74, 1835–1851. [Google Scholar] [CrossRef] [Green Version]
- Mogensen, I.; James, A.; Malinovschi, A. Systemic and breath biomarkers for asthma: An update. Curr. Opin. Allergy Clin. Immunol. 2020, 20, 71–79. [Google Scholar] [CrossRef]
- arożna, B.; Hoffmann, A.; Sobkowiak, P.; Schoneich, N.; Bręborowicz, A.; Szczepankiewicz, A. Polymorphisms in the interleukin 4, interleukin 4 receptor and interleukin 13 genes and allergic phenotype: A case control study. Adv. Med Sci. 2016, 61, 40–45. [Google Scholar] [CrossRef]
Gene | SNP | Primer Sequences | Product Size (bp) | Restriction Enzyme | Alleles (bp) |
---|---|---|---|---|---|
NOS1 | C5266T rs2682826 | F: 5-ACTCCTTGAGTTTTCCTGCTGCGATG-3 R: 5-CCATGTTCCAGTGGTTTCATGCACAC-3 | 128 | Eco72I | T: 128 C: 100, 28 |
NOS2 | -1659C/T rs10459953 | F: 5′-TGCTGCAGGTATAGCCAGAAT-3′ R: 5′-ATGGAGGGATGGTATGGTGCTGAT-3′ | 159 | FspBI | C: 160 T: 129, 31 |
608C/T rs2297518 | F: 5′-ATCCCCTGAACCCAGACTTT-3′ R: 5′-GGCCAGGTTTCCAGAAGAA-3′ | 198 | TasI | C: 175, 113 T: 142, 113 | |
NOS3 | G894T rs1799983 | F: 5′-AAGGCAGGAGACAGTGGATG-3′ R: 5′-CAGTCAATCCCTTTGGTGCT-3′ | 246 | MboI | G: 246 T: 158, 88 |
Parameter | Patients Group (n = 220) | Control Group (n = 223) |
---|---|---|
Gender, male (%) | 59% | 48% |
Age, years (mean ± SD) | 11.45 ± 3.56 | 12.14 ± 3.31 |
Asthma severity | - | |
Mild, n (%) | 29 (13.2) | - |
Moderate, n (%) | 121 (55.0) | - |
Severe, n (%) | 70 (31.8) | - |
Positive SPT (%) | 68.2 | - |
FEV1/FVC pred (mean ± SD) | 88.5 ± 12.5 | 104.35 ± 8.18 |
FEV1% pred (mean ± SD) | 85.3 ± 15.1 | 106.15 ± 12.1 |
FVC% pred (mean ± SD) | 89.9 ± 15.1 | 100.5 ± 10.9 |
PEF% pred (mean ± SD) | 81.3 ± 15.8 | 90.3 ± 12.9 |
FeNO (ppb) (mean ± SD) | 28.6 ± 34.3 | 16.6 ± 14.4 |
IgE (IU/mL) (mean ± SD) | 257.5 ± 326.7 | - |
Gene | Polymorphism | Asthma (%) | Control (%) | p Value | ||
---|---|---|---|---|---|---|
NOS1 | C5266T rs2682826 | Genotypes | CC CT TT | 57.3 37.3 5.45 | 58.6 33.3 8.1 | 0.659 |
Alleles | C T | 24.1 75.9 | 24.7 75.3 | 0.912 | ||
NOS2 | -1659C/T rs10459953 | Genotypes | CC CT TT | 67.2 31.3 1.5 | 86.8 12.4 0.8 | 0.001 * |
Alleles | C T | 82.8 17.2 | 93.0 7.0 | 0.0006 * | ||
608C/T rs2297518 | Genotypes | CC CT TT | 70.8 26.9 2.3 | 68.5 29.7 1.8 | 0.866 | |
Alleles | C T | 84.2 15.8 | 84.1 15.9 | 0.532 | ||
NOS3 | G894T rs1799983 | Genotypes | GG GT TT | 54.5 40.0 5.5 | 51.2 42.2 6.6 | 0.855 |
Alleles | G T | 74.5 25.5 | 72.3 27.7 | 0.590 |
Model | Loci Combination | Testing Balanced Accuracy (%) | Cross-Validation Consistency | p-Value |
---|---|---|---|---|
Asthma | ||||
2-locus | NOS2 (608) and NOS2 (C/T) | 62.3 | 8 | 0.025 * |
3-locus | NOS1, NOS2 (608) and NOS2 (C/T) | 58.4 | 6 | 0.201 |
4-locus | NOS1, NOS3, NOS2 (608) and NOS2 (C/T) | 53.7 | 10 | 0.640 |
Increased FeNO | ||||
2-locus | NOS2 608 and NOS3 | 44.9 | 6 | 0.961 |
3-locus | NOS1, NOS2 608 and NOS3 | 51.1 | 8 | 0.763 |
4-locus | NOS1, NOS3, NOS2 (608) and NOS2 (C/T) | 55.7 | 10 | 0.476 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Nowakowska, J.; Sobkowiak, P.; Bręborowicz, A.; Mrówczyńska, M.; Wojsyk-Banaszak, I.; Szczepankiewicz, A. Nitric Oxide Synthase 2 Promoter Polymorphism Is a Risk Factor for Allergic Asthma in Children. Medicina 2021, 57, 1341. https://doi.org/10.3390/medicina57121341
Nowakowska J, Sobkowiak P, Bręborowicz A, Mrówczyńska M, Wojsyk-Banaszak I, Szczepankiewicz A. Nitric Oxide Synthase 2 Promoter Polymorphism Is a Risk Factor for Allergic Asthma in Children. Medicina. 2021; 57(12):1341. https://doi.org/10.3390/medicina57121341
Chicago/Turabian StyleNowakowska, Joanna, Paulina Sobkowiak, Anna Bręborowicz, Magdalena Mrówczyńska, Irena Wojsyk-Banaszak, and Aleksandra Szczepankiewicz. 2021. "Nitric Oxide Synthase 2 Promoter Polymorphism Is a Risk Factor for Allergic Asthma in Children" Medicina 57, no. 12: 1341. https://doi.org/10.3390/medicina57121341