Background: Nitric oxide (NO) is involved in asthma pathogenesis and is synthesized by three isoforms of NO synthase, one of them encoded by NOS1 gene. The CA-repeat and the C5266T SNP in NOS1 exon 29 have been associated with asthma and IgE levels. We thought to test the association of asthma and asthma-related phenotypes with the exon 29 CA-repeat and the C5266T SNP in a Colombian population sample. Methods: The CA-repeat and the C5266T SNP were genotyped in 167 asthmatics and 166 controls using PCR-based fragment length polymorphism and TaqMan assay. We also determined total and mite-specific IgE against Blomia tropicalis and Dermatophagoides pteronyssinus. Results: Three new CA-repeat alleles, 14, 23 and 24 repeats were detected. Allele comprising 16 repeats was associated with asthma (OR: 1.90 (CI 1.22–2.97, pc = 0.028) and low total (pc = 0.02) and specific IgE to B. tropicalis (pc < 0.0001) and D. pteronyssinus (pc < 0.0001). We found no association of the C5266T SNP and asthma or IgE levels. Conclusion:NOS1 exon 29 CA-repeat may be a risk factor for asthma susceptibility and mite specific IgE response in a Colombian population.

1.
Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al: International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995;8:483–491.
2.
Beasley R: The burden of asthma with specific reference to the United States. J Allergy Clin Immunol 2002;109(5 suppl):S482–S489.
3.
Dennis R, Caraballo L, Garcia E, Caballero A, Aristizabal G, Cordoba H, et al: Asthma and other allergic conditions in Colombia: a study in 6 cities. Ann Allergy Asthma Immunol 2004;93:568–574.
4.
Cookson W: The alliance of genes and environment in asthma and allergy. Nature 1999;402(6760 suppl):B5–B11.
5.
Barnes KC, Neely JD, Duffy DL, Freidhoff LR, Breazeale DR, Schou C, et al: Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations. Genomics 1996;37:41–50.
6.
A genome-wide search for asthma susceptibility loci in ethnically diverse populations. The Collaborative Study on the Genetics of Asthma (CSGA). Nat Genet 1997;15:389–392.
7.
Wjst M, Fischer G, Immervoll T, Jung M, Saar K, Rueschendorf F, et al: A genome-wide search for linkage to asthma. German Asthma Genetics Group. Genomics 1999;58:1–8.
8.
Dizier MH, Besse-Schmittler C, Guilloud-Bataille M, Annesi-Maesano I, Boussaha M, Bousquet J, et al: Genome screen for asthma and related phenotypes in the French EGEA study. Am J Respir Crit Care Med 2000;162:1812–1818.
9.
Gao PS, Kawada H, Kasamatsu T, Mao XQ, Roberts MH, Miyamoto Y, et al: Variants of NOS1, NOS2, and NOS3 genes in asthmatics. Biochem Biophys Res Commun 2000;267:761–763.
10.
Konno S, Hizawa N, Yamaguchi E, Jinushi E, Nishimura M: (CCTTT)n repeat polymorphism in the NOS2 gene promoter is associated with atopy. J Allergy Clin Immunol 2001;108:810–814.
11.
Lee YC, Cheon KT, Lee HB, Kim W, Rhee YK, Kim DS: Gene polymorphisms of endothelial nitric oxide synthase and angiotensin-converting enzyme in patients with asthma. Allergy 2000;55:959–963.
12.
Holla LI, Buckova D, Kuhrova V, Stejskalova A, Francova H, Znojil V, et al: Prevalence of endothelial nitric oxide synthase gene polymorphisms in patients with atopic asthma. Clin Exp Allergy 2002;32:1193–1198.
13.
Leung TF, Liu EK, Tang NL, Ko FW, Li CY, Lam CW, et al: Nitric oxide synthase polymorphisms and asthma phenotypes in Chinese children. Clin Exp Allergy 2005;35:1288–1294.
14.
Belvisi MG, Ward JK, Mitchell JA, Barnes PJ: Nitric oxide as a neurotransmitter in human airways. Arch Int Pharmacodyn Ther 1995;329:97–110.
15.
Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ: Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994;343:133–135.
16.
Massaro AF, Mehta S, Lilly CM, Kobzik L, Reilly JJ, Drazen JM: Elevated nitric oxide concentrations in isolated lower airway gas of asthmatic subjects. Am J Respir Crit Care Med 1996;153:1510–1514.
17.
Kharitonov SA, Yates DH, Barnes PJ: Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996;153:454–457.
18.
De Sanctis GT, MacLean JA, Hamada K, Mehta S, Scott JA, Jiao A, et al: Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma. J Exp Med 1999;189:1621–1630.
19.
De Sanctis GT, Mehta S, Kobzik L, Yandava C, Jiao A, Huang PL, et al: Contribution of type I NOS to expired gas NO and bronchial responsiveness in mice. Am J Physiol 1997;273:L883–L888.
20.
Bogdan C: Nitric oxide and the immune response. Nat Immunol 2001;2:907–916.
21.
Taylor-Robinson AW: Inhibition of IL-2 production by nitric oxide: a novel self-regulatory mechanism for Th1 cell proliferation. Immunol Cell Biol 1997;75:167–175.
22.
Bauer H, Jung T, Tsikas D, Stichtenoth DO, Frolich JC, Neumann C: Nitric oxide inhibits the secretion of T-helper 1- and T-helper 2-associated cytokines in activated human T cells. Immunology 1997;90:205–211.
23.
Chang RH, Feng MH, Liu WH, Lai MZ: Nitric oxide increased interleukin-4 expression in T lymphocytes. Immunology 1997;90:364–369.
24.
Huang FP, Niedbala W, Wei XQ, Xu D, Feng GJ, Robinson JH, et al: Nitric oxide regulates Th1 cell development through the inhibition of IL-12 synthesis by macrophages. Eur J Immunol 1998;28:4062–4070.
25.
Morita R, Uchiyama T, Hori T: Nitric oxide inhibits IFN-alpha production of human plasmacytoid dendritic cells partly via a guanosine 3′,5′-cyclic monophosphate-dependent pathway. J Immunol 2005;175:806–812.
26.
Eriksson U, Egermann U, Bihl MP, Gambazzi F, Tamm M, Holt PG, et al: Human bronchial epithelium controls TH2 responses by TH1-induced, nitric oxide-mediated STAT5 dephosphorylation: implications for the pathogenesis of asthma. J Immunol 2005;175:2715–2720.
27.
Grasemann H, Yandava CN, Storm van’s Gravesande K, Deykin A, Pillari A, Ma J, et al: A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma. Biochem Biophys Res Commun 2000;272:391–394.
28.
Shao C, Suzuki Y, Kamada F, Kanno K, Tamari M, Hasegawa K, et al: Linkage and association of childhood asthma with the chromosome 12 genes. J Hum Genet 2004;49:115–122.
29.
Immervoll T, Loesgen S, Dutsch G, Gohlke H, Herbon N, Klugbauer S, et al: Fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes. Hum Mutat 2001;18:327–336.
30.
Holla LI, 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.
31.
Ali M, Khoo SK, Turner S, Stick S, Le Souef 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.
32.
Wechsler ME, Grasemann H, Deykin A, Silverman EK, Yandava CN, Israel E, et al: Exhaled nitric oxide in patients with asthma: association with NOS1 genotype. Am J Respir Crit Care Med 2000;162:2043–2047.
33.
Puerta L, Fernandez-Caldas E, Lockey RF, Caraballo LR: Mite allergy in the tropics: sensitization to six domestic mite species in Cartagena, Colombia. J Invest Allergol Clin Immunol 1993;3:198–204.
34.
Chew FT, Lim SH, Goh DY, Lee BW: Sensitization to local dust-mite fauna in Singapore. Allergy 1999;54:1150–1159.
35.
Ferrandiz R, Casas R, Dreborg S: Sensitization to Dermatophagoides siboney, Blomia tropicalis, and other domestic mites in asthmatic patients. Allergy 1996;51:501–505.
36.
Caraballo L, Puerta L, Fernandez-Caldas E, Lockey RF, Martinez B: Sensitization to mite allergens and acute asthma in a tropical environment. J Invest Allergol Clin Immunol 1998;8:281–284.
37.
Global Strategy for Asthma Management and Prevention: Global Initiative for Asthma. NIH Publication No 01-3659, NHLBI/WHO, 2002.
38.
Caraballo L, Cadavid A, Mendoza J: Prevalence of asthma in a tropical city of Colombia. Ann Allergy 1992;68:525–529.
39.
Caraballo LR, Marrugo J, Erlich H, Pastorizo M: HLA alleles in the population of Cartagena (Colombia). Tissue Antigens 1992;39:128–133.
40.
Builes JJ, Martinez B, Gomez A, Caraballo L, Espinal C, Aguirre D, et al: Y chromosome STR haplotypes in the Caribbean city of Cartagena (Colombia). Forensic Sci Int 2007;167:62–69.
41.
Puerta Llerena L, Fernandez-Caldas E, Caraballo Gracia LR, Lockey RF: Sensitization to Blomia tropicalis and Lepidoglyphus destructor in Dermatophagoides spp-allergic individuals. J Allergy Clin Immunol 1991;88:943–950.
42.
Labrada M, Uyema K, Sewer M, Labrada A, Gonzalez M, Caraballo L, et al: Monoclonal antibodies against Blo t 13, a recombinant allergen from Blomia tropicalis. Int Arch Allergy Immunol 2002;129:212–218.
43.
Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.
44.
Schneider S, Roessli D, Excoffier L: Arlequin ver 2.000: A Software for population genetics data analysis. Genetics and Biometry Laboratory, University of Geneva, Switzerland, 2000.
45.
Grasemann H, Drazen JM, Deykin A, Israel E, De Sanctis GT, Pillari A, et al: Simple tandem repeat polymorphisms in the neuronal nitric oxide synthase gene in different ethnic populations. Hum Hered 1999;49:139–141.
46.
Ober C: Perspectives on the past decade of asthma genetics. J Allergy Clin Immunol 2005;116:274–278.
47.
Fernandez-Caldas E, Puerta L, Caraballo L, Mercado D, Lockey RF: Sequential determinations of Dermatophagoides spp. allergens in a tropical city. J Invest Allergol Clin Immunol 1996;6:98–102.
48.
Puerta L, Fernandez-Caldas E, Mercado D, Lockey RF, Caraballo LR: Sequential determinations of Blomia tropicalis allergens in mattress and floor dust samples in a tropical city. J Allergy Clin Immunol 1996;97:689–691.
49.
Ioannidis JP, Ntzani EE, Trikalinos TA: ‘Racial’ differences in genetic effects for complex diseases. Nat Genet 2004;36:1312–1318.
50.
Hall AV, Antoniou H, Wang Y, Cheung AH, Arbus AM, Olson SL, et al: Structural organization of the human neuronal nitric oxide synthase gene (NOS1). J Biol Chem 1994;269:33082–33090.
51.
Wang Y, Newton DC, Marsden PA: Neuronal NOS: gene structure, mRNA diversity, and functional relevance. Crit Rev Neurobiol 1999;13:21–43.
52.
Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J: Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol 2005;175:342–349.
53.
Togashi H, Sasaki M, Frohman E, Taira E, Ratan RR, Dawson TM, et al: Neuronal (type I) nitric oxide synthase regulates nuclear factor kappaB activity and immunologic (type II) nitric oxide synthase expression. Proc Natl Acad Sci USA 1997;94:2676–2680.
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