Probable Role of Beta 2-Adrenergic Receptor Gene Haplotype in Toluene Diisocyanate-Induced Asthma

다국어 초록 (Multilingual Abstract)

Purpose: A genetic polymorphism of the beta 2-adrenergic receptor is a major factor associated with the asthmatic phenotype. The association of this polymorphism with toluene diisocyanate (TDI)-induced asthma has not been investigated. We examined 103 TDI-induced asthma patients (TDIOA),60 asymptomatic exposed controls (AEC), and 263 unexposed healthy controls (NC) in order to identify beta 2-adrenergic receptor gene (ADRB2)polymorphisms and the possible association with TDI-induced asthma. Methods: Single nucleotide polymorphisms (SNPs) of ADRB2 were genotyped by direct sequencing. Serum-specific IgE and IgG levels were measured using an enzyme-linked immunosorbent assay. Phenotypes and clinical patient parameters were compared. Results: SNPs were identified (−47 T>C, −20 T>C, Arg16Gly A>G, Gln27Glu C>G, Leu134Leu G>A, Arg175Arg C>A) during ADRB2 screening (from –231 to 793 bp). No significant differences in allelic and genotypic frequencies were noted for any of the six ADRB2SNPs. The Arg16Gly A>G, Leu134Leu G>A, and Arg175Arg C>A SNPs and haplotype 1 [TTACGC] were significantly associated with specific IgE antibodies to the TDI-human serum albumin (HSA) conjugate in TDI- exposed subjects (P<0.05). Exposed workers with the ADRB2 ht1/ht1 homozygote had a significantly higher TDI-HSA conjugate-specific IgE sensitization rate than did those with the null ht1 haplotype (odds ratio, 15.40; 95% confidence interval, 1.81–131.06). Conclusions: ADRB2 polymorphisms may affect IgE-specific sensitization to TDI-HSA conjugate in TDI-exposed workers.

참고문헌 (Reference)

1 Burkett K, "hapassoc: Software for likelihood inference of trait associations with SNP haplotypes and other attri­butes" 16 : 1-19, 2006

2 Mapp CE, "What is the role of genetics in occupational asthma?" 33 : 459-460, 2009

3 Hawn TR, "Toll-like receptor polymorphisms and susceptibility to urinary tract infec­tions in adult women" 4 : e5990-, 2009

4 Sitkauskiene B, "The role of beta(2)-adrenergic recep­tors in inflammation and allergy" 4 : 157-162, 2005

5 Liggett SB, "The pharmacogenetics of beta2-adrenergic receptors: relevance to asthma" 105 : S487-492, 2000

6 Choi JH, "The haplotype is a risk factor for toluene diisocyanate-induced occupa­tional asthma" 150 : 156-163, 2009

7 Park HS, "Specific immunoglob­ulin E and immunoglobulin G antibodies to toluene diisocyanate­human serum albumin conjugate: useful markers for predicting long-term prognosis in toluene diisocyanate-induced asthma" 32 : 551-555, 2002

8 Hawkins GA, "Se­quence, haplotype, and association analysis of ADRbeta2 in a mul­tiethnic asthma case-control study" 174 : 1101-1109, 2006

9 Ober C, "Rethinking genetic models of asthma: the role of environmental modifiers" 17 : 670-678, 2005

10 Ye YM, "Relationship between neurokinin 2 receptor gene polymorphisms and serum vascular endothelial growth factor levels in patients with toluene diisocyanate-induced asthma" 36 : 1153-1160, 2006

11 Coqueret O, "Regulation of IgE production from human mononuclear cells by beta 2-adreno­ceptor agonists" 25 : 304-311, 1995

12 Fedyk ER, "Regulation of IgE and cy­tokine production by cAMP: implications for extrinsic asthma" 81 : 101-113, 1996

13 Wikman H, "N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk" 12 : 227-233, 2002

14 Reihsaus E, "Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmat­ic subjects" 8 : 334-339, 1993

15 Contopoulos-Ioannidis DG, "Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes" 115 : 963-972, 2005

16 Maestrelli P, "Mechanisms of oc­cupational asthma" 123 : 531-542, 2009

17 Kim WJ, "Lung function response to 12-week treatment with combined inhalation of long-acting beta2 agonist and glucocorticoid according to ADRB2 polymorphism in patients with chronic obstructive pulmonary disease" 186 : 381-386, 2008

18 Park HS, "Isocyanate-induced occupa­tional asthma in far-east Asia: pathogenesis to prognosis" 32 : 198-204, 2002

19 Wisnewski AV, "Isocyanate vapor-induced antigenicity of human albumin" 113 : 1178-1184, 2004

20 Kay LJ, "Influence of beta2-adrenoceptor gene polymorphisms on beta2-adrenoceptor­mediated responses in human lung mast cells" 152 : 323-331, 2007

21 Borm PJ, "In vitro effect of toluene diisocya­nate on beta adrenergic and muscarinic receptor function in lung tissue of the rat" 46 : 56-59, 1989

22 Green SA, "Implications of genetic vari­ability of human beta 2-adrenergic receptor structure" 8 : 1-10, 1995

23 Wass U, "Immunologic specificity of isocyanate-induced IgE antibodies in serum from 10 sensitized workers" 83 : 126-135, 1989

24 McAlees JW, "Hematopoietic protein tyrosine phospha­tase mediates beta2-adrenergic receptor-induced regulation of p38 mitogen-activated protein kinase in B lymphocytes" 29 : 675-686, 2009

25 Mapp CE, "Glutathione S-transferase GSTP1 is a susceptibility gene for occupational asthma induced by isocyanates" 109 : 867-872, 2002

26 Park HS, "Genotypes and haplotypes of beta2-adren­ergic receptor and parameters of the metabolic syndrome in Kore­an adolescents" 57 : 1064-1070, 2008

27 Seung-Hyun Kim, "Effect of β2-Adrenergic Receptor Polymorphism in Asthma Control of Patients Receiving Combination Treatment" 연세대학교의과대학 50 (50): 182-188, 2009

28 McKay RT, "Effect of toluene diisocyanate on beta adren­ergic receptor function. Biochemical and physiologic studies" 128 : 50-53, 1983

29 Israel E, "Effect of polymorphism of the beta(2)-adrenergic receptor on re­sponse to regular use of albuterol in asthma" 124 : 183-186, 2001

30 Ye YM, "Biophysical determinants of toluene di-isocyanate antigenicity associated with exposure and asthma" 118 : 885-891, 2006

31 Holloway JW, "Beta2-Adrenergic receptor polymorphism and asthma: true or false?" 115 : 960-962, 2005

32 Taylor DR, "Beta-adrenergic receptor polymorphisms and drug responses in asthma" 3 : 173-184, 2002

33 Kim SH, "Associa­tion of beta2-adrenoreceptor polymorphisms with nocturnal cough among atopic subjects but not with atopy and nonspecific bron­chial hyperresponsiveness" 109 : 630-635, 2002

34 Ramsay CE, "Association of polymorphisms in the beta2-adrenoreceptor gene with higher levels of parasitic in­fection" 104 : 269-274, 1999

35 Cho SH, "Association between bronchodilating response to short-acting beta-agonist and non-synonymous single-nucleotide polymor­phisms of beta-adrenoceptor gene" 35 : 1162-1167, 2005

36 Mapp CE, "Association between HLA genes and sus­ceptibility to toluene diisocyanate-induced asthma" 30 : 651-656, 2000

37 Llanes E, "Analysis of polymorphisms in ol­ive pollen allergy: IL13, IL4RA, IL5 and ADRB2 genes" 148 : 228-238, 2009