在台灣地區兒童氣喘盛行率高達10.8﹪，因此氣喘可說是目前公共衛生的重要課題。在環境因子方面，研究發現若暴露於塵瞞、貓毛、燃燒木材、蟑螂、抽煙及花粉下會增加氣喘危險性。在基因方面， IL4/IL4R-α/STAT6 訊息傳遞路徑(signal transducer pathway)目前被認為是氣喘相當重要的致病機轉，IL4/IL4R-α/STAT6是屬於同一傳遞途徑，彼此相互影響。因此，本研究的目的是要來探討環境因子與IL4R-α/STAT6基因多型性與氣喘之相關性。
本研究從高雄某兩家教學醫院收集了171位經小兒科專科醫師確認為過敏性氣喘兒童為對象，然後從高雄市立某國小收集186位健康的小朋友當對照組。為便於探討與氣喘相關的基因，本研究以過敏性氣喘兒童為對象。其中過敏性氣喘定義為total IgE >200ku/l或特異性過敏原（specific IgE）檢查至少一項陽性反應。
我們發現男性、家中有蟑螂出現、家中有霉斑霉味、父母親有過敏疾病史以及IL4R-α中的S478P、Q551R還有STAT6的基因多型性都會增加氣喘發生的危險性。但是在經過校正其他干擾因子之後發現僅剩男性（勝算比OR=2.35，95%信賴區間CI：1.38-4.00）以及母親有過敏病史（OR=2.19，95%CI=1.18-4.04）與氣喘之間有相關性。在基因方面，控制性別、父母親過敏病史、家中有無出現蟑螂、家中有無霉斑霉味、IL4R-478、IL4R-551、STAT6後，Q551R這個SNP中QR型為QQ型的4.05倍(95%CI：2.31-7.08)、RR型為QQ型的15.62倍(95%CI：4.02-60.69)，與氣喘間有顯著性相關；至於在S478P中PP型對SS型的OR值由原本的7.27校正為2.72倍而與氣喘間沒有顯著的相關性存在；在STAT6也一樣，MM型對WW型的OR值由4.19校正為2.25倍而與氣喘間也沒有顯著的相關性存在。若是單看對偶基因的危險對比值，結果發現在校正過干擾因子後，S478P的對偶基因P對S的相對危險性為2.08(95% CI：1.12-3.86)；Q551R的對偶基因R對Q的相對危險性為3.58(95% CI：2.36-5.43)。E375A、C406R、S478P、Q551R彼此間分別有連鎖不平衡的關係存在。E375A與Q551R之連鎖不平衡係數D’在氣喘與非氣喘兩組皆為1.00，表示E375A與Q551R間屬於高度連鎖。C406R與Q551R之連鎖不平衡係數D’在氣喘與非氣喘兩組分別為0.43與0.71，S478P與Q551R之連鎖不平衡係數D’在氣喘與非氣喘兩組分別為0.56與0.20，E375A與C406之連鎖不平衡係數D’在氣喘與非氣喘兩組分別為0.47與0.11。因為這四個基因多型性彼此間相互連鎖，所以在探討的同時也應該一併討論較為合適。在探討S478P與Q551R時發現P478/R551型之相對危險性為S478/Q551型之5.79倍，若同時把C406R加入考慮，結果發現當基因型屬於P478/R551型時若是其C406R是屬於C406型時，其相對危險性會由原本的5.79提升為6.63。再考慮E375A的話，則當基因型屬於P478/R551/C406型時，若是其E375A是屬於E375型，其相對危險性會由原本的6.63提升為7.48。
本研究發現性別以及母親的過敏病史對與氣喘有顯著的相關。當我們同時考慮了IL4R E375A、C406R、S478P、Q551R四個SNP時發現E375/C406/P478/R551的危險性會是A375/R406/S478/Q551的7.48倍。這比單看單一或是兩組單套基因型或三組單套基因型對氣喘的危險對比值更高。由此推論，當單獨觀察一個基因多型性時，雖然有時候我們仍然可以看到基因多型性對於疾病的影響力，但似乎會忽略了多個基因及多個單一核酸多型性連鎖在一起之後對於疾病的共同影響。

In Taiwan, the prevalence of asthma among school children exceeds 10.8 %, and therefore asthma constitutes an important public health problem. Among environment factors, researchers found that exposures to mite, cat, cockroach, and smoking might increase the risk of asthma. Among genetic factors, the IL4/IL4R-α/STAT6 signal transducer pathway plays an important role in the pathogenesis of asthma, and IL4, IL4R-α, and STAT6 influence each other. The objectives of this study are to assess the associations between the IL4R-α/STAT6 polymorphisms and asthma and to assess the biological interaction between IL4/IL4R-α/ STAT6 polymorphisms and environmental factors on asthma.

We recruited 171 children from the Kaohsiung Medical University Hospital and the Kaohsiung Veterans General Hospital who were less than 18 years old and were confirmed by pediatricians as asthmatic. We also recruited 186 comparison children from the Bo Ai Elementary School. To facilitate the evaluation of asthma related genes, we included only atopic asthma patients. The definition of atopic is a total IgE level over 200ku/l or at elast one specific IgE test showed positive.

We find that male, cockroach in the house, mold in the house, parental allergic disease history, and genetic polymorphisms of IL4R-α, S478P, Q551R, and STAT6 were risk factors of asthma. But, after adjusting for some confounding factors, we found only male gneder (odd ratio [OR] = 2.35, 95% confidence interval [CI] = 1.38 to 4.00) and maternal allergic disease history were significant risk factors of asthma. Among genetic factors, after adjusting for sex, parental allergic disease history, cockroach in the house, mold in the house, and polymorphisms of IL4R-478, IL4R-551, and STAT6, Q551R polymorphism is significantly associated with asthma (QR vs. QQ, OR = 4.05, 95%CI: 2.31 to 7.08; RR vs. QQ, OR = 15.62, 95%CI: 4.02 to 60.69). Among S478P polymorphisms, the OR of PP type in comparison with SS type decreased from 7.27 to 2.72 after the adjustment, and S478P polymorphisma were not associated with asthma. The observatuions on STAT6 were similar to those on S478P. The OR of MM type in comparison with WW type decreased from 4.19 to 2.25 after the adjustment, and STAT6 polymorphisms were not associated with asthma. As to the allele type, after adjusting for some confounding factors, we found the P allele type had an OR of 2.08 (95% CI:1.12 to 3.86) regarding the S478P polymorphisms, and the Q allele type had an OR of 3.58 (95% CI:2.36 to 5.43) regarding the S478P polymorphisms. The four groups of polymorphisms (E375A, C406R, S478P, and Q551R) were in linkage disequilibrium. The linkage disequilibrium coefficient (D’) was 1.00 and 1.00 in cases and controls for E375A and Q551R; 0.71 in cases and controls for C406R and Q551R; 0.56 and 0.20 in cases and controls for S478P and Q551R; and 0.47 and 0.11 in cases and controls for E375A and C406R. Because the four SNPs were linked to each other, we studied the four SNPs at the same time. The OR of P478/R551 in compariosn with S478/Q551 was 5.79 if we studied C406R at the same time. We found the OR increased from 5.79 to 6.63 if the C406R SNP was of the C406 type. When haplotype was C406/P478/R551, and the E375A SNP was E375, the OR increased from 6.63 to 7.48.
In this study we found that male gender and maternal allergic disease history were significant risk factors for asthma. We also found hat the OR of E375/C406/P478/R551 in comparison with A375/R406/S478/Q551 was 7.48, higher than having just one, two, or three high risk SNPs. Therefore, we might under- or over-estimate the effect of the linkage genes or SNPs if we study the polymorphisms of just one gene.

Adilah N, Fitzharris P, Crane J, Siebers RW. 1997. The effect of frequent vacuum cleaning on the house dust mite allergen, Der p 1 in carpets: a pilot study. N Z Med J 110(1056):438-439.
Anonymous. 1850. The British Museum reading room. Nature 2:199.
Arruda LK, Vailes LD, Hayden ML, Benjamin DC, Chapman MD. 1995. Cloning of cockroach allergen, Bla g 4, identifies ligand binding proteins (or calycins) as a cause of IgE antibody responses. Journal of Biological Chemistry 270(52):31196-31201.
Arruda LK, Vailes LD, Mann BJ, Shannon J, Fox JW, Vedvick TS, et al. 1995. Molecular cloning of a major cockroach (Blattella germanica) allergen, Bla g 2. Sequence homology to the aspartic proteases. Journal of Biological Chemistry 270(33):19563-19568.
Arruda LK, Vailes LD, Platts-Mills TA, Hayden ML, Chapman MD. 1997. Induction of IgE antibody responses by glutathione S-transferase from the German cockroach (Blattella germanica). Journal of Biological Chemistry 272(33):20907-20912.
Barrett JC, Fry B, Maller J, Daly MJ. 2005. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263-265.
Beghe B, Barton S, Rorke S, Peng Q, Sayers I, Gaunt T, et al. 2003. Polymorphisms in the interleukin-4 and interleukin-4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin Exp Allergy 33(8):1111-1117.
Birnbaum J, Orlando JP, Charpin D, Vervloet D. 1995. Cockroaches and mites share the same beds.[see comment]. Journal of Allergy & Clinical Immunology 96(4):561-562.
Bjornsdottir US, Cypcar DM. 1999. Asthma: an inflammatory mediator soup. Allergy 54(Suppl 49):55-61.
Borish L, Mascali JJ, Klinnert M, Leppert M, Rosenwasser LJ. 1994. SSC polymorphisms in interleukin genes. Hum Mol Genet 3(9):1710.
Burchard EG, Silverman EK, Rosenwasser LJ, Borish L, Yandava C, Pillari A, et al. 1999. Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma. Am J Respir Crit Care Med 160(3):919-922.
Burr ML, Anderson HR, Austin JB, Harkins LS, Kaur B, Strachan DP, et al. 1999. Respiratory symptoms and home environment in children: a national survey. Thorax 54(1):27-32.
Burrows B, Halonen M, Barbee RA, Lebowitz MD. 1981. The relationship of serum immunoglobulin E to cigarette smoking. Am Rev Respir Dis 124(5):523-525.
Chakir J, Hamid Q, Bosse M, Boulet LP, Laviolette M. 2002. Bronchial inflammation in corticosteroid-sensitive and corticosteroid-resistant asthma at baseline and on oral corticosteroid treatment. Clin Exp Allergy 32(4):578-582.
Chen HE, Chang S, Trub T, Neel BG. 1996. Regulation of colony-stimulating factor 1 receptor signaling by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol Cell Biol 16(7):3685-3697.
Chilmonczyk BA, Salmun LM, Megathlin KN, Neveux LM, Palomaki GE, Knight GJ, et al. 1993. Association between exposure to environmental tobacco smoke and exacerbations of asthma in children.[see comment]. N Engl J Med 328(23):1665-1669.
Clark NM. 1989. Asthma self-management education. Research and implications for clinical practice. Chest 95(5):1110-1113.
Cui T, Wu J, Pan S, Xie J. 2003. Polymorphisms in the IL-4 and IL-4R [alpha] genes and allergic asthma. Clin Chem Lab Med 41(7):888-892.
Curiel RE, Lahesmaa R, Subleski J, Cippitelli M, Kirken RA, Young HA, et al. 1997. Identification of a Stat-6-responsive element in the promoter of the human interleukin-4 gene. European Journal of Immunology 27(8):1982-1987.
Custovic A, Simpson A, Pahdi H, Green RM, Chapman MD, Woodcock A. 1998. Distribution, aerodynamic characteristics, and removal of the major cat allergen Fel d 1 in British homes. Thorax 53(1):33-38.
Custovic A, Taggart SC, Francis HC, Chapman MD, Woodcock A. 1996. Exposure to house dust mite allergens and the clinical activity of asthma. Journal of Allergy & Clinical Immunology 98(1):64-72.
Dales RE, Zwanenburg H, Burnett R, Franklin CA. 1991. Respiratory health effects of home dampness and molds among Canadian children. Am J Epidemiol 134(2):196-203.
Daniel C, Salvekar A, Schindler U. 2000. A gain-of-function mutation in STAT6. Journal of Biological Chemistry 275(19):14255-14259.
Duetsch G, Illig T, Loesgen S, Rohde K, Klopp N, Herbon N, et al. 2002. STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study. Human Molecular Genetics 11(6):613-621.
Evans R, 3rd, Mullally DI, Wilson RW, Gergen PJ, Rosenberg HM, Grauman JS, et al. 1987. National trends in the morbidity and mortality of asthma in the US. Prevalence, hospitalization and death from asthma over two decades: 1965-1984. Chest 91(6 Suppl):65S-74S.
Floyer SJ. 1726. A Treatise of Asthma, 3rd ed. London.
Gao PS, Mao XQ, Roberts MH, Arinobu Y, Akaiwa M, Enomoto T, et al. 2000. Variants of STAT6 (signal transducer and activator of transcription 6) in atopic asthma. Journal of Medical Genetics 37(5):380-382.
Hackstein H, Hecker M, Kruse S, Bohnert A, Ober C, Deichmann KA, et al. 2001. A novel polymorphism in the 5' promoter region of the human interleukin-4 receptor alpha-chain gene is associated with decreased soluble interleukin-4 receptor protein levels. Immunogenetics 53(4):264-269.
Harris JR, Magnus P, Samuelsen SO, Tambs K. 1997. No evidence for effects of family environment on asthma. A retrospective study of Norwegian twins. Am J Respir Crit Care Med 156(1):43-49.
Heinzmann A, Grotherr P, Jerkic SP, Lichtenberg A, Braun S, Kruse S, et al. 2000. Studies on linkage and association of atopy with the chromosomal region 12q13-24. Clinical and Experimental Allergy 30(11):1555-1561.
Helm R, Cockrell G, Stanley JS, Brenner RJ, Burks W, Bannon GA. 1996. Isolation and characterization of a clone encoding a major allergen (Bla g Bd90K) involved in IgE-mediated cockroach hypersensitivity. Journal of Allergy & Clinical Immunology 98(1):172-180.
Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. 1997. The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. New England Journal of Medicine 337(24):1720-1725.
Hesselmar B, Aberg N, Aberg B, Eriksson B, Bjorksten B. 1999. Does early exposure to cat or dog protect against later allergy development? Clinical & Experimental Allergy 29(5):611-617.
Hizawa N, Freidhoff LR, Ehrlich E, Chiu YF, Duffy DL, Schou C, et al. 1998. Genetic influences of chromosomes 5q31-q33 and 11q13 on specific IgE responsiveness to common inhaled allergens among African American families. Collaborative Study on the Genetics of Asthma (CSGA). Journal of Allergy & Clinical Immunology 102(3):449-453.
Holloway JW, Beghe B, Holgate ST. 1999. The genetic basis of atopic asthma. Clin Exp Allergy 29(8):1023-1032.
Howard TD, Koppelman GH, Xu J, Zheng SL, Postma DS, Meyers DA, et al. 2002. Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am J Hum Genet 70(1):230-236.
Huang J.L. ea. 1997. Increasing prevalence of childhood allergic disease and the risk factors for development of allergy in Taipei, Taiwan.Proceeding of 5th West-Pacific Allergy Symposium. Seoul,Korea:23-27.
Hytonen AM, Lowhagen O, Arvidsson M, Balder B, Bjork AL, Lindgren S, et al. 2004. Haplotypes of the interleukin-4 receptor alpha chain gene associate with susceptibility to and severity of atopic asthma. Clin Exp Allergy 34(10):1570-1575.
Jaakkola JJ, Jaakkola N, Ruotsalainen R. 1993. Home dampness and molds as determinants of respiratory symptoms and asthma in pre-school children. J Expo Anal Environ Epidemiol 3 Suppl 1:129-142.
Janeway C, Travers P, Walport M ea. 1999. Immunobiology: the immune system in health and disease. fourth edition. Garland Pub, New York:115-162.
Jarvis MJ. 1989. Application of biochemical intake markers to passive smoking measurement and risk estimation. Mutat Res 222(2):101-110.
Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T, et al. 2001. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force.[see comment][erratum appears in Allergy 2001 Dec;56(12):1229]. Allergy 56(9):813-824.
Kauppi P, Lindblad-Toh K, Sevon P, Toivonen HT, Rioux JD, Villapakkam A, et al. 2001. A second-generation association study of the 5q31 cytokine gene cluster and the interleukin-4 receptor in asthma. Genomics 77(1-2):35-42.
Kawachi I, Colditz GA. 1996. Invited commentary: confounding, measurement error, and publication bias in studies of passive smoking. Am J Epidemiol 144(10):909-915.
Kjellman NI. 1981. Effect of parental smoking on IgE levels in children. Lancet 1(8227):993-994.
Klingmuller U, Lorenz U, Cantley LC, Neel BG, Lodish HF. 1995. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80(5):729-738.
Kotanides H, Reich NC. 1996. Interleukin-4-induced STAT6 recognizes and activates a target site in the promoter of the interleukin-4 receptor gene. Journal of Biological Chemistry 271(41):25555-25561.
Kruse S, Japha T, Tedner M, Sparholt SH, Forster J, Kuehr J, et al. 1999. The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction. Immunology 96(3):365-371.
Kuehr J, Frischer T, Meinert R, Barth R, Forster J, Schraub S, et al. 1994. Mite allergen exposure is a risk for the incidence of specific sensitization. Journal of Allergy & Clinical Immunology 94(1):44-52.
Laitinen T, Rasanen M, Kaprio J, Koskenvuo M, Laitinen LA. 1998. Importance of genetic factors in adolescent asthma: a population-based twin-family study. Am J Respir Crit Care Med 157(4 Pt 1):1073-1078.
Lau S, Falkenhorst G, Weber A, Werthmann I, Lind P, Buettner-Goetz P, et al. 1989. High mite-allergen exposure increases the risk of sensitization in atopic children and young adults. Journal of Allergy & Clinical Immunology 84(5 Pt 1):718-725.
Lee PN. 1995. "Marriage to a smoker" may not be a valid marker of exposure in studies relating environmental tobacco smoke to risk of lung cancer in Japanese non-smoking women. Int Arch Occup Environ Health 67(5):287-294.
Lee SG, Kim BS, Kim JH, Lee SY, Choi SO, Shim JY, et al. 2004. Gene-gene interaction between interleukin-4 and interleukin-4 receptor alpha in Korean children with asthma. Clin Exp Allergy 34(8):1202-1208.
Masu K, Ohno I, Suzuki K, Okada S, Hattori T, Shirato K. 2002. Proliferative effects of eosinophil lysates on cultured human airway smooth muscle cells. Clin Exp Allergy 32(4):595-601.
McKenzie AN. 2000. Regulation of T helper type 2 cell immunity by interleukin-4 and interleukin-13. Pharmacology and Therapeutics 88(2):143-151.
Melen E, Pomes A, Vailes LD, Arruda LK, Chapman MD. 1999. Molecular cloning of Per a 1 and definition of the cross-reactive Group 1 cockroach allergens. Journal of Allergy & Clinical Immunology 103(5 Pt 1):859-864.
Mitsuyasu H, Izuhara K, Mao XQ, Gao PS, Arinobu Y, Enomoto T, et al. 1998. Ile50Val variant of IL4R alpha upregulates IgE synthesis and associates with atopic asthma. Nature Genetics 19(2):119-120.
Mitsuyasu H, Yanagihara Y, Mao XQ, Gao PS, Arinobu Y, Ihara K, et al. 1999. Cutting edge: dominant effect of Ile50Val variant of the human IL-4 receptor alpha-chain in IgE synthesis. J Immunol 162(3):1227-1231.
Mujica-Lopez KI, Flores-Martinez SE, Ramos-Zepeda R, Castaneda-Ramos SA, Gazca-Aguilar A, Garcia-Perez J, et al. 2002. Association analysis of polymorphisms in the interleukin-4 receptor (alpha) gene with atopic asthma in patients from western Mexico. Eur J Immunogenet 29(5):375-378.
Mullings RE, Wilson SJ, Puddicombe SM, Lordan JL, Bucchieri F, Djukanovic R, et al. 2001. Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium. Journal of Allergy & Clinical Immunology 108(5):832-838.
Neddenriep D, Schumacher MJ, Lemen RJ. 1989. Asthma in childhood. Curr Probl Pediatr 19(7):325-385.
Newman-Taylor A. 1995. Environmental determinants of asthma. Lancet 345(8945):296-299.
Noguchi E, Shibasaki M, Arinami T, Takeda K, Yokouchi Y, Kawashima T, et al. 1998. Association of asthma and the interleukin-4 promoter gene in Japanese. Clinical & Experimental Allergy 28(4):449-453.
Paulson RF, Vesely S, Siminovitch KA, Bernstein A. 1996. Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1. Nat Genet 13(3):309-315.
Peat JK, Tovey E, Toelle BG, Haby MM, Gray EJ, Mahmic A, et al. 1996. House dust mite allergens. A major risk factor for childhood asthma in Australia. Am J Respir Crit Care Med 153(1):141-146.
Peruzzi M, de Luca M, Novembre E, de Martino M, Vierucci A. 1999. Incidence of cockroach allergy in atopic Italian children. Ann Allergy Asthma Immunol 83(2):167-171.
Pollart SM, Mullins DE, Vailes LD, Hayden ML, Platts-Mills TA, Sutherland WM, et al. 1991. Identification, quantitation, and purification of cockroach allergens using monoclonal antibodies. Journal of Allergy & Clinical Immunology 87(2):511-521.
Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, et al. 1995. Genetic susceptibility to asthma--bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 333(14):894-900.
Quelle FW, Shimoda K, Thierfelder W, Fischer C, Kim A, Ruben SM, et al. 1995. Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol Cell Biol 15(6):3336-3343.
Risma KA, Wang N, Andrews RP, Cunningham CM, Ericksen MB, Bernstein JA, et al. 2002. V75R576 IL-4 receptor alpha is associated with allergic asthma and enhanced IL-4 receptor function. J Immunol 169(3):1604-1610.
Rosenwasser LJ, Klemm DJ, Dresback JK, Inamura H, Mascali JJ, Klinnert M, et al. 1995. Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clinical & Experimental Allergy 25(Suppl 2):74-78; discussion 95-76.
Rubin BK, Tomkiewicz R, Fahy JV, Green FH. 2001. Histopathology of fatal asthma: drowning in mucus. Pediatr Pulmonol Suppl(23):88-89.
Samet JM, Marbury MC, Spengler JD. 1987. Health effects and sources of indoor air pollution. Part I. Am Rev Respir Dis 136(6):1486-1508.
Sandford A, Weir T, Pare P. 1996. The genetics of asthma. Am J Respir Crit Care Med 153(6 Pt 1):1749-1765.
Santos AB, Chapman MD, Aalberse RC, Vailes LD, Ferriani VP, Oliver C, et al. 1999. Cockroach allergens and asthma in Brazil: identification of tropomyosin as a major allergen with potential cross-reactivity with mite and shrimp allergens. Journal of Allergy & Clinical Immunology 104(2 Pt 1):329-337.
Schou C, Lind P, Fernandez-Caldas E, Lockey RF, Lowenstein H. 1990. Identification and purification of an important cross-reactive allergen from American (Periplaneta americana) and German (Blattella germanica) cockroach. Journal of Allergy & Clinical Immunology 86(6 Pt 1):935-946.
Sherrill DL, Martinez FD, Lebowitz MD, Holdaway MD, Flannery EM, Herbison GP, et al. 1992. Longitudinal effects of passive smoking on pulmonary function in New Zealand children. Am Rev Respir Dis 145(5):1136-1141.
Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, et al. 1996. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380(6575):630-633.
Squillace SP, Sporik RB, Rakes G, Couture N, Lawrence A, Merriam S, et al. 1997. Sensitization to dust mites as a dominant risk factor for asthma among adolescents living in central Virginia. Multiple regression analysis of a population-based study. Am J Respir Crit Care Med 156(6):1760-1764.
Stavnezer J. 1996. Antibody class switching. Adv Immunol 61:79-146.
Stirling RG, Chung KF. 2001. Severe asthma: definition and mechanisms. Allergy 56(9):825-840.
Strachan DP, Carey IM. 1995. Home environment and severe asthma in adolescence: a population based case-control study. Bmj 311(7012):1053-1056.
Strachan DP, Cook DG. 1997. Health effects of passive smoking. 1. Parental smoking and lower respiratory illness in infancy and early childhood. Thorax 52(10):905-914.
Strachan DP, Flannigan B, McCabe EM, McGarry F. 1990. Quantification of airborne moulds in the homes of children with and without wheeze. Thorax 45(5):382-387.
Svanes C, Jarvis D, Chinn S, Burney P. 1999. Childhood environment and adult atopy: results from the European Community Respiratory Health Survey. Journal of Allergy & Clinical Immunology 103(3 Pt 1):415-420.
Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, et al. 1996. Essential role of Stat6 in IL-4 signalling. Nature 380(6575):627-630.
Tamura K, Arakawa H, Suzuki M, Kobayashi Y, Mochizuki H, Kato M, et al. 2001. Novel dinucleotide repeat polymorphism in the first exon of the STAT-6 gene is associated with allergic diseases. Clinical and Experimental Allergy 31(10):1509-1514.
Trautmann A, Schmid-Grendelmeier P, Kruger K, Crameri R, Akdis M, Akkaya A, et al. 2002. T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma. J Allergy Clin Immunol 109(2):329-337.
Tregouet DA, Barbaux S, Escolano S, Tahri N, Golmard JL, Tiret L, et al. 2002. Specific haplotypes of the P-selectin gene are associated with myocardial infarction. Hum Mol Genet 11(17):2015-2023.
Tregouet DA, Escolano S, Tiret L, Mallet A, Golmard JL. 2004. A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm. Ann Hum Genet 68(Pt 2):165-177.
Tregouet DA, Tiret L. 2004. Cox proportional hazards survival regression in haplotype-based association analysis using the Stochastic-EM algorithm. Eur J Hum Genet 12(11):971-974.
Turktas I, Ozkaya O, Bostanci I, Bideci A, Cinaz P. 2001. Safety of inhaled corticosteroid therapy in young children with asthma. Ann Allergy Asthma Immunol 86(6):649-654.
van Strien RT, Verhoeff AP, van Wijnen JH, Doekes G, de Meer G, Brunekreef B. 1996. Infant respiratory symptoms in relation to mite allergen exposure. Eur Respir J 9(5):926-931.
Verhoeff AP, Burge HA. 1997. Health risk assessment of fungi in home environments. Ann Allergy Asthma Immunol 78(6):544-554; quiz 555-546.
Verhoeff AP, van Strien RT, van Wijnen JH, Brunekreef B. 1995. Damp housing and childhood respiratory symptoms: the role of sensitization to dust mites and molds. Am J Epidemiol 141(2):103-110.
Weiss ST, Tager IB, Munoz A, Speizer FE. 1985. The relationship of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atopy. Am Rev Respir Dis 131(4):573-578.
Willers S, Skarping G, Dalene M, Skerfving S. 1995. Urinary cotinine in children and adults during and after semiexperimental exposure to environmental tobacco smoke. Arch Environ Health 50(2):130-138.
Wu CH, Lee MF, Liao SC, Luo SF. 1996. Sequencing analysis of cDNA clones encoding the American cockroach Cr-PI allergens. Homology with insect hemolymph proteins. Journal of Biological Chemistry 271(30):17937-17943.
Yi T, Mui AL, Krystal G, Ihle JN. 1993. Hematopoietic cell phosphatase associates with the interleukin-3 (IL-3) receptor beta chain and down-regulates IL-3-induced tyrosine phosphorylation and mitogenesis. Mol Cell Biol 13(12):7577-7586.
王志堯, 江伯倫, 呂克桓 ea. 2000. 氣喘診療指引. first edition. 行政院衛生署,台灣(15-7).
江伯倫. 2002. 科學發展. 353:14-19.
吳家興等. 1998. 台灣北部國中生氣喘盛行率調查. 中華衛教 17:214-225.
衛生署. 2000. 氣喘診療指引. 衛生署保健處.