- Email: [email protected]
The interaction of IL1A and endothelial nitric oxide synthase polymorphisms is associated with the degree of atopy
284 Letters to the Editor
Letters to the Editor
discharged home with transdermal fentanyl, oral fentanyl for breakthrough pain, acetaminophen, and hydroxyzine. The patient was already in possession of self-injectable epinephrine because of her latex allergy, and she was familiar with its use in the event that she developed dyspnea secondary to the fentanyl after discharge. The patient reported only pruritis and intermittent, mild urticaria with the use of the transdermal fentanyl patch in association with scheduled hydroxyzine. In addition, she did not require the use of the oral fentanyl because her pain was adequately controlled with the transdermal formulation. Three months after discharge, the patient was readmitted to the hospital for another shunt revision. Because doses of fentanyl necessary for pain control were not previously well tolerated, it was decided to attempt the administration of hydromorphone based on the patient’s report that this medication provided excellent pain control in the past. The patient was premedicated with diphenhydramine and hydroxyzine, and escalating doses of hydromorphone were administered (Table II). The patient tolerated as much as 1 mg with the development of generalized pruritis but no urticaria or dyspnea. She was started on a continuous hydromorphone infusion at 0.2 mg/h and was maintained at this dose and taken to the operating room 8 hours later. The operation was once again successfully completed, but the patient was inadvertently administered a bolus dose of 1 mg hydromorphone in the postanesthesia care unit in addition to the continuous infusion. This led to severe dyspnea requiring the administration of epinephrine intramuscularly. No further bolus doses were administered after this event, and the patient’s pain was well controlled by increasing the infusion rate by 0.05 mg/h as needed, to a maximum of 0.35 mg/h, plus the addition of acetaminophen. After achieving adequate pain control, the drip rate was decreased by 0.05 mg/h every 8 hours to a minimum dose of 0.05 mg/h. Attempting to wean at a faster rate or discontinuing the drip at a higher dose of hydromorphone led to loss of pain control. The patient has since been readmitted for repeat neurosurgical procedures, and after premedication with diphenhydramine and hydroxyzine, she has been placed immediately on a continuous infusion of hydromorphone at 0.2 mg/h with rate increases and decreases as noted above. She is able to maintain good pain control with this regimen and does not develop significant adverse events. To our knowledge, this is the first report of the use of continuous opioid infusions to provide analgesia in an opioid-intolerant patient. This report demonstrates that patients who fail to respond to traditional measures for the prevention of pseudoallergic reactions secondary to opioid medications and who have an absolute need for this class of medication may tolerate continuous opioid infusions with slow dose escalations. Continuous infusions may be superior to bolus doses of opioids, such as in patient-controlled analgesia, because histamine release from mast cells secondary to opioids is dose-dependent, and the total dose of opioid administered and peak serum concentrations attained are less with continuous infusions
J ALLERGY CLIN IMMUNOL JULY 2006
than with bolus doses.5,6 In the case of hydromorphone, serum hydromorphone concentrations of at least 4 ng/ mL are required for adequate analgesia.8 To achieve this goal, dosing guidelines recommend hydromorphone infusion rates of up to 0.2 mg/h with the addition of bolus doses as needed.9 Because bolus doses of opioids may lead to pseudoallergic reactions in opioid-intolerant patients, higher infusion rates than those routinely recommended may be required to achieve adequate pain control. Haig Tcheurekdjian, MDa,b Katherine Gundling, MDa From the Division of Allergy and Immunology, Departments of aMedicine and bPediatrics, University of California, San Francisco. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. REFERENCES 1. Veien M, Szlam F, Holden J, Yamaguchi K, Denson DD, Levy JH. Mechanisms of nonimmunological histamine and tryptase release from human cutaneous mast cells. Anesthesiology 2000;92:1074-81. 2. Joint Council of Allergy Asthma and Immunology. Practice parameters for drug hypersensitivity. Ann Allergy Asthma Immunol 1999;83:S665-700. 3. Grammer LC, Greenberger PA. Individual drugs or problems: summary of useful techniques. Allergy Asthma Proc 2005;26:66-72. 4. Nasser SMS, Ewan PW. Opiate-sensitivity: clinical characteristics and the role of skin prick testing. Clin Exp Allergy 2001;31:1014-20. 5. Ebertz JM, Hermens JM, McMillan JC, Uno H, Hirshman C, Hanifin JM. Functional differences between human cutaneous mast cells and basophils: a comparison of morphine-induced histamine release. Agents Actions 1986; 18:455-62. 6. Hermens JM, Ebertz JM, Hanifin JM, Hirshman CA. Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 1985;62:124-9. 7. White PF. Use of continuous infusion versus intermittent bolus administration of fentanyl or ketamine during outpatient anesthesia. Anesthesiology 1983;59:294-300. 8. Reidenberg MM, Goodman H, Erle H, Gray G, Lorenzo B, Leipzig RM, et al. Hydromorphone levels and pain control in patients with severe chronic pain. Clin Pharmacol Ther 1988;44:376-82. 9. Thompson Micromedex Healthcare Series DRUGDEX Evaluation [database on internet]. Greenwood Village (CO): Thomson Healthcare, Inc; 1974-2006. Available at: http://www.thomsonhc.com/home/dispatch. Accessed February 20, 2006. Available online May 10, 2006. doi:10.1016/j.jaci.2006.03.026
The interaction of IL1A and endothelial nitric oxide synthase polymorphisms is associated with the degree of atopy To the Editor: There is increasing evidence that nitric oxide (NO) may play an important role in allergic inflammation. Endothelial NO synthase (eNOS) is one of the enzymes catalyzing NO synthesis. It is induced in a variety of cell types by proinflammatory cytokines, such as IL-1, TNF-a, IFN-g, and by microbial products such as LPSs.1 Previous studies on the role of the eNOS gene in the pathogenesis of atopy have produced conflicting results.2,3 IL-1a is a proinflammatory cytokine that mediates the inflammatory reaction in the skin.4 IL1a has also been found to accelerate cutaneous inflammation.5 We have
Letters to the Editor 285
J ALLERGY CLIN IMMUNOL VOLUME 118, NUMBER 1
TABLE I. Independent effect of IL1A (single nucleotide polymorphism 14845) and eNOS (single nucleotide polymorphism 1894) on sensitization on allergen: the degree of atopy* SPT2
IL1A GG IL1A GT/ TT eNOS TT/ TG eNOS GG
SPT1(1)
SPT1(2)
SPT2 vs SPT1(1)
SPT2 vs SPT1(2)
N
%
N
%
N
%
P
P
99 148 112 135
40.1 59.9 45.3 54.7
43 35 41 37
55.1 44.9 52.6 47.4
42 30 31 41
58.3 41.7 43.1 56.9
.02
.006
.226
.73
*P value calculated in 2 3 2 table by x2 test.
TABLE II. Epistatic effect of IL1A (single nucleotide polymorphism 14845) and eNOS (single nucleotide polymorphism 1894) on sensitization on allergen: the degree of atopy Interaction analyses SPT2
eNOS eNOS eNOS eNOS
TT/TG&IL1A GG TT/TG&IL1A GT/TT GG&IL1A GG GG&IL1A GT/TT
SPT1(1)
SPT1(2)
All groups
SPT2 vs SPT1(1)
SPT2 vs SPT1(2)
N
%
N
%
N
%
P*
Py
Py
44 68 55 80
39.3 60.7 40.7 59.3
23 18 20 17
56.1 43.9 54.1 45.9
23 8 19 22
74.2 25.8 46.3 53.7
.08
.785
.026
earlier shown that IL1A (G/T base change at 14845) polymorphism is associated with atopy; the risk for atopy was higher in subjects having genotype GG of IL1A gene.6 We have expanded the study by analyzing eNOS (T/G base change at 1894) polymorphism from the same cohort and investigated whether these genes show an epistatic effect on the degree of atopy. Altogether 254 female and 151 male (mean age, 60 years; age range, 31-89 years) participated in the study. The subjects were controls without asthma of a Finnish population-based case-control study intended to investigate the risk factors of adult asthma. Detailed information about the whole material has been presented earlier in the Journal.6 IL1A (14845G>T, rs17561) polymorphism was detected as previously described.6 The eNOS (1894T>G, rs1799983) polymorphism was analyzed by allele-specific hybridization method (TaqMan; Applied Biosystems, Foster City, Calif). The nucleotide sequences of the primers and probes used in the PCR were deduced from published sequences deposited in the GenBank database and chosen and synthesized in conjunction with Applied Biosystems (Foster City, Calif). The genotype distributions followed Hardy-Weinberg equilibrium. Sensitization to allergens was determined by skin prick test (SPT) performed as previously described.6 The degree of atopy was defined as the number of positive SPTs. Thus, the SPT-positive patients were divided into those with 1 or 2 positive SPTs (SPT1[1]) and 3 or more positive SPTs (SPT1[2]). As seen in Table I, IL1A genotype GG increased the risk for sensitization to allergen; the number of patients in SPT1(2) group was especially increased (odds ratio [OR], 2.09; 95% CI, 1.23-3.57; P 5 .006, x2 test; df 5 1). eNOS polymorphism did not have an independent
effect on sensitization to allergen but interacted with IL1A gene. The interaction of these genes was calculated by using multinomial logistic regression analysis. The model showed that there is a slight interaction between these genes on the degree of sensitization (P 5 .08; Table II). There was a significant interaction between the SPT-negative and SPT1(2) groups (P 5 .026), but not between the SPT-negative and SPT1(1) groups (P 5 .785, bilogistic regression analysis; Table II). If the age and sex were included in the model, the results did not change (data not shown). Earlier studies have shown that exhaled NO levels in adults correlate with atopy (with a number of positive SPTs and total IgE) rather than bronchial hyperreactivity and lung function.7,8 Here the eNOS gene did not have an independent role in the pathogenesis of atopy. Its effect was dependent on IL1A gene. In addition, eNOS polymorphism itself or together with IL1A polymorphism did not have an effect on asthma susceptibility (Pessi et al, Unpublished data, November 2005). It seems that the effect of eNOS gene on atopy is dependent on another proinflammatory gene, like IL1A. This interaction between eNOS and IL1A genes may also explain some earlier conflicting results2,3 on the effect of eNOS polymorphisms on atopy. We cannot exclude the possibility that the effect of the eNOS gene is on the diagnostic phase—that is, the high producer allele T of eNOS gene9 makes the SPT more sensitive by inducing stronger endothelial enlargement on the site of allergen application. However, we did not observe any effect of the eNOS genotype on the response induced by the histamine control (data not shown), thus speaking against this alternative.
Letters to the Editor
*Multinomial logistic regression analysis. Bilogistic regression analysis.
286 Letters to the Editor
J ALLERGY CLIN IMMUNOL JULY 2006
In our study, we show for the first time that IL1A and eNOS genes have an interactive effect on the degree of atopy (ie, the epistatic effect of 2 genes). Both genes are involved in the initiation of the immune response and probably affect the TH1/TH2 balance.1 At the inductive phase of TH1 cells, NO has shown an enhancing effect on the induction and differentiation of TH1 cells, whereas it has little or no effect on fully committed T cells. On the other hand, NO at noncytotoxic concentrations has been demonstrated to downregulate the TH1-type cytokines and/or increase the TH2-associated molecules.1 The high NO synthesis is linked to atopy7 and to the genotypes of TT and GT of eNOS gene.9 Previously, we showed that subjects having genotype GG of IL1A had a significantly increased risk for SPT positivity.6 Probably the allele G is associated with low capacity to produce IL-1a, a weak inflammatory response induced is known to favor the differentiation of the TH2 cells.10 Thus, it can be concluded that if a subject has 2 atopy risk genes, such as a high NO-producing allele of eNOS gene together with IL1A atopy risk gene, TH2 responses like sensitization to allergens are even further increased. Tanja Pessi, PhDa ˚ djers, MSca Kati A Jussi Karjalainen, MD, PhDb Riikka Rontu, PhDc Mikko Hurme, MD, PhDa,c From athe Department of Microbiology and Immunology and bthe Department of Respiratory Medicine, Medical School, University of Tampere; and cthe Center for Laboratory Medicine, Tampere University Hospital, Finland. Supported by the Academy of Finland, the Tampere Tuberculosis Foundation, the Medical Research Fund of Tampere University Hospital, and the Rehabilitation Fund of the Finnish Social Insurance Institution.
Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
REFERENCES 1. Kolb H, Kolb-Bachofen V. Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator? Immunol Today 1998;19:556-61. 2. 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;32:1193-8. 3. Yanamandra K, Boggs PB, Thurmon TF, Lewis D, Bocchini JA Jr, Dhanireddy R. Novel allele of the endothelial nitric oxide synthase gene polymorphism in Caucasian asthmatics. Biochem Biophys Res Commun 2005;335:545-9. 4. La E, Fischer SM. Transcriptional regulation of intracellular IL-1 receptor antagonist gene by IL-1 alpha in primary mouse keratinocytes. J Immunol 2001;166:6149-55. 5. Konishi H, Tsutsui H, Murakami T, Yumikura-Futatsugi S, Yamanaka K, Tanaka M, et al. IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/ stat6 under specific pathogen-free conditions. Proc Natl Acad Sci U S A 2002;99:11340-5. 6. Karjalainen J, Hulkkonen J, Pessi T, Huhtala H, Nieminen MM, Aromaa A, et al. The IL1A genotype associates with atopy in nonasthmatic adults. J Allergy Clin Immunol 2002;110:429-34. 7. 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;14:261-5. 8. Ho LP, Wood FT, Robson A, Innes JA, Greening AP. Atopy influences exhaled nitric oxide levels in adult asthmatics. Chest 2000;118:1327-31. 9. Yoon Y, Song J, Hong SH, Kim JQ. Plasma nitric oxide concentrations and nitric oxide synthase gene polymorphisms in coronary artery disease. Clin Chem 2000;46:1626-30. 10. Perussia B, Loza MJ. Linear ‘‘2-0-1’’ lymphocyte development: hypotheses on cellular bases for immunity. Trends Immunol 2003;24:235-41.
Available online May 28, 2006. doi:10.1016/j.jaci.2006.03.032
Letters to the Editor
Letters to the Editor
discharged home with transdermal fentanyl, oral fentanyl for breakthrough pain, acetaminophen, and hydroxyzine. The patient was already in possession of self-injectable epinephrine because of her latex allergy, and she was familiar with its use in the event that she developed dyspnea secondary to the fentanyl after discharge. The patient reported only pruritis and intermittent, mild urticaria with the use of the transdermal fentanyl patch in association with scheduled hydroxyzine. In addition, she did not require the use of the oral fentanyl because her pain was adequately controlled with the transdermal formulation. Three months after discharge, the patient was readmitted to the hospital for another shunt revision. Because doses of fentanyl necessary for pain control were not previously well tolerated, it was decided to attempt the administration of hydromorphone based on the patient’s report that this medication provided excellent pain control in the past. The patient was premedicated with diphenhydramine and hydroxyzine, and escalating doses of hydromorphone were administered (Table II). The patient tolerated as much as 1 mg with the development of generalized pruritis but no urticaria or dyspnea. She was started on a continuous hydromorphone infusion at 0.2 mg/h and was maintained at this dose and taken to the operating room 8 hours later. The operation was once again successfully completed, but the patient was inadvertently administered a bolus dose of 1 mg hydromorphone in the postanesthesia care unit in addition to the continuous infusion. This led to severe dyspnea requiring the administration of epinephrine intramuscularly. No further bolus doses were administered after this event, and the patient’s pain was well controlled by increasing the infusion rate by 0.05 mg/h as needed, to a maximum of 0.35 mg/h, plus the addition of acetaminophen. After achieving adequate pain control, the drip rate was decreased by 0.05 mg/h every 8 hours to a minimum dose of 0.05 mg/h. Attempting to wean at a faster rate or discontinuing the drip at a higher dose of hydromorphone led to loss of pain control. The patient has since been readmitted for repeat neurosurgical procedures, and after premedication with diphenhydramine and hydroxyzine, she has been placed immediately on a continuous infusion of hydromorphone at 0.2 mg/h with rate increases and decreases as noted above. She is able to maintain good pain control with this regimen and does not develop significant adverse events. To our knowledge, this is the first report of the use of continuous opioid infusions to provide analgesia in an opioid-intolerant patient. This report demonstrates that patients who fail to respond to traditional measures for the prevention of pseudoallergic reactions secondary to opioid medications and who have an absolute need for this class of medication may tolerate continuous opioid infusions with slow dose escalations. Continuous infusions may be superior to bolus doses of opioids, such as in patient-controlled analgesia, because histamine release from mast cells secondary to opioids is dose-dependent, and the total dose of opioid administered and peak serum concentrations attained are less with continuous infusions
J ALLERGY CLIN IMMUNOL JULY 2006
than with bolus doses.5,6 In the case of hydromorphone, serum hydromorphone concentrations of at least 4 ng/ mL are required for adequate analgesia.8 To achieve this goal, dosing guidelines recommend hydromorphone infusion rates of up to 0.2 mg/h with the addition of bolus doses as needed.9 Because bolus doses of opioids may lead to pseudoallergic reactions in opioid-intolerant patients, higher infusion rates than those routinely recommended may be required to achieve adequate pain control. Haig Tcheurekdjian, MDa,b Katherine Gundling, MDa From the Division of Allergy and Immunology, Departments of aMedicine and bPediatrics, University of California, San Francisco. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. REFERENCES 1. Veien M, Szlam F, Holden J, Yamaguchi K, Denson DD, Levy JH. Mechanisms of nonimmunological histamine and tryptase release from human cutaneous mast cells. Anesthesiology 2000;92:1074-81. 2. Joint Council of Allergy Asthma and Immunology. Practice parameters for drug hypersensitivity. Ann Allergy Asthma Immunol 1999;83:S665-700. 3. Grammer LC, Greenberger PA. Individual drugs or problems: summary of useful techniques. Allergy Asthma Proc 2005;26:66-72. 4. Nasser SMS, Ewan PW. Opiate-sensitivity: clinical characteristics and the role of skin prick testing. Clin Exp Allergy 2001;31:1014-20. 5. Ebertz JM, Hermens JM, McMillan JC, Uno H, Hirshman C, Hanifin JM. Functional differences between human cutaneous mast cells and basophils: a comparison of morphine-induced histamine release. Agents Actions 1986; 18:455-62. 6. Hermens JM, Ebertz JM, Hanifin JM, Hirshman CA. Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 1985;62:124-9. 7. White PF. Use of continuous infusion versus intermittent bolus administration of fentanyl or ketamine during outpatient anesthesia. Anesthesiology 1983;59:294-300. 8. Reidenberg MM, Goodman H, Erle H, Gray G, Lorenzo B, Leipzig RM, et al. Hydromorphone levels and pain control in patients with severe chronic pain. Clin Pharmacol Ther 1988;44:376-82. 9. Thompson Micromedex Healthcare Series DRUGDEX Evaluation [database on internet]. Greenwood Village (CO): Thomson Healthcare, Inc; 1974-2006. Available at: http://www.thomsonhc.com/home/dispatch. Accessed February 20, 2006. Available online May 10, 2006. doi:10.1016/j.jaci.2006.03.026
The interaction of IL1A and endothelial nitric oxide synthase polymorphisms is associated with the degree of atopy To the Editor: There is increasing evidence that nitric oxide (NO) may play an important role in allergic inflammation. Endothelial NO synthase (eNOS) is one of the enzymes catalyzing NO synthesis. It is induced in a variety of cell types by proinflammatory cytokines, such as IL-1, TNF-a, IFN-g, and by microbial products such as LPSs.1 Previous studies on the role of the eNOS gene in the pathogenesis of atopy have produced conflicting results.2,3 IL-1a is a proinflammatory cytokine that mediates the inflammatory reaction in the skin.4 IL1a has also been found to accelerate cutaneous inflammation.5 We have
Letters to the Editor 285
J ALLERGY CLIN IMMUNOL VOLUME 118, NUMBER 1
TABLE I. Independent effect of IL1A (single nucleotide polymorphism 14845) and eNOS (single nucleotide polymorphism 1894) on sensitization on allergen: the degree of atopy* SPT2
IL1A GG IL1A GT/ TT eNOS TT/ TG eNOS GG
SPT1(1)
SPT1(2)
SPT2 vs SPT1(1)
SPT2 vs SPT1(2)
N
%
N
%
N
%
P
P
99 148 112 135
40.1 59.9 45.3 54.7
43 35 41 37
55.1 44.9 52.6 47.4
42 30 31 41
58.3 41.7 43.1 56.9
.02
.006
.226
.73
*P value calculated in 2 3 2 table by x2 test.
TABLE II. Epistatic effect of IL1A (single nucleotide polymorphism 14845) and eNOS (single nucleotide polymorphism 1894) on sensitization on allergen: the degree of atopy Interaction analyses SPT2
eNOS eNOS eNOS eNOS
TT/TG&IL1A GG TT/TG&IL1A GT/TT GG&IL1A GG GG&IL1A GT/TT
SPT1(1)
SPT1(2)
All groups
SPT2 vs SPT1(1)
SPT2 vs SPT1(2)
N
%
N
%
N
%
P*
Py
Py
44 68 55 80
39.3 60.7 40.7 59.3
23 18 20 17
56.1 43.9 54.1 45.9
23 8 19 22
74.2 25.8 46.3 53.7
.08
.785
.026
earlier shown that IL1A (G/T base change at 14845) polymorphism is associated with atopy; the risk for atopy was higher in subjects having genotype GG of IL1A gene.6 We have expanded the study by analyzing eNOS (T/G base change at 1894) polymorphism from the same cohort and investigated whether these genes show an epistatic effect on the degree of atopy. Altogether 254 female and 151 male (mean age, 60 years; age range, 31-89 years) participated in the study. The subjects were controls without asthma of a Finnish population-based case-control study intended to investigate the risk factors of adult asthma. Detailed information about the whole material has been presented earlier in the Journal.6 IL1A (14845G>T, rs17561) polymorphism was detected as previously described.6 The eNOS (1894T>G, rs1799983) polymorphism was analyzed by allele-specific hybridization method (TaqMan; Applied Biosystems, Foster City, Calif). The nucleotide sequences of the primers and probes used in the PCR were deduced from published sequences deposited in the GenBank database and chosen and synthesized in conjunction with Applied Biosystems (Foster City, Calif). The genotype distributions followed Hardy-Weinberg equilibrium. Sensitization to allergens was determined by skin prick test (SPT) performed as previously described.6 The degree of atopy was defined as the number of positive SPTs. Thus, the SPT-positive patients were divided into those with 1 or 2 positive SPTs (SPT1[1]) and 3 or more positive SPTs (SPT1[2]). As seen in Table I, IL1A genotype GG increased the risk for sensitization to allergen; the number of patients in SPT1(2) group was especially increased (odds ratio [OR], 2.09; 95% CI, 1.23-3.57; P 5 .006, x2 test; df 5 1). eNOS polymorphism did not have an independent
effect on sensitization to allergen but interacted with IL1A gene. The interaction of these genes was calculated by using multinomial logistic regression analysis. The model showed that there is a slight interaction between these genes on the degree of sensitization (P 5 .08; Table II). There was a significant interaction between the SPT-negative and SPT1(2) groups (P 5 .026), but not between the SPT-negative and SPT1(1) groups (P 5 .785, bilogistic regression analysis; Table II). If the age and sex were included in the model, the results did not change (data not shown). Earlier studies have shown that exhaled NO levels in adults correlate with atopy (with a number of positive SPTs and total IgE) rather than bronchial hyperreactivity and lung function.7,8 Here the eNOS gene did not have an independent role in the pathogenesis of atopy. Its effect was dependent on IL1A gene. In addition, eNOS polymorphism itself or together with IL1A polymorphism did not have an effect on asthma susceptibility (Pessi et al, Unpublished data, November 2005). It seems that the effect of eNOS gene on atopy is dependent on another proinflammatory gene, like IL1A. This interaction between eNOS and IL1A genes may also explain some earlier conflicting results2,3 on the effect of eNOS polymorphisms on atopy. We cannot exclude the possibility that the effect of the eNOS gene is on the diagnostic phase—that is, the high producer allele T of eNOS gene9 makes the SPT more sensitive by inducing stronger endothelial enlargement on the site of allergen application. However, we did not observe any effect of the eNOS genotype on the response induced by the histamine control (data not shown), thus speaking against this alternative.
Letters to the Editor
*Multinomial logistic regression analysis. Bilogistic regression analysis.
286 Letters to the Editor
J ALLERGY CLIN IMMUNOL JULY 2006
In our study, we show for the first time that IL1A and eNOS genes have an interactive effect on the degree of atopy (ie, the epistatic effect of 2 genes). Both genes are involved in the initiation of the immune response and probably affect the TH1/TH2 balance.1 At the inductive phase of TH1 cells, NO has shown an enhancing effect on the induction and differentiation of TH1 cells, whereas it has little or no effect on fully committed T cells. On the other hand, NO at noncytotoxic concentrations has been demonstrated to downregulate the TH1-type cytokines and/or increase the TH2-associated molecules.1 The high NO synthesis is linked to atopy7 and to the genotypes of TT and GT of eNOS gene.9 Previously, we showed that subjects having genotype GG of IL1A had a significantly increased risk for SPT positivity.6 Probably the allele G is associated with low capacity to produce IL-1a, a weak inflammatory response induced is known to favor the differentiation of the TH2 cells.10 Thus, it can be concluded that if a subject has 2 atopy risk genes, such as a high NO-producing allele of eNOS gene together with IL1A atopy risk gene, TH2 responses like sensitization to allergens are even further increased. Tanja Pessi, PhDa ˚ djers, MSca Kati A Jussi Karjalainen, MD, PhDb Riikka Rontu, PhDc Mikko Hurme, MD, PhDa,c From athe Department of Microbiology and Immunology and bthe Department of Respiratory Medicine, Medical School, University of Tampere; and cthe Center for Laboratory Medicine, Tampere University Hospital, Finland. Supported by the Academy of Finland, the Tampere Tuberculosis Foundation, the Medical Research Fund of Tampere University Hospital, and the Rehabilitation Fund of the Finnish Social Insurance Institution.
Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
REFERENCES 1. Kolb H, Kolb-Bachofen V. Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator? Immunol Today 1998;19:556-61. 2. 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;32:1193-8. 3. Yanamandra K, Boggs PB, Thurmon TF, Lewis D, Bocchini JA Jr, Dhanireddy R. Novel allele of the endothelial nitric oxide synthase gene polymorphism in Caucasian asthmatics. Biochem Biophys Res Commun 2005;335:545-9. 4. La E, Fischer SM. Transcriptional regulation of intracellular IL-1 receptor antagonist gene by IL-1 alpha in primary mouse keratinocytes. J Immunol 2001;166:6149-55. 5. Konishi H, Tsutsui H, Murakami T, Yumikura-Futatsugi S, Yamanaka K, Tanaka M, et al. IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/ stat6 under specific pathogen-free conditions. Proc Natl Acad Sci U S A 2002;99:11340-5. 6. Karjalainen J, Hulkkonen J, Pessi T, Huhtala H, Nieminen MM, Aromaa A, et al. The IL1A genotype associates with atopy in nonasthmatic adults. J Allergy Clin Immunol 2002;110:429-34. 7. 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;14:261-5. 8. Ho LP, Wood FT, Robson A, Innes JA, Greening AP. Atopy influences exhaled nitric oxide levels in adult asthmatics. Chest 2000;118:1327-31. 9. Yoon Y, Song J, Hong SH, Kim JQ. Plasma nitric oxide concentrations and nitric oxide synthase gene polymorphisms in coronary artery disease. Clin Chem 2000;46:1626-30. 10. Perussia B, Loza MJ. Linear ‘‘2-0-1’’ lymphocyte development: hypotheses on cellular bases for immunity. Trends Immunol 2003;24:235-41.
Available online May 28, 2006. doi:10.1016/j.jaci.2006.03.032
Letters to the Editor