IJ Doull, S Lawrence, M Watson, T Begishvili, RW Beasley, F Lampe, T Holgate and NE Morton
Genetic Epidemiology, University Medicine, University of Southampton, Southampton General Hospital, United Kingdom.

To investigate genetic factors in asthma and atopy, we sought allelic associations for 12 markers near candidate loci for serum total, immunoglobulin E (IgE), and bronchial hyperresponsiveness (BHR) to inhaled histamine in 131 families comprising 685 individuals, selected randomly without regard to atopy or asthma. Nonparametric linkage and association analyses were performed with the Nonparametric Analysis of Lineage and Association (NOPAR) program, and parametric analyses were performed with the Complex Inheritance with Diathesis and Severity (COMDS) program on an ordered polychotomy of ranked scores. On chromosome 11q, allele 168 at the D11S527 locus was significantly associated with BHR (p<0.0003) but not with log IgE. At the D11S534 locus, allele 235 was significantly associated with log IgE (p = 0.007) but not with BHR. Both D11S527 and D11S534 were too distant from the gene encoding the high-affinity IgE receptor FcepsilonRIbeta to account for the association. At the interleukin-9 (IL-9) locus, the 118 allele showed significant association with serum total IgE (p<0.003) but not with histamine BHR. Parametric tests are more conservative, perhaps because they demand consistency with mendelian inheritance and tight linkage. These findings provide support for the view that both chromosomes 5 and 11 may contain genes relevant to asthma and atopy, a possible candidate being the interleukin-4 (IL-4) gene cluster. Because these associations are extremes in a large number of tests, they require confirmation in other samples.

This article has been cited by other articles:

				V. Steenwinckel, J. Louahed, C. Orabona, F. Huaux, G. Warnier, A. McKenzie, D. Lison, R. Levitt, and J.-C. Renauld IL-13 Mediates In Vivo IL-9 Activities on Lung Epithelial Cells but Not on Hematopoietic Cells J. Immunol., March 1, 2007; 178(5): 3244 - 3251. [Abstract] [Full Text] [PDF]

				Y.-L. Lee, T.-R. Hsiue, Y.-C. Lee, Y.-C. Lin, and Y. L. Guo The Association Between Glutathione S-Transferase P1, M1 Polymorphisms and Asthma in Taiwanese Schoolchildren Chest, September 1, 2005; 128(3): 1156 - 1162. [Abstract] [Full Text] [PDF]

				M-A Kedda, F Lose, D Duffy, E Bell, P J Thompson, and J Upham The CD14 C-159T polymorphism is not associated with asthma or asthma severity in an Australian adult population Thorax, March 1, 2005; 60(3): 211 - 214. [Abstract] [Full Text] [PDF]

				Y. Chiba, T. Kusakabe, and S. Kimura Decreased expression of uteroglobin-related protein 1 in inflamed mouse airways is mediated by IL-9 Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1193 - L1198. [Abstract] [Full Text] [PDF]

				C E Ruse and S G Parker Genetics and the Dutch Hypothesis Chronic Respiratory Disease, April 1, 2004; 1(2): 105 - 113. [Abstract] [PDF]

				K. Shinagawa and M. Kojima Mouse Model of Airway Remodeling: Strain Differences Am. J. Respir. Crit. Care Med., October 15, 2003; 168(8): 959 - 967. [Abstract] [Full Text] [PDF]

				J. R. Reader, D. M. Hyde, E. S. Schelegle, M. C. Aldrich, A. M. Stoddard, M. P. McLane, R. C. Levitt, and J. S. Tepper Interleukin-9 Induces Mucous Cell Metaplasia Independent of Inflammation Am. J. Respir. Cell Mol. Biol., June 1, 2003; 28(6): 664 - 672. [Abstract] [Full Text] [PDF]

				G. Cheng, M. Arima, K. Honda, H. Hirata, F. Eda, N. Yoshida, F. Fukushima, Y. Ishii, and T. Fukuda Anti-Interleukin-9 Antibody Treatment Inhibits Airway Inflammation and Hyperreactivity in Mouse Asthma Model Am. J. Respir. Crit. Care Med., August 1, 2002; 166(3): 409 - 416. [Abstract] [Full Text] [PDF]

				F. F. Little, W. W. Cruikshank, and D. M. Center IL-9 Stimulates Release of Chemotactic Factors from Human Bronchial Epithelial Cells Am. J. Respir. Cell Mol. Biol., September 1, 2001; 25(3): 347 - 352. [Abstract] [Full Text] [PDF]

				T. D. Howard, P. A. Whittaker, A. L. Zaiman, G. H. Koppelman, J. Xu, M. T. Hanley, D. A. Meyers, D. S. Postma, and E. R. Bleecker Identification and Association of Polymorphisms in the Interleukin-13 Gene with Asthma and Atopy in a Dutch Population Am. J. Respir. Cell Mol. Biol., September 1, 2001; 25(3): 377 - 384. [Abstract] [Full Text] [PDF]

				J-C Renauld New insights into the role of cytokines in asthma J. Clin. Pathol., August 1, 2001; 54(8): 577 - 589. [Abstract] [Full Text] [PDF]

				S. H. Arshad, S. M. Tariq, S. Matthews, and E. Hakim Sensitization to Common Allergens and Its Association With Allergic Disorders at Age 4 Years: A Whole Population Birth Cohort Study Pediatrics, August 1, 2001; 108 (2): e33 - e33. [Abstract] [Full Text] [PDF]

				A. L. PILON Rationale for the Development of Recombinant Human CC10 as a Therapeutic for Inflammatory and Fibrotic Disease Ann. N.Y. Acad. Sci., December 1, 2000; 923(1): 280 - 299. [Abstract] [Full Text] [PDF]

				N. SIMON THOMAS, J. WILKINSON, C. LONJOU, N. E. MORTON, and S. T. HOLGATE Linkage Analysis of Markers on Chromosome 11q13 with Asthma and Atopy in a United Kingdom Population Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): 1268 - 1272. [Abstract] [Full Text] [PDF]

				A. S. Gounni, B. Gregory, E. Nutku, F. Aris, K. Latifa, E. Minshall, J. North, J. Tavernier, R. Levit, N. Nicolaides, et al. Interleukin-9 enhances interleukin-5 receptor expression, differentiation, and survival of human eosinophils Blood, September 15, 2000; 96(6): 2163 - 2171. [Abstract] [Full Text] [PDF]

				D. S. POSTMA, G. H. KOPPELMAN, and D. A. MEYERS The Genetics of Atopy and Airway Hyperresponsiveness Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S118 - 123. [Full Text] [PDF]

				E. SUMMERHILL, S. A. LEAVITT, H. GIDLEY, R. PARRY, J. SOLWAY, and C. OBER beta 2-Adrenergic Receptor Arg16/Arg16 Genotype Is Associated with Reduced Lung Function, but Not with Asthma, in the Hutterites Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 599 - 602. [Abstract] [Full Text] [PDF]

				V. Azuara and P. Pereira Genetic Mapping of Two Murine Loci that Influence the Development of IL-4-Producing Thy-1dull {gamma}{delta} Thymocytes J. Immunol., July 1, 2000; 165(1): 42 - 48. [Abstract] [Full Text] [PDF]

				J. Louahed, M. Toda, J. Jen, Q. Hamid, J.-C. Renauld, R. C. Levitt, and N. C. Nicolaides Interleukin-9 Upregulates Mucus Expression in the Airways Am. J. Respir. Cell Mol. Biol., June 1, 2000; 22(6): 649 - 656. [Abstract] [Full Text]

				L. Hultner, S. Kolsch, M. Stassen, U. Kaspers, J.-P. Kremer, R. Mailhammer, J. Moeller, H. Broszeit, and E. Schmitt In Activated Mast Cells, IL-1 Up-Regulates the Production of Several Th2-Related Cytokines Including IL-9 J. Immunol., June 1, 2000; 164(11): 5556 - 5563. [Abstract] [Full Text] [PDF]

				A. A. FRYER, A. BIANCO, M. HEPPLE, P. W. JONES, R. C. STRANGE, and M. A. SPITERI Polymorphism at the Glutathione S-transferase GSTP1 Locus . A New Marker for Bronchial Hyperresponsiveness and Asthma Am. J. Respir. Crit. Care Med., May 1, 2000; 161(5): 1437 - 1442. [Abstract] [Full Text]

				A. J. SANDFORD and P. D. PARE The Genetics of Asthma . The Important Questions Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S202 - 206. [Full Text] [PDF]

				J. P. BREWER, A. B. KISSELGOF, and T. R. MARTIN Genetic Variability in Pulmonary Physiological, Cellular, and Antibody Responses to Antigen in Mice Am. J. Respir. Crit. Care Med., October 1, 1999; 160(4): 1150 - 1156. [Abstract] [Full Text]

				K F Chung and P J Barnes Cytokines in asthma Thorax, September 1, 1999; 54(9): 825 - 857. [Full Text]

				A. H. MANSUR, D. T. BISHOP, A. F. MARKHAM, N. E. MORTON, S. T. HOLGATE, and J. F. J. MORRISON Suggestive Evidence for Genetic Linkage Between IgE Phenotypes and Chromosome 14q Markers Am. J. Respir. Crit. Care Med., June 1, 1999; 159(6): 1796 - 1802. [Abstract] [Full Text]

				F. D. MARTINEZ, S. SOLOMON, C. J. HOLBERG, P. E. GRAVES, M. BALDINI, and R. P. ERICKSON Linkage of Circulating Eosinophils to Markers on Chromosome 5q Am. J. Respir. Crit. Care Med., December 1, 1998; 158(6): 1739 - 1744. [Abstract] [Full Text] [PDF]

				U.-A. Temann, G. P. Geba, J. A. Rankin, and R. A. Flavell Expression of Interleukin 9 in the Lungs of  Transgenic Mice Causes Airway Inflammation, Mast Cell Hyperplasia, and Bronchial Hyperresponsiveness J. Exp. Med., October 5, 1998; 188(7): 1307 - 1320. [Abstract] [Full Text] [PDF]

				S.-S. Soo, B. Villarreal-Ramos, C. M. A. Khan, C. E. Hormaeche, and J. M. Blackwell Genetic Control of Immune Response to Recombinant Antigens Carried by an Attenuated Salmonella typhimurium Vaccine Strain: Nramp1 Influences T-Helper Subset Responses and Protection against Leishmanial Challenge Infect. Immun., May 1, 1998; 66(5): 1910 - 1917. [Abstract] [Full Text] [PDF]

				G G Anderson and J F J Morrison Molecular biology and genetics of allergy and asthma Arch. Dis. Child., May 1, 1998; 78(5): 488 - 496. [Full Text]

				L. J. Rosenwasser Interleukin-4 and the Genetics of Atopy N. Engl. J. Med., December 11, 1997; 337(24): 1766 - 1767. [Full Text]

				N. C. Nicolaides, K. J. Holroyd, S. L. Ewart, S. M. Eleff, M. B. Kiser, C. R. Dragwa, C. D. Sullivan, L. Grasso, L.-Y. Zhang, C. J. Messler, et al. Interleukin 9: A candidate gene for asthma PNAS, November 25, 1997; 94(24): 13175 - 13180. [Abstract] [Full Text] [PDF]

				E. NOGUCHI, M. SHIBASAKI, T. ARINAMI, K. TAKEDA, T. MAKI, T. MIYAMOTO, T. KAWASHIMA, K. KOBAYASHI, and H. HAMAGUCHI Evidence for Linkage Between Asthma/Atopy in Childhood and Chromosome 5q31-q33 in a Japanese Population Am. J. Respir. Crit. Care Med., November 1, 1997; 156(5): 1390 - 1393. [Abstract] [Full Text]

				E. R. BLEECKER, D. S. POSTMA, and D. A. MEYERS Evidence for Multiple Genetic Susceptibility Loci for Asthma Am. J. Respir. Crit. Care Med., October 1, 1997; 156(4): S113 - S116. [Abstract] [Full Text] [PDF]

				N. S. THOMAS, J. WILKINSON, and S. T. HOLGATE The Candidate Region Approach to the Genetics of Asthma and Allergy Am. J. Respir. Crit. Care Med., October 1, 1997; 156(4): S144 - S151. [Abstract] [Full Text] [PDF]