Abstract
Background: A study was undertaken to validate a locus modulating total serum IgE levels on 14q13–24.
Methods: A linkage and association study was performed between total serum IgE and a panel of seven microsatellites which map to the 14q13–24 region in 69 families with asthma recruited from Leeds, UK.
Results: Non-parametric, multipoint, sib pair analysis showed no evidence of genetic linkage between the quantitative trait "log IgE" and any of the tested markers. However, a significant association was observed between locus D14S63 (14q23) and total serum IgE (p = 0.017). Allelic analysis showed an association between low total IgE and allele 157 of D14S63 (p = 0.01, OR = 0.63, 95% CI 0.44 to 0.90). Modelling of allele 157 genotypes as a continuous covariate indicated evidence of a significant inverse linear trend across the three genotypes where 157 homozygotes had the lowest mean log IgE (p = 0.045). Association of D14S63 with log IgE was confirmed in the analysis of a combined dataset of 53 families from Southampton, UK and the 69 families from Leeds (total 122 families). An association was observed at the locus level (p = 0.022) and the allelic level where allele 165 showed an association with high total IgE (p = 0.001, OR = 3.79, 95% CI 1.54 to 9.7) and allele 157 showed an association with low total IgE (p = 0.041, OR = 0.77, 95% CI 0.6 to 0.99). The transmission disequilibrium test was positive for allele 165 (p<0.05) and negative for allele 157 (p>0.05).
Conclusions: Despite the lack of linkage, the findings of this study support the previous observation of a gene(s) at 14q23 that modulates total serum IgE.
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Selected References
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- Abecasis G. R., Cardon L. R., Cookson W. O. A general test of association for quantitative traits in nuclear families. Am J Hum Genet. 2000 Jan;66(1):279–292. doi: 10.1086/302698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barbee R. A., Halonen M., Lebowitz M., Burrows B. Distribution of IgE in a community population sample: correlations with age, sex, and allergen skin test reactivity. J Allergy Clin Immunol. 1981 Aug;68(2):106–111. doi: 10.1016/0091-6749(81)90167-6. [DOI] [PubMed] [Google Scholar]
- Barnes K. C., Neely J. D., Duffy D. L., Freidhoff L. R., Breazeale D. R., Schou C., Naidu R. P., Levett P. N., Renault B., Kucherlapati R. Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations. Genomics. 1996 Oct 1;37(1):41–50. doi: 10.1006/geno.1996.0518. [DOI] [PubMed] [Google Scholar]
- Bazaral M., Orgel H. A., Hamburger R. N. IgE levels in normal infants and mothers and an inheritance hypothesis. J Immunol. 1971 Sep;107(3):794–801. [PubMed] [Google Scholar]
- Burrows B., Martinez F. D., Halonen M., Barbee R. A., Cline M. G. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989 Feb 2;320(5):271–277. doi: 10.1056/NEJM198902023200502. [DOI] [PubMed] [Google Scholar]
- Busse W. W., Coffman R. L., Gelfand E. W., Kay A. B., Rosenwasser L. J. Mechanisms of persistent airway inflammation in asthma. A role for T cells and T-cell products. Am J Respir Crit Care Med. 1995 Jul;152(1):388–393. doi: 10.1164/ajrccm.152.1.7599853. [DOI] [PubMed] [Google Scholar]
- Busse W. W. Inflammation in asthma: the cornerstone of the disease and target of therapy. J Allergy Clin Immunol. 1998 Oct;102(4 Pt 2):S17–S22. doi: 10.1016/s0091-6749(98)70002-8. [DOI] [PubMed] [Google Scholar]
- Clamp M., Andrews D., Barker D., Bevan P., Cameron G., Chen Y., Clark L., Cox T., Cuff J., Curwen V. Ensembl 2002: accommodating comparative genomics. Nucleic Acids Res. 2003 Jan 1;31(1):38–42. doi: 10.1093/nar/gkg083. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Collins A., Frezal J., Teague J., Morton N. E. A metric map of humans: 23,500 loci in 850 bands. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14771–14775. doi: 10.1073/pnas.93.25.14771. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Collins A., Teague J., Keats B. J., Morton N. E. Linkage map integration. Genomics. 1996 Aug 15;36(1):157–162. doi: 10.1006/geno.1996.0436. [DOI] [PubMed] [Google Scholar]
- Daniels S. E., Bhattacharrya S., James A., Leaves N. I., Young A., Hill M. R., Faux J. A., Ryan G. F., le Söuef P. N., Lathrop G. M. A genome-wide search for quantitative trait loci underlying asthma. Nature. 1996 Sep 19;383(6597):247–250. doi: 10.1038/383247a0. [DOI] [PubMed] [Google Scholar]
- Demoly P., Basset-Seguin N., Chanez P., Campbell A. M., Gauthier-Rouvière C., Godard P., Michel F. B., Bousquet J. c-fos proto-oncogene expression in bronchial biopsies of asthmatics. Am J Respir Cell Mol Biol. 1992 Aug;7(2):128–133. doi: 10.1165/ajrcmb/7.2.128. [DOI] [PubMed] [Google Scholar]
- Dizier M. H., Hill M., James A., Faux J., Ryan G., le Souef P., Lathrop M., Musk A. W., Demenais F., Cookson W. Detection of a recessive major gene for high IgE levels acting independently of specific response to allergens. Genet Epidemiol. 1995;12(1):93–105. doi: 10.1002/gepi.1370120109. [DOI] [PubMed] [Google Scholar]
- Fasman K. H., Letovsky S. I., Li P., Cottingham R. W., Kingsbury D. T. The GDB Human Genome Database Anno 1997. Nucleic Acids Res. 1997 Jan 1;25(1):72–81. doi: 10.1093/nar/25.1.72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gerrard J. W., Rao D. C., Morton N. E. A genetic study of immunoglobulin E. Am J Hum Genet. 1978 Jan;30(1):46–58. [PMC free article] [PubMed] [Google Scholar]
- Grimbacher B., Schäffer A. A., Holland S. M., Davis J., Gallin J. I., Malech H. L., Atkinson T. P., Belohradsky B. H., Buckley R. H., Cossu F. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet. 1999 Sep;65(3):735–744. doi: 10.1086/302547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hagel I., Lynch N. R., Di Prisco M. C., Rojas E., Pérez M., Alvarez N. Ascaris reinfection of slum children: relation with the IgE response. Clin Exp Immunol. 1993 Oct;94(1):80–83. doi: 10.1111/j.1365-2249.1993.tb05981.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hakonarson Hakon, Bjornsdottir Unnur S., Halapi Eva, Palsson Snaebjorn, Adalsteinsdottir Elva, Gislason David, Finnbogason Gudmundur, Gislason Thorarinn, Kristjansson Kristleifur, Arnason Thor. A major susceptibility gene for asthma maps to chromosome 14q24. Am J Hum Genet. 2002 Jul 15;71(3):483–491. doi: 10.1086/342205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haseman J. K., Elston R. C. The investigation of linkage between a quantitative trait and a marker locus. Behav Genet. 1972 Mar;2(1):3–19. doi: 10.1007/BF01066731. [DOI] [PubMed] [Google Scholar]
- Hasstedt S. J., Meyers D. A., Marsh D. G. Inheritance of immunoglobulin E: genetic model fitting. Am J Med Genet. 1983 Jan;14(1):61–66. doi: 10.1002/ajmg.1320140110. [DOI] [PubMed] [Google Scholar]
- Ishizaka K., Ishizaka T. IgE and reaginic hypersensitivity. Ann N Y Acad Sci. 1971 Dec 31;190:443–456. doi: 10.1111/j.1749-6632.1971.tb13554.x. [DOI] [PubMed] [Google Scholar]
- Johansson S. G., Bennich H. H., Berg T. The clinical significance of IgE. Prog Clin Immunol. 1972;1:157–181. [PubMed] [Google Scholar]
- Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. doi: 10.1038/ng1195-241. [DOI] [PubMed] [Google Scholar]
- Le Beau M. M., Ito C., Cogswell P., Espinosa R., 3rd, Fernald A. A., Baldwin A. S., Jr Chromosomal localization of the genes encoding the p50/p105 subunits of NF-kappa B (NFKB2) and the I kappa B/MAD-3 (NFKBI) inhibitor of NF-kappa B to 4q24 and 14q13, respectively. Genomics. 1992 Oct;14(2):529–531. doi: 10.1016/s0888-7543(05)80261-7. [DOI] [PubMed] [Google Scholar]
- Mansur A. H., Bishop D. T., Markham A. F., Morton N. E., Holgate S. T., Morrison J. F. Suggestive evidence for genetic linkage between IgE phenotypes and chromosome 14q markers. Am J Respir Crit Care Med. 1999 Jun;159(6):1796–1802. doi: 10.1164/ajrccm.159.6.9804036. [DOI] [PubMed] [Google Scholar]
- Marsh D. G., Neely J. D., Breazeale D. R., Ghosh B., Freidhoff L. R., Ehrlich-Kautzky E., Schou C., Krishnaswamy G., Beaty T. H. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science. 1994 May 20;264(5162):1152–1156. doi: 10.1126/science.8178175. [DOI] [PubMed] [Google Scholar]
- Martinez F. D., Holberg C. J., Halonen M., Morgan W. J., Wright A. L., Taussig L. M. Evidence for Mendelian inheritance of serum IgE levels in Hispanic and non-Hispanic white families. Am J Hum Genet. 1994 Sep;55(3):555–565. [PMC free article] [PubMed] [Google Scholar]
- Mastrianni D. M., Eddy R. L., Rosenberg H. F., Corrette S. E., Shows T. B., Tenen D. G., Ackerman S. J. Localization of the human eosinophil Charcot-Leyden crystal protein (lysophospholipase) gene (CLC) to chromosome 19 and the human ribonuclease 2 (eosinophil-derived neurotoxin) and ribonuclease 3 (eosinophil cationic protein) genes (RNS2 and RNS3) to chromosome 14. Genomics. 1992 May;13(1):240–242. doi: 10.1016/0888-7543(92)90237-m. [DOI] [PubMed] [Google Scholar]
- Meyers D. A., Bias W. B., Marsh D. G. A genetic study of total IgE levels in the Amish. Hum Hered. 1982;32(1):15–23. doi: 10.1159/000153262. [DOI] [PubMed] [Google Scholar]
- Meyers D. A., Postma D. S., Panhuysen C. I., Xu J., Amelung P. J., Levitt R. C., Bleecker E. R. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics. 1994 Sep 15;23(2):464–470. doi: 10.1006/geno.1994.1524. [DOI] [PubMed] [Google Scholar]
- Moffatt M. F., Hill M. R., Cornélis F., Schou C., Faux J. A., Young R. P., James A. L., Ryan G., le Souef P., Musk A. W. Genetic linkage of T-cell receptor alpha/delta complex to specific IgE responses. Lancet. 1994 Jun 25;343(8913):1597–1600. doi: 10.1016/s0140-6736(94)93057-0. [DOI] [PubMed] [Google Scholar]
- Nygaard T. G., Wilhelmsen K. C., Risch N. J., Brown D. L., Trugman J. M., Gilliam T. C., Fahn S., Weeks D. E. Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q. Nat Genet. 1993 Dec;5(4):386–391. doi: 10.1038/ng1293-386. [DOI] [PubMed] [Google Scholar]
- Ober C., Cox N. J., Abney M., Di Rienzo A., Lander E. S., Changyaleket B., Gidley H., Kurtz B., Lee J., Nance M. Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma. Hum Mol Genet. 1998 Sep;7(9):1393–1398. doi: 10.1093/hmg/7.9.1393. [DOI] [PubMed] [Google Scholar]
- Risch N., Merikangas K. The future of genetic studies of complex human diseases. Science. 1996 Sep 13;273(5281):1516–1517. doi: 10.1126/science.273.5281.1516. [DOI] [PubMed] [Google Scholar]
- Schulman E. S. Development of a monoclonal anti-immunoglobulin E antibody (omalizumab) for the treatment of allergic respiratory disorders. Am J Respir Crit Care Med. 2001 Oct 15;164(8 Pt 2):S6–11. doi: 10.1164/ajrccm.164.supplement_1.2103025. [DOI] [PubMed] [Google Scholar]
- Sears M. R., Burrows B., Flannery E. M., Herbison G. P., Hewitt C. J., Holdaway M. D. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N Engl J Med. 1991 Oct 10;325(15):1067–1071. doi: 10.1056/NEJM199110103251504. [DOI] [PubMed] [Google Scholar]
- Sham P. C., Curtis D. An extended transmission/disequilibrium test (TDT) for multi-allele marker loci. Ann Hum Genet. 1995 Jul;59(Pt 3):323–336. doi: 10.1111/j.1469-1809.1995.tb00751.x. [DOI] [PubMed] [Google Scholar]
- Spielman R. S., McGinnis R. E., Ewens W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PMC free article] [PubMed] [Google Scholar]
- Suarez B. K., Hampe C. L. Linkage and association. Am J Hum Genet. 1994 Mar;54(3):554–563. [PMC free article] [PubMed] [Google Scholar]
- Wilkinson J., Grimley S., Collins A., Thomas N. S., Holgate S. T., Morton N. Linkage of asthma to markers on chromosome 12 in a sample of 240 families using quantitative phenotype scores. Genomics. 1998 Nov 1;53(3):251–259. doi: 10.1006/geno.1998.5485. [DOI] [PubMed] [Google Scholar]
- Wu C. Y., Brinkmann V., Cox D., Heusser C., Delespesse G. Modulation of human IgE synthesis by transforming growth factor-beta. Clin Immunol Immunopathol. 1992 Mar;62(3):277–284. doi: 10.1016/0090-1229(92)90103-u. [DOI] [PubMed] [Google Scholar]
- Xu J., Postma D. S., Howard T. D., Koppelman G. H., Zheng S. L., Stine O. C., Bleecker E. R., Meyers D. A. Major genes regulating total serum immunoglobulin E levels in families with asthma. Am J Hum Genet. 2000 Oct 6;67(5):1163–1173. doi: 10.1086/321190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Young R. P., Sharp P. A., Lynch J. R., Faux J. A., Lathrop G. M., Cookson W. O., Hopkin J. M. Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13. J Med Genet. 1992 Apr;29(4):236–238. doi: 10.1136/jmg.29.4.236. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zetterström O., Johansson S. G. IgE concentrations measured by PRIST in serum of healthy adults and in patients with respiratory allergy. A diagnostic approach. Allergy. 1981 Nov;36(8):537–547. doi: 10.1111/j.1398-9995.1981.tb01871.x. [DOI] [PubMed] [Google Scholar]
