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Human Molecular Genetics Pages 959-962
A new variant of the [beta] subunit of the high-affinity receptor for Immunoglobulin E (Fc[epsilon]RI-[beta] E237G): associations with measures of atopy and bronchial hyper-responsiveness
Introduction
Results
Discussion
Materials And Methods
   Subjects
   Clinical protocol
   Serology
   DNA testing
   Statistical analysis
Acknowledgements
References

A new variant of the [beta] subunit of the high-affinity receptor for Immunoglobulin E (Fc[epsilon]RI-[beta] E237G): associations with measures of atopy and bronchial hyper-responsiveness

A new variant of the [beta] subunit of the high-affinity receptor for Immunoglobulin E (Fc [epsilon] RI- [beta] E237G): associations with measures of atopy and bronchial hyper-responsiveness M. R. Hill* and W. O. C. M. Cookson

Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK

Received January 25, 1996; Revised and Accepted April 16, 1996

The high affinity receptor for IgE (Fc[epsilon]RI) has a central role in mast cell degranulation and IgE mediated allergy. A systematic search through the coding regions of the beta subunit of Fc[epsilon]RI (Fc[epsilon]RI-[beta]) has identified a novel coding polymorphism in exon seven. An adenine to guanine substitution changes amino acid residue 237 from glutamic acid to glycine (E237G), in the cytoplasmic tail of the protein. E237G is predicted to introduce a hydrophobicity change within the C-terminus of Fc[epsilon]RI-[beta]. It is adjacent to the immunoreceptor tyrosine activation motif (ITAM), and may affect the intracellular signalling capacity of Fc[epsilon]RI. E237G was detected in 53 subjects from an Australian general population sample of 1004 individuals (5.3%). E237G positive subjects had a significantly elevated skin test response to grass (p = 0.0004) and house dust mite (p = 0.04), RAST to grass (p = 0.002) and bronchial reactivity to methacholine (p = 0.0009). The relative risk of individuals with E237G having asthma compared to subjects without the variant was 2.3 (95% CI 1.26-4.19; p = 0.005).

INTRODUCTION

Atopic asthma is a complex familial disease that is due to the interaction of several genes with strong environmental factors (1 ,2 ). Atopy is characterised by sustained Immunoglobulin E (IgE) responses to common allergens (3 ), which can be measured by skin prick tests and specific IgE titres (RAST scores). Asthma is characterised by increased bronchial responsiveness to methacholine or histamine, which can be quantified by challenge testing (4 ).

Previous studies have found linkage of atopy and bronchial hyper-responsiveness to markers on chromosome 11q13 (5 -9 ). Linkage to this region was strongest in maternally derived alleles (8 ,10 ). The beta chain of the high affinity receptor for IgE (Fc[epsilon]RI-[beta]) has been identified as a candidate gene for this linkage (11 ). Two coding variants in exon 6, I181L/I183V and I181L, positioned in the fourth transmembrane domain of Fc[epsilon]RI-[beta], have been previously described in selected British subjects, where they appeared quite common (12 ). However in an Australian population sample of 1004 subjects, I181L/I183V was only found at a 4.5% prevalence and I181L was not found at all (13 ). A high false-negative rate for polymerase chain reaction (PCR) based tests for these variants has been observed, the reasons for which remain unclear (14 ). Although these variants were strongly associated with atopy, they cannot explain the strength of the linkage to chromosome 11q13. We have therefore searched for further polymorphisms in the exons of Fc[epsilon]RI-[beta].

We now report a new coding polymorphism in Fc[epsilon]RI-[beta]. We show its relationship to measures of atopy and bronchial responsiveness in a general population sample.

RESULTS

The seven exons of Fc[epsilon]RI-[beta] were amplified separately by PCR from 12 atopic subjects and examined for polymorphism by SSCP. No variants were detected in the first six exons. However, a mobility change was detected in PCR product from exon 7 in one subject. Direct sequencing demonstrated a single nucleotide substitution of adenine to guanine at nucleotide base 6843 of the published sequence (Fig. 1 ) (15 ). The substitution results in a coding variant with glycine replacing a glutamic acid at residue 237 (E237G) of the protein. This change is predicted to introduce a hydrophobicity change within the C-terminus of Fc[epsilon]RI-[beta].


Figure 1. Direct sequencing of genomic DNA. Subject 45.1 shows heterozygote sequence at the position of the arrow with a single nucleotide substitution from adenine to guanine. Subject 45.2 shows wild type sequence.

Using ARMS PCR (Fig. 2 ), 53 individuals in an Australian population sample of 1004 subjects were found to be positive for the E237G variant (population frequency = 5.3%). Compared to subjects without the variant (wild type) they were found to have significantly elevated skin test responses to grass pollen (mean 3.6 mm> negative control +- Standard Error 0.5 compared to 1.9 +- 0.1, p = 0.0004) and house dust mite (3.5 +- 0.5 compared to 2.6 +- 0.1, p = 0.04), and specific IgE titres to grass pollen (1.4 +- 0.2 RAST units compared to 1.0 +- 0.0, p = 0.002), and had significantly higher bronchial reactivity as determined by loge PD20 response to methacholine (geometric mean 13.3 [mu]mol +- 1.5 compared to 41.0 [mu]mol +- 1.1, p = 0.0009). A trend for the loge total serum IgE to be elevated in E237G positive subjects was observed but the levels were not significantly different from the remaining population (geometric mean 68.0 KU/L +- 1.3 compared to 46.4 KU/L +- 1.1, p = 0.09). Eosinophil counts were not significantly different between E237G positive individuals and subjects with the wild type allele (36.6 * 109/L +- 5.0 compared to 29.2 * 109/L +- 0.8, p = 0.14). Thirty of the 53 Australian subjects positive for E237G were children; 17 (in nine sibships) had inherited the variant paternally and 13 (in nine sibships) maternally. Unlike Fc[epsilon]RI-[beta] variants I181L and I181L/I183V (12 ), E237G did not show a parent of origin effect in this population. A close correlation between loge bronchial responsiveness and asthma was observed in the subjects (r = -0.404, p = 0.000). The relative risk of individuals with E237G having asthma compared to those with the wild type allele was 2.3 (95%CI 1.26-4.19; p = 0.005).


Figure 2.ARMS-PCR of genomic DNA. DNA molecular weight marker (Boehringer Mannheim, Marker VIII) (M), a negative PCR control (-ve) and a nuclear family (father, mother and three sons). ARMS-PCR shows a 446 bp control band, the 280 bp band indicates the presence of the wild type allele and the 238 bp band indicates the presence of the E237G variant.

DISCUSSION

A novel coding polymorphism, Fc[epsilon]RI-[beta]-E237G, has been found in 5.3% of an Australian general population sample, and was associated with measures of atopy and asthma. One of the strongest associations with E237G was to bronchial responsiveness. It is of interest that genetic linkage of Fc[epsilon]RI-[beta] to bronchial responsiveness, independent of atopy, has recently been reported in Australian asthmatic sib pairs (9 ).

The association of E237G with asthma related phenotypes requires replication. Previously identified polymorphisms in Fc[epsilon]RI-[beta] have shown the prevalence and statistical strength of associations are likely to differ between different sets of subjects (12 ,13 ). These differences may be due to variation in environmental exposure to allergens between recruitment areas and different selection criteria (16 ).

Fc[epsilon]RI is a heterotetramer of polypeptide subunits consisting of an IgE binding [alpha]-chain, a [beta]-chain and a homodimer of [gamma]-chains (17 ). The functional significance of E237G to Fc[epsilon]RI is not yet known. It may be important that E237G lies adjacent to the immunoreceptor tyrosine activation motif (ITAM) of Fc[epsilon]RI-[beta] (Fig. 3 ) (18 ). Two forms of ITAM appear in Fc[epsilon]RI, one in the beta chain, the other in the gamma chain. It has been proposed that they operate synergistically, associating with specific protein tyrosine kinases that are capable of triggering cell activation via protein-tyrosine phosphorylation. Two protein tyrosine kinases, Lyn and Syk, are known to be involved with Fc[epsilon]RI (19 ). E237G alters the hydrophilic nature of the C-terminus of the beta chain adjacent to the ITAM by the substitution of a polar uncharged glycine for the larger negatively charged polar glutamic acid residue. This change may alter the intracellular signalling capacity of Fc[epsilon]RI through the interaction of the protein tyrosine kinase Lyn with the ITAM of the beta chain.


Figure 3.Schematic diagram of the human Fc[epsilon]RI, based on Blank et al. (17), with the [beta]-subunit (Fc[epsilon]RI-[beta]) highlighted. The position of the E237G polymorphism and the reputed immunoreceptor tyrosine activation motif (ITAM) found in Fc[epsilon]RI-[beta] are shown.

Although E237G associates with atopy, and may be of functional importance, it cannot on its own or in combination with I181L/I183V explain the strength of the chromosome 11q13 linkage. It is therefore likely that further structural changes in and around Fc[epsilon]RI-[beta] remain to be discovered.

MATERIALS AND METHODS

Subjects

The subjects were from the rural coastal town of Busselton, Western Australia, as previously described (13 ). The population comprised 1004 individuals in 230 two-generation families.

Clinical protocol

A modified American Thoracic Society questionnaire was administered to all subjects. Asthma was defined as a positive answer to the questions `Have you had an attack of asthma?' and `If yes, has this happened on more than one occasion?' All subjects were skin prick tested to house dust mite (Dermatophagoides pteronyssinus), mixed grass pollen and a negative control (Dome-Hollister-Steir, Spokane, United States) as described previously (20 ). Bronchial responsiveness to methacholine (maximum dose 12 [mu]mol) was measured as described previously (4 ,21 ). Eosinophil, basophils and white cell counts were determined by automated Coulter counter.

Serology

Total serum IgE and specific IgE to whole D. pteronyssinus and Phleum pratense (Timothy grass) were measured using an enzyme fluorescent immunoassay (Pharmacia CAP FEIA system, Pharmacia Limited, Sweden).

DNA testing

DNA was extracted from peripheral blood leucocytes by standard techniques (22 ). The exon regions of Fc[epsilon]RI-[beta] were amplified from twelve atopic subjects using a nested polymerase chain reaction (PCR) and then examined by SSCP (Single Strand Conformational Polymorphism) (23 ).

For first round PCR 50-100 ng genomic DNA was used as template in a final reaction volume of 10 [mu]l. The primer sets used for first round PCR were:

exon 1: CAG GCA AAA TTA TGC TCC AGG and CCA CAT GGA AAG TAC AGC AAG

exon 2: CTT GGT CAG TTA CTT GGA TGC and TTC TGG CTC TTC CCA AAA GGA

exon 3: AGT GGC TAG GGT ATC CTG GAA and GGC TAA ATG TTT AAC CCA CCG

exon 4: ACA CCC GCC TTA TTC GTA TAC and ACA ATG CCG GTG TAG GAC AC

exon 5: TGC GGA CAT TTT CAG GGT TTC and GCT GTG TGA ACT TAC AGA ACC

exon 6: TAC TGC AAG TGA CGA TCT CTG and CAT GCT CCA CAC ACT TTA AGG

exon 7: CCA GCT AGT CTG GTT TGG TTT and ATT AAG GTG GAC AGA AGC AGC.

Second round PCR using 1 [mu]l of a 1/100 dilution of the first round product was then performed with a final reaction volume of 50 [mu]l. The primer sets used for second round PCR were:

exon 1: GCC TGT TGA TCT TAA TCA GC and AGT TTC ATC TCC TAA GCA CC

exon 2: TCT GTC TGT CGA GAA TGT TG and GAC CTA ACA CCT CTC ATG AA

exon 3: CGC AGT TTC TCA TGT TTG GC and CTG GTT AGA TCT GAG AAA GAG

exon 4: GTA ACT TTA TCG AGT ACC CC and GCA AAA AGC CTT AGG ACA CA

exon 5: CCA GCC CTG AAA TGA AGA TA and AGG ATG GTG TTC ATG GAA CA

exon 6: GGA GAT GAA AAC AGG AGA TG and GTT TCA GAA AAC CCA GGC C

exon 7: GAT GAG GTA AGT CTC TTG AG and CAA AAC CTT GGC CTT CTG G.

For both PCR reactions the remaining constituents consisted of 0.2 [mu]M final concentration of forward and reverse primers, 200 [mu]M dNTPs, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 1.5 mM MgCl2 and 0.2 U Taq DNA polymerase (Boehringer Mannheim, UK Ltd).

The reaction conditions for first round PCR were: 1 cycle of 94oC for 5 min, followed by 35 cycles of 94oC for 1 min, 59oC for 1 min and 72oC for 1 min, followed by a single cycle of 72oC for 10 min. For second round PCR, the conditions were 1 cycle of 94oC for 5 min, 20 cycles of 94oC for 1 min, 50oC for 0.5 min and 72oC for 0.5 min, followed by one cycle of 72oC for 10 min.

For SSCP, 4 [mu]l of second round PCR product was electrophoresed at 10 W per gel, using a Bio-Rad Protean® II (Bio-Rad Laboratory Ltd, UK), at 4oC for 22 h in a 10% (w/v) polyacrylamide (19:1 acrylamide: bis)/10% (v/v) glycerol gel with 1 * TBE buffer. After electrophoresis, product was visualised using a Bio-Rad Silver Stain Kit. For each exon, SSCP patterns were compared across all subjects. Products with altered mobility patterns were submitted to direct sequencing (24 ).

Screening for the E237G variant was carried out using Amplification Refractory Mutation System (ARMS) (25 ). The following primers were used:

B7FA1: TGG CCA GCT AGT CTG GTT TGG TTT TCT GGA

B7FA2: GGA GCA TAT TAA GGT GGA CAG AAG CAG CAG

B7M1: ATT CAG CTA CTT ACA GTG AGT TGG AAG ACC CAG GCG G

B7W2: CAC GTG ATT CTT ATA AAT CAA TGG GAG GAG ACA ATT.

Genomic DNA (0.1-0.2 [mu]g) was used as template in a total reaction volume of 50 [mu]l containing 0.5 [mu]M each of primers B7FA1, B7FA2, B7W2 and 0.25 [mu]M of primer B7M1, 200 [mu]M dNTPs, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 1.5 mM MgCl2. A hot start PCR was used with addition of 2 U Taq DNA polymerase (Boehringer Mannheim, UK Ltd) after an initial 5 min denaturation at 95oC. PCR conditions then followed 35 cycles of 94oC for 1 min, 60oC for 2 min and 72oC for 2 min followed by a single cycle of 72oC for 10 min. Amplified products were separated in a 4% (w/v) agarose gel (3:1 NuSieve GTG:LMP agarose). The primers B7FA1-B7FA2 gave a 446 bp control band, B7FA1-B7W2 gave a 280 bp band in the presence of adenine at nucleotide position 6843 of the published sequence (15 ) and B7M1-B7FA2 gave a 238 bp band in the presence of guanine at position 6843.

Statistical analysis

Measures of atopy in subjects with different Fc[epsilon]RI-[beta] genotypes were compared non-parametrically by the Mann-Whitney U test (SPSS program, SPSS Inc., USA). Contingency table analysis, odds ratios and 95% confidence intervals were estimated by exact methods (StatXact 3 program, Cytel corp., United States).

ACKNOWLEDGEMENTS

We would like to thank J. A. Faux, A. L. James, G. Ryan and A. W. Musk for their collection and phenotyping of subjects and M. F. Moffatt and A. J. Walley for comments on the manuscript. The study was financed by the Wellcome Trust.

REFERENCES

1 Platts-Mills,T.A. (1994) How environment affects patients with allergic disease: indoor allergens and asthma. Ann. Allergy, 72, 381-384. MEDLINE Abstract

2 Cookson,W.O.C.M. (1994) The genetics of atopy. J. Allergy Clin. Immunol., 94, 643-644.

3 Ishizaka,K. (1971) Mechanisms of reaginic hypersensitivity. Clin. Allergy, 1, 9-24. MEDLINE Abstract

4 Yan,K., Salome,C. and Woolcock,A.J. (1983) Rapid method of measuring bronchial responsiveness. Thorax, 38, 760-765. MEDLINE Abstract

5 Cookson,W.O.C.M., Sharp,P.A., Faux,J.A. and Hopkin,J.M. (1989) Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet, I, 1292-1295.

6 Young,R.P., Lynch,J., Sharp,P.A., Faux,J.A. and Hopkin,J.M. (1992) Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13. J. Med. Genet., 29, 236-238. MEDLINE Abstract

7 Collée,J.M., ten Kate,L.P., de Vries,H.G., Kliphuis,J.W., Bouman,K., Scheffer,H. and Gerritsen,J. (1993) Allele sharing on chromosome 11q13 in sibs with asthma and atopy. Lancet, 342, 936. MEDLINE Abstract

8 Shirakawa,T., Morimoto,K., Hashimoto,T., Furuyama,J., Yamamoto,M. and Takai,S. (1994) Linkage between severe atopy and chromosome 11q in Japanese families. Clin. Genet., 46, 228-232. MEDLINE Abstract

9 Herwerden,L., Harrap,S.B., Wong,Z.Y.H., Abramson,M.J., Kutin,J.J., Forbes,A.B., Raven,J., Lanigan,A. and Walters,E.H. (1995) Linkage of high-affinity IgE receptor gene with bronchial hyperreactivity, even in absence of atopy. Lancet, 346, 1262-1265.

10 Cookson,W.O.C.M, Young,R.P., Sandford,A.J., Moffatt,M.F., Shirakawa,T., Sharp,P.A., Faux,J.A., Julier,C., le Souëf,P.N., Nakamura,Y., Lathrop,G.M. and Hopkin,J.M. (1992) Maternal inheritance of atopic IgE responsiveness on chromosome 11q. Lancet, 340, 381-384.

11 Sandford,A.J., Shirakawa,T., Moffatt,M.F., Daniels,S.E., Ra,C., Faux,J.A., Young,R.P., Nakamura,Y., Lathrop,G.M., Cookson,W.O.C.M. and Hopkin,J.M. (1993) Localisation of atopy and the beta subunit of the high affinity IgE receptor (Fc[epsilon]RI) on chromosome 11q. Lancet, 341, 332-334. MEDLINE Abstract

12 Shirakawa,T., Li,A., Dubowitz,M., Dekker,J.W., Shaw,A.W., Faux,J.A., Ra,C., Cookson,W.O.C.M. and Hopkin,J.M. (1994) Association between atopy and variants of the [beta] subunit of the high affinity immunoglobulin E receptor. Nature Genet., 7, 125-129. MEDLINE Abstract

13 Hill,M.R., James,A.L., Faux,J.A., Ryan,G., Hopkin,J.M., le Souëf,P., Musk,A.W. and Cookson,W.O.C.M. (1995) Fc[epsilon]RI-[beta] polymorphism and risk of atopy in a general population sample. Br. Med. J., 311, 776-779.

14 Hill,M.R. and Cookson,W.O.C.M. (1995) Atopy in Australia. Nature Genet., 10, 260.

15 Küster,H., Zhang,L., Brini,A.T., MacGlashan,D.W.J. and Kinet,J.P. (1992) The gene and cDNA for the human high affinity immunoglobulin E receptor [beta] chain and expression of the complete human receptor. J. Biol. Chem., 267, 12782-12787. MEDLINE Abstract

16 Moffatt,M.F., Hill,M.R., Cornélis,F., Schou,C., Faux,J.A., Young,R.P., James,A.L., Ryan,G., leSouëf,P., Musk,A.W, Hopkin,J.M. and Cookson,W.O.C.M. (1994) Genetic linkage of T-cell receptor [alpha]/[delta] complex to specific IgE responses. Lancet, 343, 1597-1600. MEDLINE Abstract

17 Blank,U., Ra,C., Miller,L., White,K., Metzger,H. and Kinet,J.P. (1989) Complete structure and expression in transfected cells of high affinity IgE receptor. Nature, 337, 187-189. MEDLINE Abstract

18 Reth,M. (1989) Antigen receptor tail clue. Nature, 338, 383-384. MEDLINE Abstract

19 Jouvin,M.H.E., Adamczewski,M., Numerof,R., Letourneur,O., Vallé,A. and Kinét,J.P. (1994) Differential control of the tyrosine kinases Lyn and Syk by the two signalling chains of the high affinity Immunoglobulin E receptor. J. Biol. Chem., 269, 5918-5925.

20 Cookson,W.O.C.M. and Hopkin,J.M. (1988) Dominant inheritance of atopic immunoglobulin-E responsiveness. Lancet, i, 86-88.

21 Cookson,W.O.C.M., de Klerk,N.H., Ryan,G.R., James,A.L. and Musk,A.W. (1991) Relative risks of bronchial hyperresponsiveness associated with skin-prick test responses to common antigens in young adults. Clin. Exp. Allergy, 21, 473-479.

22 Blin,N. and Stafford,D.W. (1976) A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res., 3, 2303. MEDLINE Abstract

23 Orita,M., Iwahana,H., Kanazawa,H., Hayashi,K. and Sekiya,T. (1989) Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. Natl Acad. Sci. USA, 86, 2766-2770. MEDLINE Abstract

24 Sanger,F., Nicklen,S. and Coulson,A.R. (1977) DNA sequencing with chain-terminating inhibitors. Proc. Natl Acad. Sci. USA, 74, 5463-5467. MEDLINE Abstract

25 Newton,C.R., Graham,A., Heptinstall,L.E., Powell,S.J., Summers,C., Kalsheker,N., Smith, J.C. and Markham, A.F. (1989) Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res., 17, 2503-2516. MEDLINE Abstract

*To whom correspondence should be addressed

This page is maintained by OUP admin. Last updated Thu Oct 31 15:25:15 GMT 1996. Part of the OUP Journals World Wide Web service.Copyright Oxford University Press, 1996


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POLYMORPHISM OF THE BETA CHAIN OF THE HIGH AFFINITY IMMUNOGLOBULIN E RECEPTOR (Fcvarepsilon RI-beta ) IN SOUTH AFRICAN BLACK AND WHITE ASTHMATIC AND NONASTHMATIC INDIVIDUALS
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