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Fc(epsilon)RI-(beta) polymorphism and risk of atopy in a general population sample

^a Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, ^b Department of Respiratory Medicine, Queen Elizabeth II Medical Centre, Perth, Western Australia 6009, ^c Osler Chest Unit, Churchill Hospital, Oxford OX3 7LJ, ^d University Department of Paediatrics, Princess Margaret Hospital, Perth, Western Australia

Correspondence to: Dr Cookson.

Abstract

Objective: To establish the prevalence of Fc(epsilon)RI- ß polymorphisms Leu181 and Leu181/Leu183 on chromosome 11q13 in the general population and to examine whether when maternally inherited they confer a risk of atopy.
Design: A population based survey for measures of atopy (skin prick test reactions, specific IgE titres, total serum IgE concentration), bronchial hyperresponsiveness, and carriage of Fc(epsilon)RI-ß Leu181 and Leu181/Leu183.
Setting: The rural coastal town of Busselton, Western Australia.
Subjects: 1004 members of 230 two generation families identified through adults aged under 55.
Results: Fc(epsilon)RI-ß Leu181/Leu183 was identified in 45 subjects (4.5%). All 13 children who had inherited the variant maternally were atopic. Six had asthma and nine rhinitis. The odds ratio of a positive skin prick test reaction to house dust mite or grass pollen in these children compared with the other 523 children was 7.37 (95% confidence interval 1.62 to 33.60). The 95% confidence interval for the odds ratio of a positive specific IgE response (radioallergosorbent test) was 3.00 to (infinity), and the odds ratio for bronchial hyperresponsiveness was 3.70 (1.21 to 11.60). By contrast, the eight children who had derived the variant paternally had negative skin prick and radioallergosorbent test results and did not have increased bronchial responsiveness.
Conclusion: Fc(epsilon)RI"'ß Leu181/Leu183 when inherited maternally identifies a genetic risk factor for atopy and bronchial hyperresponsiveness.

Introduction

Atopy is a familial syndrome of asthma, rhinitis, and eczema which is due to the interaction of genetic and environmental factors. Genetic linkage of atopic IgE responses to chromosome 11q13¹ was initially controversial² but has now been replicated by several groups^{3 4 5} Linkage was strongest in maternally derived alleles,^{5 6} which may contribute to the maternal inheritance of atopy evidence from many studies.^{7 8 9 10 11} The gene for the ß chain of the high affinity receptor for IgE (Fc(epsilon)RI-ß) is a candidate for the chromosome 11q13 effect.¹² Sequencing of Fc-ßRI-ß has detected polymorphisms (variants)--Fc(epsilon)RI-ß Leu181/Leu183 (Leu 181/Leu183) and Fc(epsilon)RI-ß Leu181 (Leu181)--which were associated with atopy.¹³

We examined the prevalence of Leu181 and Leu181/Leu183 in an Australian general population sample and tested whether when inherited maternally the polymorphisms endowed a risk of atopy.

Subjects and methods

The subjects were from the rural coastal town of Busselton, South Western Australia. The aim was to recruit young nuclear families. Children under 5 were excluded because they could not complete respiratory testing. Families were identified through adults aged 55 or under from an electoral roll of around 9000. Families were serially recruited until a predetermined target of 1000 subjects was reached. The final sample comprised 1004 members of 230 nuclear families.

A total of 1867 subjects were approached. Of these, 177 refused to take part; 140 were not contactable; and 434, though contacted, had not been tested by the end of the study. Seven hundred and eight subjects were excluded because their spouses were aged over 55 or because they were not married with two or more natural children over the age of 5. The remaining 408 subjects and their spouses and children not on the electoral roll completed the study. Subjects knew the respiratory interest of the investigation before agreeing to participate. We emphasised that normal people were important to the study.

Clinical protocol--Testing took place in May, June, and July 1992. A respiratory questionnaire based on the American Thoracic Society questionnaire but including questions on rhinitis and allergies was administered. Skin prick testing to house dust mite (Dermatophagoides pteronyssinus), mixed grass pollen, cat and dog dander, Aspergillus fumigatus, Alternaria alternata, and a negative control (Dome-Hollister-Steir, Spokane, United States) was carried out as described.⁶ Weal diameters were calculated minus the negative control. Bronchial responsiveness to methacholine (maximum dose 12 µmol) was measured.^{14 15} The dose required to provoke a 20% fall in forced expiratory volume in one second (PD20) was estimated by linear interpolation. Subjects in whom a 20% fall was not achieved by the maximum dose of methacholine were assigned an arbitrary PD20 of 100.¹⁵ Blood was taken by venepuncture for IgE assays, eosinophil and white cell counts, and DNA studies.

Serological tests for IgE, and white cell counts--Total serum IgE and specific IgE responses to whole D pteronyssinus and Phleum pratense (timothy grass) were determined (Pharmacia CAP system, fluorescent enzyme immunoassay, Sweden). A specific IgE radioallergosorbent test class 1 result (>0.35 kU/l) was considered positive. Eosinophils and white cells were counted automatically (Western Diagnostic Laboratories, Western Australia).

DNA testing--DNA was extracted from peripheral blood leucocytes by phenol-chloroform. Fc(epsilon)RI-ß Leu181 was detected by the amplification refractory mutation system polymerase chain reaction¹⁶ and by sequencing¹⁷ (see appendix). Genotyping and phenotyping were performed double blind.

Statistical analysis--Subjects with different Fc(epsilon)RI-ß genotypes were compared non-parametrically by the Mann-Whitney U test (SPSS program, SPSS Inc, United States). Contingency table analysis, odds ratios, and 95% confidence intervals were estimated by exact methods (STATXACT program, Cytel, United States).

Results

A total of 502 subjects were male. The parents (n=460) were aged 30-55 years (mean 40.2 (SD 4.98) years) and the children (n=544) 5-27 years (mean 12.6 (4.73) years). Forty five per cent of the parents (n=207) and 43% of the children (n=234) had a positive skin prick test reaction >/=4 mm to house dust mite or rye grass or both; 41% of parents (n=189) and 44% of children (n=239) had positive specific IgE titres (radioallergosorbent tests) to either house dust mite or grass pollen or both. Twenty three per cent of the parents (n=106) and 24% of the children (n=131) reported wheezing or whistling in their chest in the previous years, and 8% of the parents (n=37) and 14% of the children (n=76) reported an attack of asthma in the same interval. Half of the parents (n=230) and 42% of the children (n=228) reported episodic sneezing. Forty two per cent of the parents (n=193) and 8% of the children (n=44) had smoked cigarettes.

The assay for Leu181 failed to amplify in five subjects (0.5%). Of the remaining 999 subjects, 45 (4.5%) were positive for Leu181. Twenty one of these were children; eight (seven sibships) had inherited the variant paternally, and 13 (seven sibships) had inherited it maternally. Sequencing of an individual from each family showed that in each case Leu181 was accompanied by Leu183, so that only the Leu181/Leu183 polymorphism was found in this population.

All 13 children who had inherited Leu181/Leu183 maternally were atopic (table I). Eleven had wheeze or rhinitis or both, and a 12th, who denied symptoms, had had asthma previously, diagnosed and treated by a physician. Compared with the 523 children in the population without Leu181/Leu183 the 13 had significantly increased skin prick test reactions and radioallergosorbent test results to house dust mite and grass pollen (table II). The odds ratio for a positive skin prick test reaction >/=4 mm to house dust mite or grass or both, compared with other children, was 7.37 (table III). The 95% confidence interval for the odds ratio of a positive radioallergosorbent test result to either or both allergens was 3.00 to (infinity). When compared only with children with skin prick test reactions >/=4 mm or positive radioallergosorbent test results, or both, children with maternal Leu181/Leu183 still had greater skin prick test reactions and radioallergosorbent test results to house dust mite (P=0.005 and P=0.035 respectively). Hence children with the variant were discernibly more atopic than other children with atopy. The trend was for the total serum IgE concentration to be raised, though the differences were not significant (P=0.08).

TABLE I--Clinical details of children with maternally and paternally inherited Fc(epsilon)RIPß Leu181/Lei 183
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
                                Skin prick test        Radioallergosorbent test
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Total
Pedigree      Age              House dust     Grass    House dust                IgE        PD20     Eosinophils
No           (years)   Sex     mite (mm)      (mm)       mite         Grass     (kU/l)     (µmol)        (x109/l)     Wheeze      Asthma     Hay fever
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                Paternally inherited Fc(epsilon)RI-ß Leu181/Leu183
  6             17      F          5          5          4             3         92        NR+             0.54                 No           No         Yes
  6              7      M          5          0          5             0        201        7.21            1.63                 Yes          Yes        Yes
 29             20      F          6         11          5             4        243        NR              0.58                 No           No         Yes
 29             18      F          7          0          3             0         63        8.87            0.01                 No           No         Yes
 29             14      F          7          5          4             2        166        0.19            0.44                 No           Yes        No
 61              8      F         17          0          5             0        215        1.94            1.10                 Yes          Yes        Yes
 61             14      M          8          8          5             3        550        3.18            0.70                 Yes          Yes        Yes
 95             11      M          6          4          4             1        178        6.67            0.59                 No           No         Yes
 95             10      M          3          2          4             2        137        0.14            0.66                 Yes          Yes        No
162             14      F          9          4          2             2         15        NR              0.42                 Yes          No         Yes
181              8      M          6          3          1             2         88        NR              0.19                 Yes          Yes        No
181              7      M          4          3          2             2        235        2.5             0.23                 No           No         Yes
209             17      F          3          0          0             1         70        NR              0.18                 No           No         No
                                                 Maternally inherited Fc(epsilon)RI-ß Leu181/Leu183
103              5      F          0          0          0             0        162        2.66            0.32                 No           No         No
141             13      F          0          0          0             0         44        NR              0.05                 Yes          No         No
150             10      F          0          0          0             0        131        1.31            0.30                 Yes          Yes        Yes
157              6      F          0          0          0             0        117        NR              0.25                 No           No         No
171             14      M          0          0          0             0          6        NR              0.10                 No           No         Yes
171             12      F          0          0          0             0         30        NR              0.04                 --           No         --
203             21      M          0          0          0             0           8       NR              0.19                 No           No         No
214             19      M          0          0          0             0         80        NR              0.02                 No           No         No
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
+NR=Not reactive to maximum dose of methacholine.

TABLE II--Comparison of children with maternally or paternally derived Fc(epsilon)RI-ß Lei 181/Leu183 and
children without variant
---------------------------------------------------------------------------------------------------------------
                                       Maternal                     Paternal
                                     Leu181/Leu183               Leu181/Leu183                 Others
Parameter                               (n=13)                      (n=8)                     (n=523)
---------------------------------------------------------------------------------------------------------------
Skin prick test:
  House mite dust (mm)+             6.65 (3.61) [<0.0001]         0 [0.1]                    2.55 (3.28)
  Grass (mm)+                       3.46 (3.33) [0.03]            0 [0.03]                   2.07 (3.33)
Radioallergosorbent test:
  House dust mite+                  3.38 (1.66) [0.0001]          0 [0.03]                   1.37 (1.94)
  Grass                             1.69 (1.25) [0.08]            0 [0.01]                   1.18 (1.56)
Total IgE (kU/l)++                129.0 (0.41) [0.08]            43.38 (3.55) [0.5]         66.82 (5.49)
Eosinophils (109/l)+          0.56 (0.42) [0.03]            0.16 (0.12) [0.02]         0.34 (0.30)
PD20 (µmol)++              8.76 (10.3) [0.03]           36.97 (6.37) [0.7]         28.62 (7.03)
---------------------------------------------------------------------------------------------------------------
+Values are means (SD)
[P compared with others by
Mann-Witney U test]
++Values are geometric means (SD)
[P compared with others by
Mann-Whitney U test]

TABLE III--Odds ratios of measures of atopy and bronchial
responsiveness and maternally inherited Fc(epsilon)RI-ß
Leu181/Leu183
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Leu181/Leu183                      Others                                95%
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                      Confidence
Parameter                                                                    Affected         Normal     Affected        Normal       Odds ratio       interval          P
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Positive skin prick test result to house dust mite and/or grass
  (>/=4 mm>negative control)                                                    11              2           284           212            7.37       1.62 to 33.60      0.002
Positive radioallergosorbent test result to house dust mite or
  grass (>/=0.35 kU/l)                                                          13              0           293           230            (infinity) 3.0 to (infinity)  0.001
Raised total serum IgE (>70% of age matched population)                          6              7           170           364            1.80       0.61 to 5.54       0.28
Raised eosinophil count (>/=0.3x109/l)                                     9              4           222           284            2.90       0.87 to 9.45       0.07
Bronchial hyperresponsiveness (PD20</=10 µmol methacholine)             8              5           159           372            3.70       1.21 to 11.60      0.02

The eosinophil counts in the 13 children were significantly raised, and the PD20 was significantly lower (table II). Seven children had increased bronchial responsiveness (PD20 </=10 µmol methacholine¹⁴; odds ratio 3.70) (table III).

The eight children who had inherited Leu181/ Leu183 paternally were, by contrast, non-atopic with negative skin prick and radioallergosorbent test results (table I). Skin prick and radioallergosorbent test results and eosinophil counts were less than those of other children (table II). The odds ratio for a positive skin prick test reaction was 0 (95% confidence interval 0 to 0.62; P=0.015), as was the odds ratio for a positive radioallergosorbent test result (0 to 0.36; P=0.002).

Of the 24 parents with Leu181/Leu183, 11 had negative skin prick and radioallergosorbent test results to house dust mite and grass pollen, whereas 13 were positive in both skin prick and radioallergosorbent tests to one or more allergens.

Discussion

Within this sample maternal inheritance of Fc(epsilon)RI-ß Leu181/Leu183 was associated with an increased risk of IgE responses to common allergens, raised eosinophil counts, and bronchial hyperresponsiveness. The variant therefore identified a genetic risk factor for atopy.

The study aimed at recruiting nuclear families in whom age had minimally affected measures of atopy and respiratory function. One hundred and seventy seven subjects declined to take part, and participants knew the survey was to study asthma. The sample may therefore not be completely representative, and the estimated 4.5% prevalence of Leu181/Leu183 may be higher than the true value. The high frequency of positive skin prick test results and atopic symptoms is, however, consistent with previous surveys in Busselton¹⁸ and other Western populations.^{19 20}

The calculations of risk assume independence of observations, though the 13 maternal inheritors of Leu181/Leu183 were from only seven sibships. The odds ratios for the various associations may therefore be somewhat higher than their true value. Nevertheless, the Leu181/Leu183 polymorphism is clearly associated with a clinically significant risk of atopy.

Though Leu181/Leu183 is comparatively rare, it should be considered to be a variant of normal rather than a mutation. The leucine substitutions are conservative but it is not possible to predict whether they are functionally important.^{21 22} It is likely that other common polymorphisms in and around Fc(epsilon)RI-ß exist and that haplotypes of these may better define genetic risk due to Fc(epsilon)RI-ß.

Leu181/Leu183 was found exclusively in Busselton, though Leu181 seems much more common in native British people.¹³ This may be due to variation in the prevalence of Fc(epsilon)RI-ß polymorphisms between populations. The possibility that the amplification refractory mutation assay failed to amplify Leu181 when it was not accompanied by Leu183 was monitored by the use of positive controls.

In order to interpret the presence of Leu181/Leu183 its parental origin needs to be known. The negative skin test results and specific IgE titres of subjects who had inherited Leu181/Leu183 paternally were unexpected given the high background level of atopy in Busselton. Thirteen of the 24 parents carrying Leu181/ Leu183 were atopic and 11 were not, consistent with active and inactive alleles in the 0.5:0.5 proportion expected from a maternal effect. Possible mechanisms for the maternal effect include genomic imprinting or influences through the placenta or breast milk.⁶

The timing and degree of exposure to allergen in early life determine the subsequent probability of atopic disease,²³ so that recognition of genetic susceptibility may result in prevention of illness.⁹ The results suggest that polymorphism in Fc(epsilon)RI-ß is one factor that can be used to assign genetic risk.

The prevalence of atopy in these subjects cannot be explained alone by the chromosome 11 effect or by variation in Fc(epsilon)RI-ß. The TCR-(alpha) region on chromosome 14²⁴ and the interleukin 4 cluster on chromosome 5²⁵ also show linkage to IgE responses. Prospective testing for Fc(epsilon)RI-ß polymorphisms and examination of the effects of other genes and the environment are required before genotyping at the Fc(epsilon)RI-ß locus can be used clinically for genetic risk estimation.

Dr Kevin Cullen pioneered studies of the Busselton population for epidemiological research and contributed to this study until his death on 9 February 1994. We thank the people of Busselton and the volunteers who carried out field testing. Gordon Rich (Western Diagnostic Laboratories) provided laboratory facilities. WOCMC is a Wellcome Trust senior clinical research fellow.

Funding: Wellcome Trust.

Conflict of interest: The University of Oxford holds a patent protecting the commercial use of Fc(epsilon)RI-ß. Two of us (WOCMC and JMH) were coinventors.

Appendix DNA METHODS

The amplification refractory mutation assay was carried out with the following oligonucleotide primers: (a) 5FU--TGT ATG TGT CAC TTT AAA AGG ACT GGT CAG; (b) 5WK--TTG TCA TTT GTT GCT GTT CAA TAG GAA GTT; (c) 3M--AAT GGT GAG AAA CAG CAT CAT CAT TAC CAA; (d) 3FU--TAA CAT ATC AGT CCT ATT ATC CCA ACC CTC. Genomic DNA samples (0.25-0.30 µg) were amplified in a total volume of 50 µl containing 0.5 µM oligonucleotide primers 5FU, 3FU, and 5WK; 0.1 µM 3M; 200 µM dNTPs; 1x reaction buffer (43 mM potassium chloride, 8.6 mM Tris-hydrochloric acid (pH 8.3), 2.5 mM magnesium chloride, 0.008% gelatin); and 2 units DNA Taq polymerase (Boehringer Mannheim) overlaid with mineral oil.

The reaction mixture (40 µl) without enzyme was heated to 95°C for five minutes in a thermal cycler (Hybaid) and held at 80°C for the addition of enzyme (2 units of enzyme in 10 µl reaction buffer). Reaction conditions then followed 35 cycles of 94°C for one minute, 60°C for two minutes, and 72°C for two minutes and one cycle of 72°C for 10 minutes. Amplified products were separated in a 3% (3:1 LMP agarose:Nusieve) gel containing ethidium bromide and visualised under ultraviolet light. Three bands potentially resulted from the primer combinations: 5FU- 3FU gave a 459 bp control band; 5WK-3FU gave a 353 bp band in the presence of the "wild type" Il(epsilon)181; 3M-5FU gave a 163 bp band in the presence of Leu181.

A member of each family segregating Leu181 was sequenced by the method of Sanger et al¹⁷ to ensure accuracy of the polymerase chain reaction and to determine whether Leu183 was present. The 459 bp 5FU-3FU band from the above reaction was taken to second round polymerase chain reaction with the following internal primers: 5D (5'biotinylated)--AAG GAC TGG TCA GAT GGT AG;3D--GGC TTC TAT CTA CCT TGT TTC. A single strand template was prepared with strepavidin labelled magnetic beads (Dynal, Oslo, Norway), and direct solid phase sequencing followed with the sequencing primer 3GS-TCC TTT GAG TTC TTC CCC A.

1. Cookson WOCM, Sharp PA, Faux JA, Hopkin JM. Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet 1989;i:1292-5.
2. Marsh DG, Myers DA. A major gene for allergy--fact or fancy? Nat Genet 1992;2:252-4.
3. Young RP, Lynch J, Sharp PA, Faux JA, Cookson WOCM, Hopkin JM. Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13. J Med Genet 1992;29:236-8. [Abstract/Free Full Text]
4. Collee JM, ten Kate LP, de Vries HG, Kliphuis JW, Bouman K, Scheffer H, et al. Allele sharing on chromosome 11q13 in sibs with asthma and atopy. Lancet 1993;342:936. [Medline]
5. Shirakawa T, Morimoto K, Hashimoto T, Furuyama J, Yamamoto M, Takai S. Linkage between severe atopy and chromosome 11q in Japanese families. Clin Genet 1994;46:228-32. [Medline]
6. Cookson WOCM, Young RP, Sandford AJ, Moffatt MF, Shirakawa T, Sharp PA, et al. Maternal inheritance of atopic IgE responsiveness on chromosome 11q. Lancet 1992;340:381-4. [Medline]
7. Magnusson CG. Cord serum IgE in relation to family history and as predictor of atopic disease in early infancy. Allergy 1988;43:241-51. [Medline]
8. Kuehr J, Karmaus W, Forster J, Frischer T, Hendel-Kramer A, Moseler M, et al. Sensitisation to four common inhalant allergens within 302 nuclear families. Clin Exp Allergy 1993;23:600-5. [Medline]
9. Arshad SH, Matthews S, Grant C, Hide DW. Effect of allergen avoidance on development of allergic disorders in infancy. Lancet 1992;339:1493-7. [Medline]
10. Halonen M, Stern D, Taussing LM, Wright A, Ray CG, Martinez FD. The predictive relationship between serum IgE levels at birth and subsequent incidences of lower respiratory illnesses and eczema in infants. Am Rev Respir Dis 1992;146:866-70. [Medline]
11. Aberg N. Familial occurrence of atopic disease: genetic versus environmental factors. Clin Exp Allergy 1994;23:829-34.
12. Sandford AJ, Shirakawa T, Moffatt MF, Daniels SE, Ra C, Faux JA, et al. Localisation of atopy and the (beta) subunit of the high affinity IgE receptor (Fc(epsilon)RI) on chromosome 11q. Lancet 1993;341:332-4. [Medline]
13. Shirakawa TS, Li A, Dubowitz M, Dekker JW, Shaw AE, Faux JA, et al. Association between atopy and variants of the (beta) subunit of the high-affinity immunoglobulin E receptor. Nat Genet 1994;7:125-9. [Medline]
14. Yan K, Salome C, Woolcok AJ. Rapid method of measuring bronchial responsiveness. Thorax 1983;38:760-5. [Abstract/Free Full Text]
15. Cookson WOCM, de Klerk NH, Ryan GR, James AL, Musk AW. Relative risks of bronchial hyper-responsiveness associated with skin-prick test responses to common antigens in young adults. Clin Exp Allergy 1991;21:473-9. [Medline]
16. Newton CR, Graham A, Heptinstall LE, Powell SJ, Summerss C, Kalsheker N, et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res 1989;17:2503-16. [Abstract/Free Full Text]
17. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain terminating inhibitors. Proc Natl Acad Sci U S A 1977;74:5463-7. [Abstract/Free Full Text]
18. Woolcock AJ, Peat JK, Salome CM, Yan K, Anderson SD, Schoeffel RE, et al. Prevalence of bronchial hyper-responsiveness and asthma in a rural adult population. Thorax 1987;42:361-8. [Abstract/Free Full Text]
19. Cline MG, Burrows BB. Distribution of allergy in a population sample residing in Tucson, Arizona. Thorax 1989;44:425-31 [Free Full Text]
20. Holford-Strevens V, Warren P, Wong C, Manfreda J. Serum total immunoglobulin E levels in Canadian adults. J Allergy Clin Immunol 1984;73:516-22. [Medline]
21. Oksenberg D, Marsters SA, O'Dowd BF, Jin H, Havlik S, Peroutka SJ, et al. A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT(sub 1B) receptors. Nature 1992;360:161-3 [Medline]
22. Beinborn M, Lee Y-M, McBride EW, Quinn SM, Kopin AS. A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non-peptide antagonists. Nature 1993;362:348-50. [Medline]
23. Holt PG, McMenamin C, Nelson D. Primary sensitisation to inhalant allergens during infancy. Pediatr Allergy Immunol 1990;1:3-13.
24. Moffatt MF, Hill MR, Cornelis F, Schou C, Faux JA, Young RP, et al. Genetic linkage of the TCR-(alpha)/(delta) region to specific immunoglobulin E responses. Lancet 1994;343:1597-600. [Medline]
25. Marsh DG, Neely JD, Breazeale DR, Ghosh B, Freidhoff LR, Ehrlich-Kautzky E, et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994;264:1152-5. [Abstract/Free Full Text]

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• PALMER, L. J., BURTON, P. R., FAUX, J. A., JAMES, A. L., WILLIAM MUSK, A., COOKSON, W. O. C. M. (2000). Independent Inheritance of Serum Immunoglobulin E Concentrations and Airway Responsiveness. Am. J. Respir. Crit. Care Med. 161: 1836-1843 [Abstract] [Full text]  
• HIZAWA, N., YAMAGUCHI, E., JINUSHI, E., KAWAKAMI, Y. (2000). A Common FCER1B Gene Promoter Polymorphism* Influences Total Serum IgE Levels in a Japanese Population. Am. J. Respir. Crit. Care Med. 161: 906-909 [Abstract] [Full text]  
• BREWER, J. P., KISSELGOF, A. B., MARTIN, T. R. (1999). Genetic Variability in Pulmonary Physiological, Cellular, and Antibody Responses to Antigen in Mice. Am. J. Respir. Crit. Care Med. 160: 1150-1156 [Abstract] [Full text]  
• Moffatt, M. F, James, A., Ryan, G., Musk, A W., Cookson, W. O C M (1999). Extended tumour necrosis factor/HLA-DR haplotypes and asthma in an Australian population sample. Thorax 54: 757-761 [Abstract] [Full text]  
• Bogardus, S. T. Jr, Concato, J., Feinstein, A. R. (1999). Clinical Epidemiological Quality in Molecular Genetic Research: The Need for Methodological Standards. JAMA 281: 1919-1926 [Abstract] [Full text]  
• Deichmann, K. A, Starke, B., Schlenther, S., Heinzmann, A., Sparholt, S. H., Forster, J., Kuehr, J. (1999). Linkage and association studies of atopy and the chromosome 11q13 region. J. Med. Genet. 36: 379-382 [Abstract] [Full text]  
• Dickson, P. W, Wong, Z. Y H, Harrap, S. B, Abramson, M. J, Walters, E H. (1999). Mutational analysis of the high affinity immunoglobulin E receptor beta  subunit gene in asthma. Thorax 54: 409-412 [Abstract] [Full text]  
• BREMNER, P. R., de KLERK, N. H., RYAN, G. F., JAMES, A. L., MUSK, M., MURRAY, C., LE SOUEF, P. N., YOUNG, S., SPARGO, R., WILLIAM MUSK, A. (1998). Respiratory Symptoms and Lung Function in Aborigines from Tropical Western Australia. Am. J. Respir. Crit. Care Med. 158: 1724-1729 [Abstract] [Full text]  
• THOMAS, N. S., WILKINSON, J., HOLGATE, S. T. (1997). The Candidate Region Approach to the Genetics of Asthma and Allergy. Am. J. Respir. Crit. Care Med. 156: S144-S151 [Abstract] [Full text]  
• Hall, I P, Wheatley, A, Dewar, J, Wilkinson, J, Morrison, J (1996). Fc(epsilon)RI-(beta) polymorphisms unlikely to contribute substantially to genetic risk of allergic disease. BMJ 312: 311-311 [Full text]