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ABSTRACT
INTRODUCTION
METHODS
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Chromosome 14q was screened for loci modulating immunoglobulin E (IgE) phenotypes in 15 extended and 45 nuclear asthmatic families using a panel of 14 microsatellite markers. We examined the reported linkage between the TCR A/D locus on 14q11.2 and specific (cognate) allergic responses and observed supportive evidence for linkage between a general skin prick test reactivity trait (but not with total serum IgE) and TCRA microsatellite (in the total sample of informative sib-pairs p = 0.039, in selected sample of one or zero affected parent p = 0.017). We also show suggestive evidence for a novel linkage between markers D14S75 and D14S63 on 14q13-23 and log total serum IgE (p = 0.034 and p = 0.0029). The evidence for linkage with marker D14S63 on 14q23 is strengthened by the finding of association of allele 165 to log IgE (p = 0.0029). We conclude that chromosome 14q may contain a locus close to TCR A/D at 14q11.2 linked to skin prick reactivity and a locus at 14q13- 23 linked to total serum IgE.
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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The atopic diseases of asthma, allergic rhinitis, and eczema affect as much as 30 to 40% of the population in industrialized countries (1, 2). These diseases have critical genetic and environmental factors of which the genetic component is estimated to explain 30 to 60% of the variance (3). Epidemiologic studies have shown a clear association between raised serum IgE levels and an increased prevalence of atopy and asthma, and raised IgE levels at birth predict the onset and the clinical expression of these diseases (4). Therefore, a major focus of atopy and asthma genetics has been directed towards loci containing genes implicated in the control of total serum IgE levels.
Serum IgE production involves both cognate and noncognate mechanisms. Noncognate mechanisms involve the interaction of mast cells, basophils, and other IgE receptor-bearing cells with the B-lymphocytes (10). The cognate IgE responses are influenced by MHC class II and TCR genes, which are central to the handling and recognition of the antigenic peptides and the subsequent propagation of the immune response (11). The HLA haplotypes have been variably implicated in the modulation of IgE reactivity to allergens (15, 16), but they cannot account for all the differences in a person's IgE reactivity to allergens (16). The role of TCR genes in the modulation of specific IgE responses to allergens was examined by Moffatt and colleagues (17) using sib-pairs analysis (17). In the later study evidence for linkage was observed between specific IgE responses to allergens, total serum IgE, and TCR A/D locus on chromosome 14q11.2 (but not to TCR B) in two sets of subjects. The strongest linkage was observed with IgE reactivity to individual allergens, and the investigators therefore claim the presence of a locus in the 14q11.2 region, which may modulate specific IgE responses. It is more likely, however, that HLA and TCR combined gene interaction at the germline level have stronger influence on an individual's specific IgE responses to allergens (18).
Total serum IgE concentration reflects the overall level of IgE production (cognate and noncognate). Twin and family studies have shown that total IgE is largely determined by genetic factors (with the heritability component ranging from 0.37 to 0.84) (19). The mode of inheritance of total IgE is not known. Recessive, dominant and codominant inheritance have all been postulated usually with a significant polygenic influence (20).
Several candidate chromosomal regions have been reported to be genetically linked to the expression of the high IgE and IgE-dependent diseases. These include in historical order 11q13 (25), 5q31-33 (26, 27), 12q15-24.1 (28), 4q, 13q, 16q (29), and 5p, 17p, 11p, 19q, and 21q (30). The extent of the risk ratio for the phenotype of each reported candidate region remains unknown. It has also proved difficult to replicate some of these linkages in different populations. This may indicate that genetic heterogeneity exists between different ethnic populations, and it also reflects the extent and the complexity of the genetic predisposition to these phenotypes.
This study is set up first to test the prior hypothesis of linkage between a marker for TCR A/D and specific IgE responses, and second to screen 14q for other loci modulating
total IgE levels. Chromosome 14q contains many genes that
could contribute to the susceptibility to IgE-dependent diseases. These include the immunoglobulin heavy chain genes
(IGH) with important functions in immunoglobulin class switching in B cells, the nuclear factor kappa B inhibitor (NF
BI)
(31), the transforming growth factor beta 3 (TGF-
) (32),
and the transcription factor FOS (35) (Figure 1).
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INTRODUCTION
METHODS
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Subjects
Fifteen extended and 39 nuclear families comprising 148 sibs (total of 355 members, 173 male) were identified through an asthmatic proband both from General Practice and hospital out-patient clinics in Southampton. Thirteen of the extended families were derived from three generations and two families from four generations. Ethnically, all recruited families were white except for one nuclear family (comprising four members), which was of Afro-Caribbean origin. Mean age of the probands was 23.9 yr (range, 5 to 72 yr), and of the other participants the mean age was 32.2 yr (range, 4 to 84 yr). All of the 60 probands were asthmatic (doctor-diagnosed), had a positive history of wheeze, and suffered a mean of 3.4 (SD = 1.76) asthmatic attacks in the year prior to the interview. All families contained more than one asthmatic member. Those with doctor-diagnosed asthma constituted 59% of the studied population. A full, verbal, and written explanation of the study was given to each family member. The study was approved by the Southampton University Hospitals Joint Ethical Committee. The children gave informed verbal consent and the parents gave informed written consent.
Clinical Measurements
Each family member completed a structured, written questionnaire
(MRC Respiratory Health) on atopic symptoms. Skin prick testing by
stylet was performed for 14 common allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, mixed grass, mixed trees, Alternaria, Cladosporium, horse, feathers, egg white, egg yolk, cow's
milk, Aspergillus fumigatus, cat fur, and dog fur; Bayer Corporation,
Spokane, WA). Short-acting antihistamines were discontinued for 2 d
prior to the test, and long-acting antihistamines were discontinued as
specified. The major and minor axes of each wheal were recorded.
Bronchial reactivity to histamine was measured by using the method
of Yan and colleagues (36). Subjects abstained from using -agonist
inhalers (6 to 12 h), oral -agonist (24 h), cromolyns (24 h), xanthines
(24 h), and anticholinergics (8 h) prior to the challenge. The total
serum IgE was measured by an enzyme-linked immunosorbent assay (ELISA). A purified mouse monoclonal antibody (HB 121) was
bound to the wells of a microtitre plate at pH 9.5. Serum samples were
diluted in PBS (0.1%)-Tween 20, and added to the plates. After incubation, plates were washed in PBS (0.1%)-Tween 20, and bound IgE
was detected by horseradish peroxidase (HRP)-labeled rabbit antihuman IgE, with orthophenylene diamine as substrate. Standard curves
were constructed using reference sera that were calibrated against a
World Health Organisation (WHO) international standard (37). Serum for IgE measurement was provided by 307 subjects. Total serum
IgE in the probands ranged between 10 and 12,200 IU/ml (mean, 674;
SD, 76). In other participants the range was 8 and 4,080 (mean, 214;
SD, 55). The total IgE distribution was skewed. Four subjects (two
probands and two other children) showed very high IgE values of
more than 4,000 IU/ml. Because of the wide range of the participants'
ages, log total IgE values for all subjects, including the probands, were
age-sex adjusted by linear standardization to male subjects at 20 yr of
age and analyzed as a continuous trait.
To examine the implication of the TCR A/D (TCRA microsatellite) in the modulation of specific allergic responses to house-dust mite antigens Dermatophagoides farinae and Dermatophagoides pteronyssinus, grass pollens, and cat fur (the common allergens in the UK), we used qualitative traits based on skin prick tests. Subjects were labeled reactive if they developed a wheal size of 3 mm or more than the negative (saline) control. Because of the limited number of the informative affected sib-pairs obtained with the allergic responses to individual antigens (Table 3), a general skin prick test reactivity was also used as a qualitative trait, which included subjects who were reactive to one or more of the 14 allergens tested.
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Molecular Methods and Genotype Data
DNA was extracted from peripheral blood leukocytes collected in EDTA-containing tubes using the phenol-chloroform method. Initially, DNA was available for only 289 subjects forming 53 families. All these subjects were genotyped for markers D14S72, TCRA, D14S50, D14S80, D14S49, D14S70, D14S75, D14S63, D14S74, D14S68, D14S51, and D14S267. All the primers were supplied by the MRC HGMP Resource Centre (38), except FCA.TAI (TCRA) (39), which was purchased from Oswel (University of Southampton, Southampton, UK). The genetic distance between these markers is illustrated in Figure 1. The polymerase chain reaction (PCR) amplification of the DNA of each subject was performed in 12 separate reactions using the fluorescently labeled primers. Reactions were performed in 96-well microtitre plates in 10-µl volume containing 40 ng of DNA, 2.5 mM MgCl2, 1.0 µl of 10× Thermo buffer, 150 µM of each dNTP, 9.4 pmolar of each primer, 0.1 U Taq (Promega, Southampton, UK). The PCR cycles were as follows: 95° C for 5 min, then 26 cycles of 56° C for 20 s, 72° C for 20 s, and 90° C for 30 s, followed by a final extension period at 72° C for 10 min. The electrophoresis of the PCR products was performed using ABI machine model 373A (Applied Biosystems, Foster City, CA). Allele sizing was performed using the GENESCAN 672 (version 1.2) software (ABI). Semiautomatic allele calling was performed using GENOTYPER (Version 1.1). The genotyping for markers D14S1010 and D14S542, close to the IGHE locus on 14q32, was performed at a later stage on the 60 families. The methods used were as described above. However, an updated version of the Gene Scanner (ABI prism 377) was used for the typing. To check for the accuracy of typing and to minimize variation in allele sizing between gels a control DNA was incorporated in all runs. Runs with inconsistent results were repeated. Data generated by GENOTYPER software were subsequently analyzed by the Genetic Analysis System (GAS) program. Inconsistencies of allele designation within families were checked by the program, and ambiguities were resolved by further genotyping if necessary. Furthermore, haplotypes were constructed by minimizing the number of recombinations between neighboring markers in each family. This allowed us first to check for the accuracy of typing by observing the number of apparent double recombinants between adjacent markers, which would indicate errors in typing, and second to infer missing alleles for intervening markers of offspring when data for adjacent markers from parents and the individuals indicated no recombination. Two-point lod scores between markers and marker order were performed using the Vitesse Engine Routine of GAS. This gave similar results to published maps (40, 41).
Statistical Methods
Sib-pair analysis for the skin test reactivity qualitative traits. Data were analyzed using the GAS package version 2.0 (Alan Young, Oxford University, 1993-95). The prior hypothesis of genetic linkage of TCRA microsatellite and specific IgE responses (17) was examined by nonparametric sib-pair analysis using the identical-by-descent (IBD) approach (42). This method relies on the fact that if a marker is linked to a disease locus then the same marker allele will be inherited by two siblings who are both affected by the disease more often than would be expected by chance. Under random Mendelian assortment rules, a pair of siblings are expected to share both marker alleles with probability of 0.25, one marker allele with probability of 0.5, and no allele with probability of 0.25. In case of linkage the overall probability of allele sharing will be increased. The 2:1:0 IBD allele sharing among affected sib-pairs was calculated using the SIBDES routine of the GAS program. Only sibs with fully informative parents were included in the analysis. This allowed accurate assignment of allele sharing status, which was further confirmed by manually checking the IBD sharing information of the included sibs through manual haplotypes construction (see under the molecular and genotypes section). The analysis was performed using the strict weight option to compensate for the disproportionate effect of multipair sibships (43).
Multipoint sib-pair analysis of the quantitative locus log IgE. For the quantitative locus IgE, in the absence of a specified genetic model, nonparametric linkage analysis was performed using the Elston-Hasemen algorithm (44). In this method siblings sharing marker alleles near the quantitative locus are more likely to have similar quantitative values than are nonsharing siblings. The mean value of the difference between siblings should decrease as the fraction of alleles shared increases. A slope is generated by a least-squares fit, using allele sharing as independent variable and trait difference as the dependent variable. A significantly negative slope would indicate linkage. Data analysis was performed using the SIBIHE routine of GAS program. This routine combines the Elston-Haseman algorithm with sib-pair interval mapping. This is a multipoint method in which information from adjacent markers is used to infer missing or ambiguous allele sharing. The sharing probabilities are calculated first at loci with definite known sharing status. Thereafter, estimated sharing at ambiguous intercrosses is calculated. Subsequently, unknown sharing loci are interpolated from the above information. The recombination distances between the markers used in this analysis (required for interval mapping) were equal to those estimated from data obtained in this study (Figure 1). Analysis was performed first by including all available sib-pairs and subsequently by including only sib-pairs with available parental marker genotypes. The results obtained using either approach were consistent. The data presented in the RESULTS included information from all available sibs.
Allelic association analysis for log IgE. Linkage analysis can detect gene effects over longer distances of the genome (as much as 20 cM), however, it usually has low resolution with subsequent difficulty in narrowing the linked region. Association studies, on the other hand, are based on the principle that linkage disequilibrium may be generated because of a "founder effect," which occurs when a large proportion of the people affected by a disease in a population is descended from a common ancestor who carries the mutation. As the gene carrying the mutation is transmitted through subsequent generations, the meiotic process of crossover and recombination means that the surrounding alleles will become gradually unlinked, and only the markers extremely close to the disease gene, with very low probability of recombination, will still be associated with the disease. The finding of significant association between a given marker allele and a trait would indicate the presence of a gene close to that allele (usually within a 1 cM distance) which modulates the associated trait. Association studies are therefore appropriate design to follow-up linkage observation, which if positive could narrow down the linked region (45). However, a significant result should be interpreted with caution. False statistical association could be observed secondary to population stratification or admixture.
In this study, markers that showed suggestive evidence for linkage were further analyzed for allelic association using the Mann-Whitney U test (ASSMWU routine). Ranks of the subjects (according to their quantitative trait) who have each allele are compared with those who do not have the allele, to indicate if the allele tends to be associated with subjects who are biased in a particular direction away from the mean. Subjects with half known genotypes were not used. The transmission disequilibrium test (TDT) was also performed for the putatively linked marker (46). In the TDT a parent heterozygous for an associated allele A1 and a nonassociated allele A2 should more often transmit A1 than A2 to an affected child (expressing high total IgE). In this analysis, all affected children were treated as independent observations, summing their transmitted and nontransmitted alleles, and the significance calculated using exact two-sided binomial distribution.
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Clinical Measurements
Data analysis was based on the 60 families (355 subjects, 173 male). These constituted a total of 148 sib pairs (92 nuclear families). Clinical data were obtained from 336 subjects, and DNA was available for genotyping from 325. The probands displayed higher mean values for total IgE, atopy, and bronchial reactivity scores as compared with the rest of the participants (Table 1). There was evidence for close correlation between log IgE, atopy, bronchial reactivity, and skin test reactivity to allergens (Table 2).
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Sib-pair Analysis for Specific Skin Test Reactivity and TCR A/D Locus
Using the IBD approach, we found significant excess of TCRA microsatellite allele sharing from both parents among the 41 informative sibs who showed positive skin prick test reactivity to at least one allergen (p = 0.039). When we considered only families with either zero or one affected parent and at least two affected offspring, the observed distribution of IBD sharing was 11:7:4 (for 2:1:0) (p = 0.017). This approach was followed to limit the possibility of both parents being carriers (47). Sib-pair analysis for skin prick test reactivity to Dermatophagoides farinae, Dermatophagoides pteronyssinus, grass pollens, or cat fur showed no evidence of linkage to TCRA (Table 3). The transmission disequilibrium tests for TCRA alleles were negative as well (data not shown). There was no evidence for linkage between total log IgE and the TCRA (Table 4).
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Multipoint sib-pair Analysis for Log IgE
The multipoint sib-pair analysis for the quantitative trait log IgE showed evidence for linkage to markers D14S75 and D14S63 (p = 0.034, and p = 0.0029, respectively). When we excluded sib-pairs with incomplete parental genotype data from the analysis, a similar result was obtained (80 pairs used, p = 0.022 and 0.0029 for D14S75 and D14S63, respectively) (Figure 2 and Table 4).
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Allelic Association Analysis for Log IgE
Markers D14S63 and D14S75 (putatively linked markers as
suggested from the sib-pair analysis) were further tested for
allelic association with log IgE. There were 10 common and
rare alleles encountered with both markers. Only allele 165 (bp) of D14S63 showed evidence for positive association. A
total of 262 cases with both log IgE and D14S63 genotype data
available were analyzed. In these, allele 165 was present in 15 cases, which gave a mean log IgE rank of 188.13. In the remaining 247 cases the mean rank was 128.06 (Z = 
2.98, p = 0.0029). This result showed borderline significance after using
the Bonferroni correction for the 20 tests performed (p = 0.058) (total number of alleles encountered with both markers). This correction is considered conservative, however,
since these tests examine the prior hypothesis of linkage produced by the sib-pair analysis. The observed association with allele 165 was further tested using the transmission disequilibrium test. Total serum IgE was dichotomized using the age-
dependent seventieth percentile as a cutoff level (The age-
dependent normal range values for total serum IgE used were
as follows: less than 50 IU/ml for 2-6-yr-olds, less than 100 IU/
ml for 6-16-yr-olds, and less than 125 IU/ml for those older
than 16 yr of age (48). Allele 165 was transmitted from an affected parent (i.e. with high total IgE) to affected sib in eight
cases and not-transmitted in one case (p = 0.02).
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Chromosome 14q contains important candidate genes, which could contribute to the genetic predisposition to allergy. In this study we examined the prior hypothesis of linkage between IgE phenotypes and TCR A/D locus on 14q11.2 and screened the whole of chromosome 14q for other loci modulating total serum IgE. The approach followed in the analysis and the results of the study are discussed along these lines.
The previously reported TCR A/D (14q11.2) linkage with specific allergic reactions (17) was examined using skin-test-based traits as dichotomy using sib-pair analysis. The traits examined included skin reactivity to house-dust mite, grass pollens, cat fur (the commonest allergens in the United Kingdom), and a general skin reactivity to any of the tested allergens. The analysis was performed by including all the informative sib-pairs and also by selecting sib-pairs with only one or zero affected parent. The latter approach was followed to limit the possibility of both parents being carriers and therefore to improve the power to detect such linkage (47). This gave evidence for linkage with the general skin reactivity trait (p = 0.017), but not with reactivity to individual allergens. This result is a replication of a previous report of linkage and therefore considered significant. The observation of linkage with general skin reactivity rather than individual allergies is intriguing. Moffatt and colleagues (17) used sib-pair analysis and found strongest evidence for linkage with the IgE responses to highly purified house-dust mite and grass pollens antigens in British and Australian populations, respectively. Two other studies, however, reported linkage with asthma (30) and total IgE (49). These studies collectively strengthen the argument for the presence of a gene (or genes) in the region that predisposes to allergic disease, but the implication of such a gene in the modulation of specific responses is not confirmed. In our study there was a limited number of informative sib-pairs for the specific allergic traits. The traits were also based on skin test reactivity rather than on specific serum IgE to purified antigens. These factors may confound the power of this study to assess the implication of this region in the modulation of specific allergies, and therefore such a phenomenon cannot be excluded.
Despite the presence of the TCRA (FCA.TAI) microsatellite within the TCR A/D locus, the transmission disequilibrium tests for this marker's alleles were negative in both our study and that of Moffatt and colleagues (17), with no reports on this test from other studies. This may imply that the putative gene (or genes) is distant from the marker, or the presence of a high recombination rate in this region precludes the presence of disequilibrium between the marker and the gene, or the power to detect such an association is limited. Modulation of specific allergic responses may involve interacting TCR and HLA alleles. Therefore, studying the association of TCR alleles with specific allergic responses within the context of HLA haplotypes may be more sensitive (18). Furthermore, although the TCR A/D locus is considered the likely candidate, we cannot exclude the presence of a different gene or more than one gene in the region to account for such linkage. For example an association was reported between a genetic variant of the mast cell chymase 1 gene mapped to 14q11.2 and eczema (50).
The second part of the study included screening 14q for
novel loci involved in the control of total serum IgE. In this
screen, we improved the power to detect linkage by analyzing
total serum IgE as a quantitative trait, using highly polymorphic markers covering 14q evenly, and by using multipoint
sib-pair analysis. This analysis provided suggestive evidence
for a novel linkage to markers D14S63 and D14S75 on 14q13-23 (p = 0.0029 and 0.034, respectively). Although the level of
significance obtained is modest, the power to detect linkage in
complex traits is limited (45). Association analysis of these
two markers provided further support for this linkage. Allele
165 of D14S63 showed positive association with IgE using
both the Mann-Whitney U test and the transmission disequilibrium test. Allele 165 may therefore be in linkage disequilibrium with a gene (or genes) in the region modulating total
IgE. The 14q13-23 region contains several candidate genes
with important function in the control of IgE and immune responses. These include the nuclear factor kappa B inhibitor (NFBI) on 14q13 (51), the transcription factor FOS on
14q23, and TGF-3 on 14q24. Polymorphisms in such genes or
other unidentified genes in the region may modulate total serum IgE and predisposition to allergic disease. However, we
cannot exclude type I error as a cause of the above finding,
and validation in a different dataset is required. Replication of
linkage claims in complex diseases has proved difficult because
of disease heterogeneity, ethnicity, methodological difficulties,
multiple hypothesis testing, and inconsistency in phenotype
definition (52). Linkage to a heterogeneous trait will normally
only be found fortuitously in samples which contain an exceptional proportion of individuals or families influenced by that
particular gene (53). Alternative approaches addressing the
current limitation in the genetics of these traits should be developed. Such developments could include the use of the more powerful association studies (45), development of analysis
models that would consider multiple genes interacting with
the critical environmental factors (55), and perhaps eventual
meta-analysis of published studies.
Of the other important candidate genes on 14q, one is the
immunoglobulin heavy chain locus, including the 
(IGHE)
mapped to 14q32.33. This region is the site for IgE isotype
switching in B-cells. Two groups have shown increased expression of the heavy chain variable family 5 (VH5), with extensive
somatic hypermutation of the heavy chain variable genes (VH)
in B-cells from patients with atopic dermatitis, and asthma (56,
57). In contrast, another study observed no evidence of major
structural abnormalities of IGHE genes in subjects expressing
increased serum IgE concentration (58). In our study, the sib-pair analysis for two markers (D14S1010 and D14S542) mapped
to 14q32 was negative, providing evidence against a major role
played by this region in modulating IgE level in this dataset.
In summary, this study supports the linkage of TCR A/D on 14q11.2 to the allergic diathesis and provides suggestive evidence for the presence of another gene (or genes) mapped to 14q13-23 modulating total serum IgE. It provides evidence against a major role played by the IGHE locus at 14q32.33 in the predisposition to high IgE phenotype. These data suggest that 14q is an important region in the genome that may influence IgE responsiveness.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Adel H. Mansur, Molecular Medicine Unit, Clinical Sciences Building, St. James's University Hospital, Leeds LS9 7TF, UK.
(Received in original form April 3, 1998 and in revised form October 28, 1998).
Acknowledgments: The writers thank the families of Southampton for their generous participation in this study; Sandy Smith, Jackie Schreiber, and Jane Wilkinson at Southampton General Hospital for assistance with the clinical characterization of the families; Peitro Lio for helping in the preparation of the phenotype data, D. A. Campbell for helping with genotyping, and Sarah Perry for assistance in figure design.
Supported by the Medical Research Council of Great Britain and by Wellcome Trust, Imperial Cancer Research Fund, National Asthma Campaign, Northern & Yorkshire Regional Health Authority, and West Riding Medical Research Trust.
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References |
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INTRODUCTION
METHODS
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REFERENCES
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