Mol. Hum. Reprod. Advance Access originally published online on March 19, 2008
Molecular Human Reproduction 2008 14(5):317-324; doi:10.1093/molehr/gan013
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Paternal contribution of HLA-G*0106 significantly increases risk for pre-eclampsia in multigravid pregnancies
1Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119074 Singapore, Singapore 2Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119074 Singapore, Singapore 3Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore 4Department of Obstetrics and Gynecology, Sultanah Aminah Hospital, Johor Bahru, Johor 80100, Malaysia 5Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119074 Singapore, Singapore 6Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Center, 169610 Singapore, Singapore 7 Duke-NUS Graduate Medical School, 169547 Singapore, Singapore 8Children’s Medical Institute and Department of Laboratory Medicine, National University Hospital, 119074 Singapore, Singapore
9 Correspondence address. Tel: +65-6772-4152; Fax: +65 6779 7486; E-mail: paecs{at}nus.edu.sg
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Abstract |
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Pre-eclampsia (PE) is a leading cause of maternal and fetal mortality and morbidity. Structural or functional alterations of human leukocyte antigen (HLA)-G present at the maternal–fetal interface may predispose women to PE. We tested the HLA-G gene for association with PE in a case–control study of 83 PE and 240 normotensive Malay women. HLA-G was amplified in a single-tube multiplex-PCR reaction and genotyped for 18 single nucleotide polymorphisms (SNPs) by multiplex-minisequencing. Case–control comparisons were performed, and associations with disease were expressed as odds ratios (ORs). Risk for PE was significantly associated with fetal allele G*0106 only in multigravid pregnancies (P = 0.002, OR = 5.0, 95% CI = 1.8–13.8). Among multigravid pregnancies, the frequency of PE babies heterozygous or homozygous for G*0106 was also significantly higher compared with normal control babies (P = 0.002, OR = 5.4, 95% CI = 1.9–15.4). Multivariate analyses with adjustment for factors associated with PE revealed similar results (P = 0.003, OR = 10.1, 95% CI = 2.2–46.8). Additionally, a significantly higher frequency of fetal–maternal G*0106 genotype mismatch was observed in PE compared with normal multigravid pregnancies (P = 0.001, OR = 9.6, 95% CI = 2.4–38.7). Thus, paternal HLA-G G*0106 contribution significantly increases risk for PE in multigravidas who do not carry this allele, potentially mediated by a gradual maternal alloimmune response to repeated exposure to the paternal HLA-G variant.
Key words: pregnancy/placenta/pre-eclampsia/HLA-G/haplotype
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Introduction |
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Pre-eclampsia (PE) is a leading cause of maternal and fetal mortality and morbidity, whose etiology remains incompletely understood, despite its being widely studied. PE occurs in
5–8% of healthy nulliparous women and 18% of previously PE women (Hauth et al., 2000; Hnat et al., 2002). The pathogenesis of PE has been postulated to be due to a combination of maternal and fetal factors. It has been generally accepted that PE is a consequence of placental ischemia that leads to a maternal systemic reaction in the form of generalized endothelial cell dysfunction via the placental release of inflammatory cytokines, since it is promptly resolved after the delivery of the placenta (Ness and Roberts, 1996). Shallow trophoblastic invasion of the spiral arteries at the maternal–fetal interface is thought to contribute to its pathogenesis (Gerretsen et al., 1981). It has also been suggested that maternal immune maladaption to fetal antigens is involved in the pathogenesis of PE, as it may bring about the release of cytokines that causes maternal endothelial cell damage (Livingston and Maxwell, 2003). This immunological hypothesis is further supported by the following epidemiological findings: the incidence of PE is higher in nulliparous women (Campbell et al., 1985) and in women who are less exposed to their partners’ antigens (Robillard et al., 1994; Trupin et al., 1996; Smith et al., 1997; Lie et al., 1998; Wang et al., 2002; Saftlas et al., 2003). Furthermore, a genetic basis for PE has also been shown; a family history of PE increases the risk for developing the condition (Chesley et al., 1968; Cincotta and Brennecke, 1998). Therefore, it is important to consider the effects of paternal alleles in the fetus in studies of pregnancy complications and their interactions with the maternal genotype, which controls the in utero environment of the developing fetus.
At the materno–fetal placental interface, human leukocyte antigen (HLA)-G is the main HLA Class Ib gene being expressed by the fetal trophoblasts (King et al., 1996). It is possible that maternal natural killer (NK) cells found at the placental interface do not lyse the semiallogenic invasive fetal cytotrophoblasts due to their expression of HLA-G. Other possible roles of HLA-G in the maintenance of pregnancy include participating in vascular remodeling through inhibition of angiogenesis (Fons et al., 2006; Le Bouteiller et al., 2007), influencing the maternal NK cell production of cytokines and angiogenic factors (Chumbley et al., 1994; Li et al., 2001; Le Bouteiller et al., 2003b) and inhibiting the transendothelial migration of NK cells across the placenta (Dorling et al., 2000), thereby enhancing maternal tolerance to the fetus. HLA-G may also play a role in ensuring maternal tolerance to paternal alloantigens by reducing the population of activated CD4+ and CD8+ killer T cells that could be present in the blood in the intervillous space and decidua (Le Bouteiller et al., 2003a). The finding that only embryos that express HLA-G are implanted successfully after in vitro fertilization (Fuzzi et al., 2002; Yie et al., 2005), and also reduced expression of HLA-G in PE (Colbern et al., 1994; Yie et al., 2004; Hackmon et al., 2007), further highlights the importance of HLA-G in establishing and maintaining pregnancy.
Although some HLA-G alleles have been found to be associated with increased risk for PE, the results are not conclusive. Furthermore, most previous studies have looked at individual HLA-G single nucleotide polymorphisms (SNPs). In this study, we utilized a case–control approach to test the hypothesis that certain paternal HLA-G alleles present in the fetus but absent in the mother may increase risk for PE.
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Materials and Methods |
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A total of 83 women with PE and 240 healthy normotensive Malay women being cared for in the Department of Obstetrics and Gynecology at the National University Hospital (Singapore) and Sultanah Aminah Hospital (Malaysia) between November 2002 and December 2006 were identified either antenatally or in labor. Diagnosis of PE was made if there were both hypertension (systolic blood pressure of at least 140 mmHg and/or a diastolic blood pressure of at least 90 mmHg, measured on two occasions at least 6 h apart after 20 weeks gestation) and proteinuria of at least 300 mg per day (Sibai, 2003). All patients were examined by a doctor for the presence of other causes of hypertension such as autoimmune diseases and cardiac or renal complications. Data on other potential confounding factors like demographic details and obstetric history and risk factors like primigravidity and change of partner were also obtained. Women with superimposed PE, i.e. pre-existing hypertension, were excluded from this study. Normal controls are classified as pregnancies without any periods of hypertension throughout gestation and a consecutive sample of women with normotensive pregnancies who consented to this study was selected. For both case and control groups, 5 ml of venous blood was collected from the mother either in the delivery suite or in the antenatal ward whereas for the babies, blood was collected from the umbilical cord after delivery. Population HLA-G allele, genotype and haplotype frequencies were also determined to confirm observed frequencies in the control group, and to compare against observed frequencies in other populations. Anonymized (except for gender and ethnicity) and unselected cord blood samples from a total of 90 Malay, 94 Chinese and 90 Indian newborns were used to represent the three major ethnic groups in Singapore and Malaysia. Genomic DNA was extracted from all blood samples using a phenol–chloroform extraction procedure (Maniatis et al., 1982) and then frozen at –86°C until needed. This study was approved by the Domain Specific Review Board of the National Healthcare Group of Singapore and Ethics Review Board of Sultanah Aminah Hospital.
For each DNA sample, the HLA-G gene was amplified in six separate fragments in a single multiplex PCR reaction (Fig. 1a). Each 25 µl PCR reaction contained 50 ng of DNA, 0.2 mM of each deoxynucleotide triphosphate (dNTP), 1 unit HotStarTaq DNA polymerase in 1x supplied PCR buffer (Qiagen, USA) and six pairs of forward and reverse primers (Supplementary Table 1). PCR cycling was performed in a T3 thermal cycler (Biometra, Germany) and the conditions were as follows: a 15 min initial denaturation at 95°C, and a subsequent 2 min denaturation at 94°C, followed by 30 cycles of 94°C for 1 min, 63°C for 1 min and 72°C for 1.5 min and ending with a final extension step at 72°C for 10 min. A 10 µl aliquot of each PCR product was analyzed by electrophoresis through a 1% agarose gel in 1xTris–Borate–EDTA buffer at 15 volts/cm for an hour.
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The PCR-amplified products were genotyped for 18 HLA-G polymorphisms in two multiplex genotyping reactions, with each reaction assaying nine polymorphic sites (Fig. 1b and c). Each minisequencing primer was designed to differ in length from the others, by the addition of non-specific GACT tetra-nucleotides at the 5' end, so that they could be clearly separated and differentiated based on size. After PCR amplification, 2.5 µl of PCR product was incubated with 0.5 µl of ExoI nuclease (10 U/µl) and 1 µl of shrimp alkaline phosphatase (SAP) (1 U/µl) (United States Biochemical, USA) at 37°C for 15 min, to remove and inactivate excess PCR primers and unincorporated dNTPs. The reaction was terminated by incubating the mixture at 80°C for 15 min. Two multiplex genotyping reactions were prepared by mixing 1 µl of ExoI-SAP treated PCR product, 0.5 µl of either Panel 1 or 2 locus-specific detection primer mixture (Supplementary Table 2), and 0.5 µl of SNaPshotTM Multiplex Ready Reaction Mix (Applied Biosystems, USA) containing AmpliTaq® DNA polymerase and fluorescently labeled dideoxynucleotide triphosphates (ddNTPs). Each genotyping reaction mixture was subjected to 25 single-base extension (minisequencing) cycles consisting of a 96°C for 10 s, 50°C for 5 s and 60°C for 30 s. One microliter of SAP (1 unit) was added to the completed cycle minisequencing reaction, and the mixture was incubated at 37°C for 1 h to inactivate unincorporated fluorescent ddNTPs, followed by a 75°C incubation for 15 min to terminate the SAP treatment.
A 1.5 µl aliquot of treated multiplex minisequencing product was mixed with 9 µl of HiDiTM formamide and 0.1 µl of GeneScan-120 LIZ internal size calibrator (Applied Biosystems). The mixture was heated at 95°C for 5 min, snap-cooled on ice, then resolved by automated capillary electrophoresis on an ABI PRISM® 3100 Genetic Analyzer and analyzed using GeneScanTM application software (Applied Biosystems). Called alleles of samples were randomly selected for further confirmation by direct sequencing.
Allele/haplotype frequencies were estimated based on an expectation-maximization (EM) algorithm using SNPHap software (Clayton, 2002). Only samples in which all loci were successfully genotyped were included in the allele/haplotype frequency estimation. The World Health Organization (WHO) allele assignments are based mainly on polymorphisms present in exons 2, 3 and 4 of the HLA-G gene. In recent years, more focus has been placed on the significance of a 14 base pair (bp) insertion/deletion in the 3'-untranslated region (3'UTR) and polymorphisms in the 5' upstream region. As such, we included these polymorphisms in our HLA-G haplotype profiles as well.
Statistical analyses of allele/haplotype and individual SNP frequencies were performed using SPSS 15.0 for Windows (SPSS Inc., USA). Fisher’s exact test was used to compare allele/haplotype and genotype frequencies between case and control mothers, as well as between case and control babies to test for paternal contribution to disease development. Logistic regression analyses were performed to determine the association between the presence of particular haplotypes in an individual and the development of PE with adjustments for maternal age, body mass index (BMI), maternal history of PE or pregnancy-induced hypertension (PIH), history of abortion, primigravidity and change of partner. In addition, the defining SNP for the particular haplotype showing significant association with PE was further analyzed at the mother–child genotype pair levels to test for association with disease. The effect of an allele/haplotype or genotype in relation to disease risk/susceptibility was expressed as an odds ratio (OR). Statistical significance was set at a more conservative P < 0.01 to adjust for type I error in multiple comparisons.
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Results |
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Group-specific demographic and clinical characteristics of cases and controls are summarized in Table I. The following factors were found to be significantly associated with PE: previous history of PE or PIH and a higher BMI. Also, a nominally higher proportion of PE women was observed to be primigravids and had changed partners. Significantly different pregnancy outcomes were also observed between babies in the PE and normal control groups, including a shorter period of gestation and lower birthweight in PE babies. The majority of the PE cases analyzed in this study involved late onset PE (68.2%) with symptoms observed after 34 weeks’ gestation.
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No significant differences in HLA-G allele frequencies were observed between case and control mothers (Table II; Supplementary Table 3). However, there was a nominally higher frequency of G*0106 in PE babies compared with normal control babies (P = 0.013) (Table II). We also observed that the frequency of PE babies heterozygous or homozygous for G*0106 was nominally higher than in the normal control group (P = 0.012) (Table III). When multivariate logistic regression analysis was performed, with adjustments for maternal age, BMI, history of PE or PIH, history of abortion, primigravidity and change of partner, the difference between PE and normal control babies reached statistical significance (P = 0.004, OR = 6.4, 95% CI 1.8–23.0) (Table III).
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As primigravidity is known to be a risk factor for PE, we further analyzed the primigravida sub-group separately from the multigravida sub-group, to exclude confounding due to unequal proportions of primigravidas between case and control groups. No significant allele or genotype differences were observed between cases and controls in either primigravid or multigravid mother sub-groups (Supplementary Table 3). However, a significantly higher frequency of G*0106 allele was observed in PE babies compared with normal control babies, but only in the multigravid sub-group (P = 0.002, OR = 5.0, 95% CI 1.8–13.8) (Table III). A significantly higher frequency of babies homozygous or heterozygous for G*0106 was also observed in the PE multigravid sub-group compared with babies in the normal control multigravid sub-group (P = 0.002, OR = 5.4, 95% CI 1.9–15.4) (Table III). Logistic regression analysis with adjustments for maternal age, BMI, history of PE or PIH, history of abortion and change of partner also yielded similarly significant association between presence of fetal G*0106 in multigravid pregnancies and PE (P = 0.003, OR = 10.1, 95% CI 2.2–46.8) (Table III).
As an independent verification of the observed allele/haplotype frequencies in control mothers and babies, we also determined the corresponding population allele/haplotype frequencies in the Southeast Asian Malays, Chinese and Indians, the three main population groups in Singapore and Malaysia. Consistent with the minimally polymorphic state of HLA-G, five or fewer WHO-designated HLA-G alleles accounted for at least 85% of the chromosomes in all three populations. All polymorphisms were in Hardy–Weinberg equilibrium except for three SNPs in the Malay population, namely NP-486 (P = 0.03), NP36 (P = 0.03) and CD309 (P = 0.04). Pair-wise comparisons between populations showed significant differences for certain haplotypes (Supplementary Table 4). Importantly, with the exception of the presumptive PE risk allele G*0106 in the PE babies, frequencies of the other HLA-G alleles in all case and control groups were very similar to each other and to the observed frequencies in the Malay population.
On the basis of WHO definitions, G*0106 is defined by a variant T-nucleotide at the second position of codon 258 instead of a C-nucleotide, which results in a non-conservative threonine to methionine amino acid change. Analysis of this SNP also revealed that the frequency of mother–child HLA-G genotype mismatches among multigravid pregnancies, where mothers who were homozygous C/C (i.e. G*0106-negative) carried fetuses who were heterozygous C/T (i.e. G*0106-positive), was significantly higher in PE pregnancies compared with normal pregnancies (P = 0.001, OR = 9.6, 95% CI 2.4–38.7) (Table IV).
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Discussion |
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In this study, we observed a significant association between presence of HLA-G allele G*0106 in the fetus and an increased risk for PE, but only in multigravid pregnancies. We also observed a significantly higher frequency of fetal–maternal HLA-G genotype mismatch in PE pregnancies compared with normal pregnancies, specifically involving G*0106-negative mothers with fetuses carrying paternally inherited G*0106. Again, this positive association involved only multigravid pregnancies. These observations strongly suggest that HLA-G variants foreign to the mother may lead to histoincompatibility between mother and child, suggesting an immunological basis for PE. Therefore, maternal rejection of the semiallogenic fetus could represent one of the major contributors to the development of PE. The observation of an association between paternal G*0106 and PE only in multigravid but not in primigravid pregnancies suggests a gradual rather than immediate alloimmune response. This supposition is consistent with the observation that the G*0106 allele is unlikely to be highly immunogenic as this allele was not more likely to elicit HLA-G antibody production in mothers lacking G*0106 (Hunt et al., 2003). However, the lack of positive results in the Hunt et al. study could possibly be due to the failure of the wild-type sHLA-G*0101 protein used in the assay to recognize the anti-G*0106 antibodies generated in G*0106-naive mothers. On the other hand, Hunt et al. demonstrated that tolerance to HLA-G can be overcome by exposure during pregnancy, thereby suggesting that it is possible that the risk of a severe alloimmune reaction to G*0106 leading to PE in G*0106-naive mothers increases with each repeated exposure to the foreign HLA-G antigen from previous pregnancies. This suggests that maternal–fetal incompatibility for G*0106 does not predispose to PE per se as no significant association was observed in primigravids, but the presence of this antigen in the fetus can lead to a recurrence in a woman with a previous PE pregnancy.
The codon 258 C
T change in the G*0106 peptide translates into a non-conservative threonine to methionine amino acid substitution, which could alter its structure and/or function. Interestingly, codon 258 is located in the 
3 domain of HLA-G, the candidate binding site for leukocyte Ig-like receptor 1 (LIR1 or ILT2) and LIR2 (or ILT4) (Clements et al., 2005; Shiroishi et al., 2006b). Both LIR1 and LIR2 receptors bind preferentially to HLA-G dimers (Shiroishi et al., 2006a), the most common HLA-G conformation present on the surface of normal first trimester trophoblast cells (Apps et al., 2007), suggesting that this antigen–receptor interaction is important in the maintenance of a healthy pregnancy. Therefore, a non-conservative amino acid substitution at this site may also alter HLA-G’s binding affinity for its inhibitory receptors, thus adversely affecting its functions in protecting the semiallogenic fetus from maternal immune surveillance.
This study is limited by a small sample size, and therefore, the strong association observed between G*0106 and PE should be interpreted conservatively. Furthermore, two earlier studies of HLA-G polymorphisms in PE did not report any data to support an association with G*0106 (Hviid et al., 2001; Hylenius et al., 2004). However, Hviid et al.’s study was based on the difference in the overall proportion of HLA-G alleles shared between couples, and no information on fetal genotype and its potential interaction with maternal genotype was provided. Similarly, information on paternal or maternal inheritance of G*0106 alleles was not provided in Hylenius et al.’s study of PE triads. As such, significant differences that were present could have been overlooked. Although the antigen-presenting functions of HLA-G are yet to be established, it is possible that mismatched fetal–maternal HLA-G genotypes may adversely affect the maternal tolerance of the semiallogenic fetus. Therefore, a study with a larger sample size is necessary to confirm the observed results.
The availability of population allele/haplotype frequencies serves a useful purpose in case–control association studies as an independent check to minimize false positive results arising from sampling error or differences in racial admixture between case and control groups. As the G*0106 allele had only been discovered relatively recently, few studies have examined its population frequencies and also its association with PE. A comparison of G*0106 allele frequencies among the Southeast Asian Chinese, Indian, Malay and Danish populations revealed differences, with frequencies of 1.1%, 8.3%, 2.2% and 4.0%, respectively (Supplementary Table 5). Since the Indian G*0106 allele frequency is nominally higher compared with the Malay population (8.33% versus 2.22%, P = 0.016) (Supplementary Table 4), a high Indian admixture could theoretically lead to a spuriously high G*0106 allele frequency within the PE babies group. However, the observed G*0104 allele frequencies in the various case, control and population groups do not support this possibility. The G*0104 allele frequencies in normal control mothers (45.28%) and babies (45.83%), as well as PE mothers (47.00%) and babies (45.00%), were very similar to each other and to the Malay population (45.00%), but significantly different compared with the Indian population (26.11%) (P < 0.001). A significant Indian admixture in the PE babies group would have been reflected by a significant, if not nominal, decrease in G*0104 allele frequency in this group, which we did not observe. Through the hospital’s records, we have also re-confirmed the Malay ethnicity of the fathers of each of the G*0106-positive babies in both case and control groups, thus ruling out the possibility of Indian paternity among the G*0106-positive PE babies.
Given the variable but low frequency of the G*0106 haplotype in the different populations, its contribution to the total number of PE cases in any population group would be expected to be small. However, the clinical significance of these findings lies in the fact that in those PE cases caused in part by maternal alloimmune response to foreign HLA-G*0106 antigen, it may now be possible to provide improved prognosis and preventive intervention in subsequent at-risk pregnancies.
Although the G*0105N haplotype contains a frameshift mutation that leads to a premature stop, resulting in reduced expression of the most abundant HLA-G1 isoform in heterozygotes (Ober et al., 1998), we did not find any association of this haplotype with PE in our study. Association studies involving different sample populations also yielded similar results (Aldrich et al., 2000; Hylenius et al., 2004), suggesting that reduced HLA-G1 expression is not a contributory factor to PE development.
The 14 bp insertion/deletion in the 3' UTR of the HLA-G gene has been reported to affect the stability of the HLA-G transcript (Rousseau et al., 2003) and has also been found to be associated with PE (O’Brien et al., 2001; Hylenius et al., 2004). However, our data do not support this conclusion (Supplementary Table 6), as did several previous reports in other population groups (Humphrey et al., 1995; Bermingham et al., 2000; Lin et al., 2006). The exact effect of this polymorphism remains unclear.
We conclude that the presence of paternal HLA-G G*0106 in the fetus significantly increases risk for PE in multigravidas who do not carry this allele. This increased risk for PE may be mediated by an increasing alloimmune response to the variant paternal HLA-G antigen expressed in the fetal trophoblast following repeated exposure to the foreign antigen. Presence of variant paternal HLA-G in the semiallogenic fetus may also cause a malfunctioning of the immune-protective effect of HLA-G due to possible changes in its interaction with maternal inhibitory receptors, especially in pregnancies where the paternal allele in the fetus is foreign to the mother. These findings are consistent with clinical observations that women are more at risk of PE with certain men (Astin et al., 1981).
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Supplementary Data |
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Supplementary data are available at http://molehr.oxfordjournals.org/.
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Funding |
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This work was supported by research grants from the National Healthcare Group, Singapore (NHG-RPR02090) and the National Medical Research Council, Singapore (NMRC/1124/2007) to Y.S.C., A.L., Y.H.C., R.J., C.G.L. and S.S.C. J.F.V.H. was a recipient of an Australasian Society of Clinical Immunology and Allergy (ASCIA) research award.
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Footnotes |
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Both authors contributed equally to this work. 
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Submitted on November 28, 2007; resubmitted on February 11, 2008; accepted on February 19, 2008.
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