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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4220-4232
Variant Genotypes of the Low-Affinity Fc Receptors in Two Control
Populations and a Review of Low-Affinity Fc Receptor Polymorphisms
in Control and Disease Populations
By
Thomas Lehrnbecher,
Charles B. Foster,
Shaoxian Zhu,
Susan F. Leitman,
Lynn R. Goldin,
Konrad Huppi, and
Stephen J. Chanock
From the Immunocompromised Host Section, Pediatric Oncology Branch,
the Genetic Epidemiology Branch, Division of Cancer Epidemiology and
Genetics, and the Laboratory of Genetics, National Cancer Institute,
and the Department of Transfusion Medicine, Clinical Center, National
Institutes of Health, Bethesda, MD.
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ABSTRACT |
Fc -receptors (FcR) provide a critical link between humoral and
cellular immunity. The genes of the low-affinity receptors for IgG and
their isoforms, namely, FcRIIa, FcRIIb, FcRIIIa, FcRIIIb,
and SH-FcRIIIb, are located in close proximity on chromosome 1q22.
Variant alleles may differ in biologic activity and a number of studies
have reported the frequencies of variant FcR alleles in both disease
and control populations. No large study has evaluated the possibility
of a nonrandom distribution of variant genotypes. We analyzed 395 normal individuals (172 African Americans [AA] and 223 Caucasians
[CA]) at the following loci: FcRIIa, FcRIIIa, and FcRIIIb,
including the SH-FcRIIIb. The genotypic distributions of FcRIIa,
FcRIIIa, and FcRIIIb conform to the Hardy-Weinberg law in each
group. There was no strong evidence that combinations of 2-locus
genotypes of the 3 loci deviated from random distributions in these
healthy control populations. The distribution of SH-FcRIIIb is
underrepresented in CA compared with AA (P < .0001) controls. A previously reported variant FcRIIb was not detected in 70 normal individuals, indicating that this allele, if it exists, is very rare
(<1%). In conclusion, we present data that should serve as the
foundation for the interpretation of association studies involving multiple variant alleles of the low-affinity FcR.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
RECEPTORS FOR THE Fc domain of IgG
(FcR) are mainly expressed on cells of hematopoietic lineage and
provide a critical link between humoral and cellular
immunity.1,2 These receptors mediate a variety of
biological responses, including antibody-dependent cellular
cytotoxicity, endocytosis, phagocytosis, release of inflammatory mediators, and augmentation of antigen presentation.1,3
FcR are divided into 3 classes: FcRI (CD64), FcRII (CD32), and
FcRIII (CD16). Within each class, isoforms have been identified that vary in molecular weight, in binding affinity to different subclasses of human IgG, and in distribution on the surface of hematopoietic cells. A further level of complexity is introduced by the presence of
variant alleles in the low-affinity receptors: FcRIIa, IIb, IIIa,
and IIIb. In some cases, variant forms of the low-affinity receptors
have been reported to have biologic differences in in vitro assays. A
burgeoning number of association studies, correlating clinical outcomes
with variant alleles, underscores the potential importance of these
variant alleles in vivo. Accordingly, it is critical to determine the
distribution of variant genotypes individually and in combination in a
large control population to interpret association studies that seek to
evaluate multiple FcR genotypes in combination.
The structural heterogeneity and complex nature of the isoforms and
their variant alleles reflect the functional diversity mediated by
these receptors. The low-affinity receptors (FcRIIa, IIb, IIIa, and
IIIb) colocalize with other genes of hematopoietic and immunologic
interest to a region in chromosome 1q22 that includes the receptor for
interleukin-6, C-reactive protein, the selectin cluster, and the Duffy
blood group.4-8 It is estimated that the maximum distance
between any of the 2 low-affinity FcR genes (FcRIIa, IIb, IIIa
and IIIb) is approximately 200 kb.4,9 The location of a
recently described variant, SH-FcRIIIb, which has been identified in
individuals in whom a polymerase chain reaction (PCR) fragment can be
amplified with NA2-specific primers derived from FcRIIIb, is not
known at this time.10,11
Preliminary results of the human genome project suggest that
polymorphisms occur approximately once every 800 to 1,200 bp.12 In regions sharing a high degree of homology, such as
the FcR, crossing over may be favored, and one might expect to see a
greater frequency of recombination events and, perhaps,
polymorphisms.13 However, only a handful of biologically or
clinically significant variant alleles of the low-affinity FcR,
FcRIIa, IIb, IIIa, and IIIb have been identified.
It has been reported that some variant alleles of the low-affinity
FcR are of functional or clinical importance. For example, FcRIIa
has 2 codominantly expressed alleles that differ at 1 amino acid, R131
and H131.14 These were initially identified on the basis of
a functional polymorphism related to murine IgG1 binding and were
designated as low responder (LR) and high responder (HR),
respectively.15,16 Several groups have shown a decreased ability of the R131 allele to bind human IgG2.14,17-20 Both
FcRIIIa, which is expressed on NK cells and phagocytic cells, and
FcRIIIb, which is expressed on neutrophils, display codominant
biallelic variants.21-24 The 158F allele of FcRIIIa has
been shown to bind IgG1, IgG3, and IgG4 less avidly.23,24
We limited our analysis of the FcRIIIa gene to the V and F alleles
at amino acid 158 and did not analyze the tri-allelic polymorphism, 48 L/H/R, which is probably linked to 158 V/F and also appears not to
confer a significant biologic difference.23,25 The 2 allotypes of FcRIIIb, assigned as neutrophil antigen (NA) 1 and 2, differ in at least 5 nucleotides, resulting in changes of 4 amino acids
in the membrane-distant Ig-like domain.21,22 In comparison
to the neutrophils obtained from NA1 homozygous donors, neutrophils
from NA2 homozygous individuals bind human IgG3 less effectively and
were consistently found to exhibit lower levels of phagocytosis of
erythrocytes sensitized with IgG1 and IgG3 anti-Rhesus D monoclonal
antibody.26-28 Furthermore, phagocytosis of IgG1-opsonized
bacteria by FcRIIIb-NA2 neutrophils was also reduced in comparison
to FcRIIIb-NA1 neutrophils, whereas no difference was found using
IgG2-opsonized bacteria.28 A single nucleotide change at
nucleotide 885 in FcRIIb1 (T  G) has been reported at the
cDNA level only.29 The proposed change of 1 amino acid
appears to alter receptor internalization and capping in in vitro
studies.29,30 In addition, we investigated the distribution
of the recently described SH-FcRIIIb, which differs from the
wild-type NA-2 allele by at least 1 single nucleotide, although a
biologic difference has not been established.10,11
The purpose of our study was to determine the frequency of selected
variant alleles of the low-affinity FcR genes in a large, healthy
control population. To this end, we genotyped 395 normal healthy
individuals (172 African Americans [AA] and 223 Caucasians [CA])
and determined the distribution and frequency of biologically important
variant alleles of FcRIIa, IIb, IIIa, and IIIb, including SH-FcRIIIb. We have sought to identify whether there is nonrandom distribution of combinations of variant genotypes in these 2 populations. Understanding the distribution of multiple FcR variant
genotypes in control populations furnishes a critical foundation upon
which to interpret future association studies. Our study provides a basis upon which the independent segregation of individual FcR genes
within a population may be estimated. Understanding the extent of the
interaction between multiple FcR genotypes could lead to further
insight into the contribution of this complex family of genes to
various pathologic conditions.31-33
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MATERIALS AND METHODS |
Subjects
Genomic DNA was isolated from peripheral blood using either a
phenol-chloroform extraction method (5 Prime-3 Prime, Inc, Boulder, CO)
or Puregene DNA isolation kit (Gentra Systems, Minneapolis, MN). Blood
samples from 395 normal healthy individuals, consisting of 172 AA and
223 CA, were available for genomic DNA extraction under an
Institutional Review Board-approved protocol for anonymous genomic DNA
collection under the supervision of the Department of Transfusion
Medicine, Clinical Center, National Institutes of Health (Bethesda,
MD). Only the race and sex were recorded and linked to an anonymous
identifier during collection of samples.
Determination of the Polymorphic Forms of the Low-Affinity
FcR
Genomic DNA was amplified according to conditions specific for each
FcR. Genotype analysis was completed before statistical analysis.
All assays were performed at least twice.
FcRIIa.
The previously reported polymorphism in the coding region of FcRIIa
was determined by allele-specific restriction digest according to
methods described by Jiang et al.34 A mutant
oligonucleotide-directed restriction site was created in the 5'
end of the amplicon using the following sense primer:
GGAAAATCCCAGAAATTCTCGC. The less frequent, variant allele, R, contains
a BstUI restriction digest site (an introduced G compared with
the wild-type A). The antisense primer, CAACAGCCTGACTACCTATTACGCGGG,
corresponding to a sequence in the next intron, assures gene specific
amplification and introduces a second BstUI restriction site
that serves as an internal control for restriction digestion. PCR
amplification was performed in a 50 µL reaction with 50 ng genomic
DNA, 100 ng of each primer, 200 µmol/L each dNTP, 0.5 U Taq DNA
polymerase (Boehringer Mannheim, Mannheim, Germany), and the
manufacturer's buffer. A denaturation step of 95°C for 5 minutes
was followed by 30 cycles of 94°C for 15 seconds, 55°C for 30 seconds, and 72°C for 40 seconds. After BstUI digestion,
samples were analyzed on a 3% agarose gel.
FcRIIb.
Direct sequence analysis was performed on amplicons amplified using the
following sense and antisense primers, TCCCATCCAACCCTGGA and
GGCAGATTCCTCAGCAAATCA, respectively. Fifty-microliter reactions containing 50 ng genomic DNA, 150 ng of each primer, 200 µmol/L dNTP,
and 0.5 U Taq polymerase were amplified under the following conditions:
initial denaturation at 95°C for 5 minutes, followed by 30 cycles
of 95°C for 30 seconds, 56°C for 30 seconds, and 72°C for
60 seconds. The primers used for amplification were used for sequencing
with the Thermo Sequenase radiolabeled terminator cycle sequencing kit
(Amersham Life Sciences, Inc, Cleveland, OH) at 35 cycles and an
annealing temperature of 55°C.
FcRIIIa.
The 158V/F-FcRIIIa polymorphism was discriminated by an
allele-specific oligohybridization of a nested PCR amplification of
genomic DNA. A gene-specific, 1.2-kb fragment was amplified using the
following sense and antisense primers, ATATTTACAGAATGGCACAGG and
GACTTGGTACCCAGGTTGAA, respectively, in a 25 µL reaction with 20 ng of
genomic DNA, 75 ng of each primer, 200 µmol/L dNTP, and 0.25 U Taq
polymerase. PCR conditions were as follows: 5 minutes of initiation
denaturation at 95°C, followed by 35 cycles at 95°C for 1 minute, 56°C for 1 minute, and 72°C for 1 minute. One
microliter of this reaction was transferred to a separate microfuge
tube for nested PCR in a total volume of 50 µL that included 150 ng of sense and antisense primers, TCATCATAATTCTGACTTCT and
CTTGAGTGATGGTGATGTTC, 200 µmol/L dNTP, and 0.5 U Taq polymerase. PCR
conditions for the second amplification consisted of 30 cycles of
95°C for 1 minute, 62°C for 1 minute, and 72°C for 1 minute. Ten microliters of the final PCR reaction was transferred to a
nylon filter in duplicate (Hybond N+; Amersham). Each filter was
hybridized with a [-32P]-ATP-labeled oligonucleotide probe
corresponding to the F or V allele, GCAGGGGGCTTTTTGGGAGTAAA
or GCAGGGGGCTTGTTGGGAGTAAA. The blots were washed in 6×
SSPE with 1% sodium dodecyl sulfate (SDS) at room temperature,
42°C, and twice for 10 minutes each time at 70.5°C for the
probe containing the T allele and at 72.5°C for the G allele.
Autoradiography was performed and analyzed between 8 and 24 hours later.
FcRIIIb.
Polymorphic forms of FcRIIIb were determined by gene- and
allele-specific PCR with the following primer pairs, NA1-sense, CTCAATGGTACAGGGTGCTC and NA1-antisense, GGCCTGGCTTGAGATGAGGT or NA2-sense, CTCAATGGTACAGCGTGCTT and NA2-antisense,
CACCTGTACTCTCCACTGTCGTT, using a modified protocol according to Hessner
et al.35 Control amplification of a 383-bp segment of the
C-myc gene was included in each tube with the following primer pair,
ACGCCCCTCAACGTTAGCTT and CGCAGATGAAACTCTGGTTCACCAT. Fifty nanograms of
genomic DNA was amplified in 50 µL reaction containing 200 µmol/L
dNTP, 10 ng of each Myc-primer, 0.5 U Taq polymerase, and either primer pair for NA1 or NA2. The PCR conditions were as follows: 30 cycles of
94°C for 1 minute, 67°C for 1 minute, and 72°C for 1 minute. PCR products were visualized on a 3% agarose gel.
SH-FcRIIIb.
The reported sequence variation observed in individuals in whom an
amplicon can be amplified with NA2-specific primers, SH-FcRIIIb, was
determined by allele-specific digest of a PCR amplicon with SfaNI as described by Bux et al.10 Using the
allele-specific primer pair for FcRIIIb-NA2 under conditions
detailed above, digestion with the restriction endonuclease
SfaNI was performed for 3 hours and the products were
visualized on a 3% agarose gel.
Literature Search
Citations including information on variant alleles of the FcR and
associated clinical studies were identified by performing searches
using PubMed extending back to 1980 (National Center for Biotechnology
and Information, National Library of Medicine, National Institutes of
Health). Keywords included polymorphism, allele, Fc receptor,
FcReceptor, and clinical association. Additional references were
identified from bibliographies of identified references.
Statistical Analysis
Allele frequencies were computed from the observed data and deviations
of observed genotypic distributions from expected distributions based
on the Hardy-Weinberg law were tested using a  2 test
statistic with 1 degree of freedom. For comparison of 2-locus genotypic
distributions from random expectations, a 2 test with 4 degrees of freedom was performed on each 3 × 3 table of
genotypes. In this exploratory analysis, P values were
corrected by a factor of 3, which correlates with the number of loci
examined. For any 2-locus test with a P value less than .05, we
looked at specific combinations of genotypes by making 3 × 2 tables and computing a 2 test with 2 degrees of freedom.
Similarly, these P values were corrected by a factor of 3 on
the premise that the analysis looked at 3 different genotypes.
Statistical analysis was performed using the Macintosh 2.0 version of
InStatR (GraphPad Software, San Diego, CA).
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RESULTS |
A total of 395 individuals (172 AA and 223 CA) were genotyped for at
least 1 low-affinity receptor, FcRIIa, FcRIIIa, or FcRIIIb
(Table 1). For each of the FcR examined,
the genotypic distributions in both populations analyzed conform to the
Hardy-Weinberg equilibrium (Table 2). In 5 individuals (1.3%), no FcRIIIb gene was detectable, in accordance
with previously reported data indicating that less than 1% of the
population lacks the FcRIIIb phenotype or that additional
polymorphisms interfere with allele-specific amplification.36 The allelic frequencies of FcRIIa, and
FcRIIIb did not differ between AA and CA, but in the FcRIIIa,
there was a marginal difference between the 2 groups for the
heterozygotes 158V/F (P = .048).
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Table 2.
Single Locus Test for Hardy-Weinberg Equilibrium of
Low-Affinity Fc Receptors: FcRIIa, FcRIIIa, and FcRIIIb
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To further investigate the possibility of a nonrandom distribution of
genotypes in a healthy population, we concentrated our analysis on 330 individuals (150 AA and 180 CA) who were successfully typed at the 3 loci for FcRIIa, FcRIIIa, and FcRIIIb. The distribution of
allelic variations in this subgroup did not differ significantly from
the distribution observed in the total group (data not shown). There
was no strong evidence for nonrandom distribution of combinations of
variant genotypes in either population
(Table 3). It should be noted that, in the
CA population, there is a marginally significant P value for
the combination of FcRIIIa and FcIIIb (P = .046), suggesting an overrepresentation of 1 or more combinations of variant
genotypes. When we analyzed this group individually, the only notable
finding was for the combination of the 158F/F genotype of FcRIIIa
and the FcRIIIb alleles (P = .016 corrected for multiple comparisons; n = 3). The other genotypes, V/F and V/V of 158, did not
demonstrate a skewed distribution of combinations of the variant
genotypes of the 2 loci.
Of the 330 individuals genotyped for both FcRIIIb and SH-FcRIIIb,
the variant sequence of SH-FcRIIIb was observed exclusively in
individuals in whom a PCR fragment could be amplified with NA2-specific
primers (Table 4). Accordingly, no
individuals homozygous for NA1 had evidence of the sequence of
SH-FcRIIIb. The A sequence, which denotes SH-FcRIIIb, was
significantly underrepresented in CA compared with AA (P < .0001; Table 4).37 We further analyzed the distribution of
the SH-FcRIIIb genotype in individuals in whom a PCR product could
be amplified with NA2 specific primers (Table 5). In the AA population, which has
a higher frequency of detecting the variant SH-FcRIIIb sequence,
there was no difference in the distribution between those individuals
with only NA2 primer-generated products (ie, no NA1 product was seen
separately) and those individuals who also had an NA1 allele. These
results suggest that SH-FcRIIIb in AA appears to be randomly
distributed between the 2 genotypes that contain fragments generated
with NA2-specific primers (ie, with and without the presence of NA1).
For those individuals in whom an amplicon was amplified with NA2
primers and complete SfaN1 digestion was observed, it is
assumed that only the SH-FcRIIIb sequence is present. From our
typing assays, it is not possible to conclude whether 1 or 2 copies of
the SH-FcRIIIb sequence are present; an FcRIIIb null gene could
be present. Furthermore, our results indicate that, in some
individuals, there might be duplication or redundancy of the FcRIIIb
gene, because SH-FcRIIIb (as indicated by heterozygosity with
respect to SfaN1 digestion) is detected in individuals with the
NA1 allele and a fragment amplified with the NA2-specific primers
(Table 5). Of the 43 AA who were positive for SH-FcRIIIb, in 29, incomplete Sfa1 digestion was observed (67% of SH-FcRIIIb
and 24% of the total population), indicating either duplication or
redundancy of the FcRIIIb gene, whereas in 14 AA individuals (33%
of SH-FcRIIIb positive and 11% overall), only the SH-FcRIIIb
sequence was detected. In only 1 of 8 CA patients who were positive for
SH-FcRIIIb, complete SfaN1 digestion was observed.
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Table 4.
Genotype Distribution of SH-FcRIIIb in
Individuals in Whom a PCR Fragment Could Be Amplified With
NA2-Specific Primers
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Table 5.
Distribution of Variant Genotypes of SH-FcRIIIb in
Individuals, as Determined by SfaN1 Digestion of PCR Fragments
Amplified With NA2-Specific Primers
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A variant cDNA has been isolated corresponding to a possible
polymorphism in FcRIIb that alters its biologic
function.29,30 We directly sequenced 140 separate
chromosomes from 52 CA and 18 AA individuals and in each case
identified T at bp 885 and no G. We conclude that this proposed variant
of FcRIIb is very rare, if it exists.
A comparison of our results with those of published studies, identified
using PubMed, which generally report on only 1 FcR variant allele,
is shown in a meta-analysis in
Table 6. The largest collection of studies has been reported for the H/R genotypes of FcRIIa. In total, 2,419 CA have been genotyped and reported in 23 studies including 24 separate populations.32,38-57,61,66 An
analysis of the distribution of variant genotypes of FcRIIa was
performed between individual study populations and the remaining published population as well as against the population reported here.
In 3 of the 23 studies, there was a difference detected by 3 × 2 2 analysis.32,38,39 Interestingly, these
included the 2 largest studies and 1 of the smallest studies.
Comparison of our study results to the total in Table 6 did not show a
significant difference overall (P = .14; 2 = 3.99) or by genotype (data not shown). Similarly, there was no
difference between the reported populations of AA at the FcRIIa locus or between our population and the total of the 3 studies.38,54,58 However, there is an appreciable
difference in the distribution of variant FcRIIa genotypes in
populations from the Far East.31,38,56,60
In comparison to the published literature on FcRIIa variant
genotypes, there are few studies with small sample sizes reporting the
frequency of variant genotypes of FcRIIIa and FcRIIIb in CA and
FcRIIIb in AA.23,24,32,35,61,62 Comparison of our results for FcRIIIa in CA to those of the published literature indicates a difference for the FF genotype only.23
Similarly, the distribution of the NA1/NA2 and NA2/NA2 genotypes in AA
differed from the one study in the literature.35
Previously, there were no published data available for FcRIIIa in AA.
In Table 7, we present an
analysis of published studies comparing the distribution of
low-affinity FcR genotypes in cohorts with a well-defined disease
versus healthy controls. These studies describe the possible
contribution of FcR variants to development of the underlying
disease listed in the left-hand column (Table 7). We analyzed the data
presented as raw numbers in each report and reported the findings
without correction. The data presented in Table 7 indicate that, in
patients with systemic lupus erythematosus (SLE), the association with
FcRIIa variant genotypes varied in different populations. For
example, in AA, 2 of 3 studies demonstrated an association, whereas
none of the studies in CA are compelling.38,58 In the
meta-analysis, the overall effect appears to be stronger for AA
compared with CA (P = .001 v P = .078). On the
other hand, the association between FcRIIIa variants and SLE has
been well demonstrated in both reported studies (P = .004 and
P = .0072).23,24
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Table 7.
Published Studies Comparing the Distribution of
Low-Affinity FcR Genotypes in Disease Versus Normal Control
Populations
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Published studies exploring the association between low-affinity FcR
genotypes and phenotypic differences within a specific disease
population are presented in Table 8. A
meta-analysis was performed on studies examining SLE and nephritis at
the FcRIIa locus; the individual studies indicate that the overall
association at this locus is weak, at best. In the absence of
significance at the locus overall, it is difficult to interpret the
marginal association observed between H/H genotype and nephritis in AA with SLE. Table 8 also includes single studies that associate 1 more
FcR with renal dysfunction in Wegener's granulomatosis, thymoma in
myasthenia gravis, granulomas or auto-immune disease in chronic
granulomatous disease, recurrence of periodontitis, hemolytic anemia in
SLE, and severe meningococcal infection.31-33,40,41,64
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Table 8.
Published Studies Exploring the Association
Between Low-Affinity FcR Genotypes and Phenotype Within a Single
Disease Population
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DISCUSSION |
In this study, we analyzed the distribution of variant alleles of
members of the low-affinity FcR family, including FcRIIa, FcRIIb, FcRIIIa, FcRIIIb, and SH-FcRIIIb, in 395 healthy, normal individuals. We present a substantially larger healthy cohort
than previously published studies and specifically examined both single
allelic frequencies and the possibility of nonrandom distribution of
variant genotypes. Our data indicate that there is a marginal
difference in the distribution of genotypes between AA and CA for the
158V/F genotype of FcRIIIa (P = .048), whereas no difference
was detected for the FcRIIa and FcRIIIb genotypes. Notably, our
study represents the largest collection of AA controls analyzed at the
FcRIIa and FcRIIIb loci. Furthermore, we report the first data on
allelic distribution of the variant alleles V and F of FcRIIIa in
the AA population.
Despite the fact that the FcRIIa, FcRIIIa, and FcRIIIb genes
are most likely derived from a common ancestral gene and are clustered
in close proximity on chromosome 1q22, we did not find strong evidence
for nonrandom distribution of variant FcR genotypes within our
healthy, control population.4 In the course of our analysis, we only found evidence for a tendency towards a skewed distribution of combinations of the 158 F/F genotype of FcRIIIa with
FcRIIIB genotypes. The significance of this finding will be borne
out in future studies of comparable healthy control populations. The
tendency towards a skewed distribution was seen only in the CA
population and not in the AA population. Overall, we conclude that, in
our population of healthy controls of AA and CA background, FcR
genotypes for the low-affinity receptors, FcRIIa, FcRIIIa, and
FcRIIIb, are randomly distributed. Although it has previously been
suggested that linkage disequilibrium exists between the NA1 phenotype
of FcRIIIb and the high responder of FcRIIa, this earlier study
relied on phenotype and not genotype data.5 Because the
study did not directly examine the distribution of genotypes or allelic
frequencies of both genes, FcRIIa and FcRIIIb, it is difficult to
conclude that linkage disequilibrium exists. However, genotype analysis
of our control population did not confirm an association between the
pairs of loci genotypes previously reported. These results provide a
foundation for future association studies that will look at multiple
genotypes of the low-affinity FcR.
Recently, a new alloantigen of FcRIIIb, named SH-FcRIIIb, has
been characterized; it differs from the FcRIIIb-NA2 allele by a
single nucleotide change (C for A at position 266) that results in the
substitution of a hydrophobic alanine with an aspartic acid
residue.10,11 The structural and functional implications of
this change are not known. We found that the frequency of the SH
variant differs between AA and CA (P < .0001); only 3.8% of CA were SH-FcRIIIb positive, whereas 25% of AA were SH-FcRIIIb positive. These data are in agreement with those of other
reports.10,11,37 Our results confirm other studies showing
that the SH-FcRIIIb is identified in individuals in whom a fragment
can be amplified with NA2-specific primers.11,37 Because
there is only a single base difference between NA2 and SH-FcRIIIb,
it could be inferred that the SH-FcRIIIb is a point-mutated allele
of NA2. However, we have considered it as a separate entity for the
present analysis. Furthermore, the ability to identify individuals with
the NA1 allele plus an amplicon generated with NA2-specific primers
that is incompletely digested with SfaN1 (ie, the sequence
includes both an A and C with the former denoting the FcRIIIB)
provides evidence for duplication of the gene in selected
individuals.11 Interestingly, in individuals in whom a
product can be amplified with NA2-specific primers, we did not see
evidence of preferential distribution of FcRIIIb-NA2 genotype and
SH-FcRIIIb. Further studies across generations are required to sort
out the exact mode of inheritance. On the other hand, in selected
individuals in whom a product could be amplified with NA2-specific
primers, only the SH-FcRIIIb sequence was detected; Table 5
indicates that there are 14 AA and 1 CA with only SH-FcRIIIb
sequence detected and no NA2 allele present. These individuals could
have the FcRIIIb null gene and would phenotype as NA2 but have no
NA2 genotype.
The FcRIIb has been shown to have an inhibitory effect on
phagocytosis mediated by FcRIIa and, to a lesser extent, on
phagocytosis mediated by FcRIIIa.65 Two cDNA clones that
differ by a single base at nucleotide 885 have been reported for the
isoform FcRIIb1 and are thought to represent allelic
variation.29 The change in an amino acid of the cytoplasmic
domain (tyrosine substituted by an aspartic acid) has been reported to
display differences in receptor internalization and
capping.30 The failure to detect a single G at nucleotide
885 at the genomic level in 70 healthy controls indicates that, if the
polymorphism exists, it is very rare. Although we cannot exclude the
possibility that our amplification primers could have preferentially
recognized a contiguous polymorphic region, linked to the T allele, it
is unlikely, because no polymorphism was identified in this region in a
previous study.29
When we compared our data with a compilation of reported healthy
controls, we uncovered a number of interesting findings. Differences in
the distribution of variant alleles within healthy controls were
apparent for some loci but not for others, depending on the group
studied. For example, comparison of our population with 27 reported
populations in Table 6 demonstrated no difference for FcRIIa (n = 2,419 for CA and n = 227 for AA), but there was an apparent difference
between our population and the reported literature at the FcRIIIb
locus (n = 392 for CA). When the Hispanic population reported by
Hessner et al35 is excluded from the FcRIIIb CA
population, there is no significant difference between our population
and the remaining CA populations (2 = 1.02, P = .60). The issue of geographic and ethnic background is critical in
interpreting these studies. Differences in either of these can account
for variations in distribution of variant alleles and probably reflect
varying evolutionary challenges. Although we analyzed AA and CA, the
published literature includes studies of populations from the Far East
and Indian subcontinent. Notably, there is an apparent difference
between populations from the Far East and CA at the FcRIIa locus.
Lastly, the data in Table 6 indicate that sample size can influence the
distribution of variant genotypes. It is not surprising to find a
difference between 1 of the smaller studies (n = 49) and the sum of 23 studies. On the other hand, 2 of the large studies of FcRIIa
differed from the sum of the remaining populations. This might reflect that there are actual differences in ethnic populations that become apparent when large enough populations are compared; in turn, these
observa-tions underscore the subtle differences between populations of
the same ethnic background yet different geographical location.
Recently, a number of groups have investigated the clinical
significance of variant alleles in FcRIIa, FcIIIa, and FcIIIb in disease populations. In Table 7, we present a compilation of
reported studies and include recalculation of raw data without correction factors. Specifically, we looked at the overall locus and
also an association between susceptibility to a disease and individual
genotypes. Although the strength of a meta-analysis is undermined by
variations in inclusion criteria and patient populations, several
points emerge from the analysis. First, the association of variant
alleles and disease susceptibility varies between ethnic groups. For
example, the meta-analysis of SLE in Table 7 indicates that the
association between SLE and FcRIIa variants is strong in populations
of AA and Pacific Rim (PR) background, whereas in CA, the association
is marginal. Second, a stronger association was observed for the same
disease, SLE, but at a different locus, FcRIIIa, in CA. These data
suggest that differences in the biological role of low-affinity FcR
receptors could influence disease susceptibility. Third, the importance
of looking at different populations with sufficient numbers is critical
for determining the validity of a proposed association. For example,
the proposed association between heparin-induced thrombocytopenia and
FcRIIa variants was based on a series of studies, some of which
included a small number of patients.39,44,45,47,57,66
However, a meta-analysis presented in Table 7 of the combined data does not support the proposed association. Lastly, the ability to discern an
association between outcomes within a population with a common disease
depends on adequate patient numbers.
An analysis of published studies exploring the association between
low-affinity FcR genotypes and phenotype within a single disease
population is presented in Table 8. We identified 5 papers reporting on
7 different populations examining a possible association between
FcRIIa variants and nephritis in SLE and found no evidence to
support such an association.38,40,49,50,58 There are a
number of promising analyses in patients with CGD, meningococcal infection, or SLE and hemolytic anemia that propose new insights into
disease pathogenesis.31,33,40,43,64 Clearly, further studies are required to validate and expand the observations, but the
ability to observe in vivo the effect of subtle biologic differences
(as demonstrated in known variants of the FcR) provides an important
avenue of investigation. In an exploratory study, the combination of
low-affinity FcR, FcRIIa, FcRIIIa, and FcRIIIb was studied
in a cohort of CGD patients; coinheritance of variant FcRIIa and
FcRIIIb genotypes was associated with a greater likelihood for
developing granulomas in CGD.33 Similarly, the study also identified a possible association between variant FcR and other molecules of innate immunity (ie, FcRIIa and mannose-binding lectin
in autoimmune complications of CGD).
In summary, we present genotype analysis of a large healthy control
population at multiple loci of low-affinity FcR and found that the
2-locus genotypes are generally randomly distributed. Accordingly, for
the purpose of interpreting population studies, the distribution of
variant genotypes of FcRIIa, FcRIIIa, and FcRIIIb may be
considered independent. These results provide a foundation for
association studies that will seek to analyze multiple FcR genotypes
simultaneously.33
| |
NOTE IN PROOF |
Even though we did not find significant distortion of the observed
frequencies of the different combinations of 2-locus genotypes from
their expected values, this does not rule out disequilibrium of
haplotypes. In fact, given the close proximity of the 3 loci, one would
expect to find disequilibrium of haplotypes. We tested for
disequilibrium among pairs of loci and for all 3 loci separately in CA
and AA using the program developed by Long et al.67 In CA,
there was significant disequilibrium (P < .001) between all pairs of the 3 loci. In AA, there was significant disequilibrium (P < .05) between IIa-IIIa and IIIa-IIIb, but not between
IIa-IIIb. Neither population showed disequilibrium of the 3 locus haplotypes.
| |
ACKNOWLEDGMENT |
The authors thank Steven Stein and Renee Chen for their technical
assistance and Drs David Stroncek and David Venzon for their advice and comments.
| |
FOOTNOTES |
Submitted January 15, 1999; accepted August 13, 1999.
T.L. was supported by a Dr. Mildred Scheel Stipendium, Deutsche
Krebshilfe e.V.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Stephen J. Chanock, MD, Immunocompromised
Host Section, Pediatric Oncology Branch, Bldg 10, Room 13N240, National
Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
e-mail: sc83a{at}nih.gov.
| |
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TOP
ABSTRACT
INTRODUCTION