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Variable-Constant Segment Genotype of Immunoglobulin Kappa is Associated with Increased Risk for Rheumatoid Arthritis.

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Objective. To further investigate the association
of rheumatoid arthritis (RA) with a particular genotype
identified by a restriction site polymorphism near the
constant segment of immunoglobulin kappa (C,).
Methods. The frequencies of genomic DNA polymorphisms detected within or near C, (the most C,proximal variable segment [V,] B3 and a T lymphocyte
marker [CDSA]) were determined by Southern blotting
and hybridization. The frequencies of coding-region
polymorphisms of C, (Km allotypes) were determined
by amplification by polymerase chain reaction followed
by restriction enzyme digestion.
Results. Although the frequencies of B3, Km, and
CD8A genotypes were not Merent between RA and
normal control populations, more individuals were homozygous for both C, and B3 in the RA group (relative
risk 2.2, P < 0.01), especially in the DR4-negative RA
subgroup (relative risk 3.9, P < 0.001).
Conclusion, The homozygous genotype of an
approximately 30,000-base region including the C, segment confers an elevated risk for RA, particularly in the
DRQnegative subgroup.
Because relatives of persons with rheumatoid
arthritis (RA) have an increased risk of developing RA
Publication 260 from the Charles W. Thomas Arthritis
From the Division of Rheumatology, Allergy and Immunology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Supported by NIAMS grant AR-38478 and by Jefiess Trust
grant J-186.
Address reprint requests to George Moxley, MD, Box 263,
MCV Station, Richmond, VA 23298-0263.
Submitted for publication February 12, 1990; accepted in
revised form August 20, 1991.
Arthritis and Rheumatism, Vol. 35, No. 1 (January 1992)
(1) and because monozygotic twins are more frequently concordant for RA than are dizygotic twins
(2), there appears to be a genetic component in RA.
Heredity determines 6 7 0 % of the clinical illness, and
the pattern of inheritance is consistent with involvement of several genes (2). Among the specific genetic
markers associated with RA are the fast-migrating
polymorphism of the third component of complement
(3,4), markers of the major histocompatibility complex
(including HLA-DR4) (5,6),and polymorphic markers
of the immunoglobulin heavy chain (7,8)and immunoglobulin lambda regions (9).
Immunoglobulin kappa is remarkably abnormal
in patients with RA. Polyclonal rheumatoid factors
(RFs) from persons with RA have a higher proportion
of kappa-to-lambda light chains than do other serum
immunoglobulins (10). About one-third of people with
RA have an expansion of clones of kappa-bearing
lymphocytes in the peripheral blood (11). In addition,
monoclonal RFs derived from individuals with mixed
cryoglobulinemia have antigenic similarities of the
variable regions (cross-reactive idiotypes) (12) which
appear to be partly due to the use of one or a small
number of V, segments (13,14). Polyclonal RFs from
persons with RA share the cross-reactive idiotypes of
monoclonal RFs (15). Reports of previous studies
using the kappa allotypic marker Km(1) showed no
significant association with RA in a study of British
subjects (16), but in a Greek population, there was a
trend toward association (17). I have found that there
is an increased frequency of the homozygous C,
genotype in RA (18), particularly in HLA-DR4 negative individuals (19). Because the immunoglobulin
kappa constant region is nearly alike in everyone, it
was reasoned that the disease-related sequence would
be located outside the coding region for C, and might
lie either among the coding region of nearby V,
segments or among nearby regulatory sequences.
The underlying hypothesis of this investigation
is that immunoglobulin kappa is a risk factor for RA.
In particular, the objective of this study was to determine whether the predisposition to RA is also found
with other polymorphic markers within or near C,,
namely, a V, (B3) that is centromeric to C,, kappa
allotypic markers (Km) that are based on allelic differences of the C, coding sequence, or a marker found on
the cytotoxic-suppressor subset of thymus-derived
lymphocytes (CD8A).
The results of C, and DRP genotyping of most of the
study subjects has been reported previously (19). Dr. D. 0.
McDaniel of the University of Alabama at Birmingham
generously provided DNA specimens from an additional 13
RA patients and 13 normal subjects. All study subjects were
The methods and results of serum testing for rheumatoid factor have been previously described (19). Briefly,
the slide agglutination test, which was used for screening
purposes, is similar in sensitivity to a latex agglutination test
and employs human RhD erythrocytes sensitized with a
human anti-RhD antibody (Ripley); the sensitized human
cell agglutination assay, which was used for titering, employs in a tube-dilution assay the same cells used for the
slide test; and the sensitized sheep cell agglutination assay
uses in a tube-dilution assay sheep erythrocytes coated with
rabbit anti-sheep erythrocyte antibody.
The methods used for the purification of genomic
DNA from peripheral blood leukocytes, restriction enzyme
digestion with 3-5 units/pg of DNA, capillary blotting to
nylon membranes (Nytran; Schleicher & Schuell, Keene,
NH or Biodyne; Pall BioSupport, East Hills, NY), hybridization, and autoradiography have been previously reported
(18). Using the restriction enzyme Sac I, a C, probe (kindly
provided by Dr. P. Leder) (20) identifies variable alleles of 5
kb and 3.7 kb; the polymorphic Sac I site is telomeric to the
coding region of the constant segment (21).
The DR types of the additional patients and controls
had been previously determined and were confirmed by DRP
genotyping. As previously outlined (19), DR typing was
performed by detection of an allele-specific DRP pattern for
DR4 using Taq I and an exon-specific DRP probe (pRTV1;
generously provided by Dr. Jeffrey Bidwell) (22).
Using Bgl 11, a probe for the sole V, segment of
subgroup IV (the third V, of the B cluster, in the form of
mAF1/7; a kind gift from Dr. Hans Zachau) identifies variable alleles of 3.5 kb and 2.2 kb (Figure 1); this V, segment
B3 is known to be 24 kb centromeric (5’) to J, (23). The
adequacy of restriction enzyme digestion was ascertained by
the absence of fragments larger than 3.5 kb, demonstration
of the same patterns in multiple digests of the same speci-
Figure 1. Demonstration of B3 polymorphisms in 3 patients with
rheumatoid arthritis (lanes 1-3) and in 3 normal control subjects
(lanes 4-6),by Southern blot analysis with the restriction endonuclease Bgl 11 and the DNA probe derived from mAFlI7. B3
genotypes are 2.2/2.2-kb (lanes 1, 3, 4, and 9, 2.213.5-kb (lane 2),
and 3.5/3.5-kb (lane 6 ) .
mens, and detection of a monomorphic c-rnyc band on
reprobing the same blots used for the B3 genotyping.
Using the restriction enzyme Dru I, the CD8A probe
(pcDLeu2-14; kindly provided by Dr.Paula Kavathas) identifies variable alleles of 3.3 kb and 2.7 kb (24). By in situ
hybridization, the human CD8A gene is near the kappa
region of chromosome 2 (25); the proximity of the two loci is
confirmed by the observation that both were translocated to
human chromosome 8 in a Burkitt cell line (25). By linkage
analysis, CD8A is 5.5 centimorgans centromeric to C, (1 cM
represents 1% recombination) (26). The actual physical
distance between C, and CD8A is not known; by pulse-field
electrophoretic methods, the CD8A gene hybridizes to a
restriction fragment of a size different from that of any of the
fragments to which kappa-region probes hybridize (27).
Kappa allotypic markers (Km) were determined using a novel method of amplification of the C, segment by
polymerase chain reaction (PCR) followed by restriction
enzyme digestion with Acc I; for products lacking an Acc I
site, Mae I1 was also used (Moxley G, Gibbs R: unpublished
observations). Cleavage of the C, PCR product by Acc I
correlates with the allotypic marker Km(3), absence of
cleavage by Acc I and presence of a restriction site for Mae
I1 corresponds to the rare allele Km(l), and absence of both
Acc I and Mae I1 sites correlates with Km(1,2). There was
complete concordance with serologic results previously obtained in 19 Km(3)-positive persons and 4 Km( 1,3)-positive
persons (19); all the Km(l,3)-positive persons had PCR
products lacking a Mae I1 restriction site and were therefore
considered to have the more common Km(1,2) allele. The
serologically untypable person had Km(3).
with Yates’ correction, if
Statistical analyses
necessary) were performed with a microcomputer, using
NWA Statpak software (Northwest Analytical, Portland,
OR). Relative risk was calculated using the Woolf method (28).
Attributable risk was calculated as previously outlined (19).
Table 1. B3 and C, genotypes in HLA-DR4 subgroups*
B3 genotype
C, genotype in RA
C, genotype in DJD
and normal controls
Table 2. Km genotypes in rheumatoid arthritis (RA) patients and
RA patients
* RA = rheumatoid arthritis; DJD = degenerative joint disease (see
ref. 19).
Demographic characteristics and disease information for the populations studied are as previously
described (19), with the addition of DNA specimens
from 13 RA patients, for whom clinical information
was not available, and 13 normal subjects, resulting in
134 RA patients and 107 control subjects in total.
B3, Km, and C, genotypes in RA. As previously
reported, there was a significant difference in the
distribution of C, genotypes between RA and degenerative joint disease (DJD)/normal (control) groups @
= 6.1, 2 degrees of freedom [dfl, P < 0.05) (Table 1).
In the RA and DJDInormal groups combined, there
was no difference in the frequency of B3 genotypes or
alleles in the groups with a C, 5/5-kb genotype and a
C, 5/3.7-kb genotype, which indicates that there is no
significant deviation from linkage equilibrium. Among
B3 and Km genotypes in all subjects, the B3 2.2-kb
variable allele was associated with Km(3), and B3 3.5
kb with Km(1,2) (2 = 24.3, 6 df, P < 0.001). Among
Km and C, genotypes, there was linkage equilibrium
(2= 1.8, 8 df, P not significant).
If the elevated relative risk conferred by the
homozygous C, genotype detected by the telomeric
Sac I polymorphism is due to a nearby V, segment or
region, a polymorphic marker closer to or among V,
segments will similarly be associated with RA. The
distribution of Km genotypes, due to C, coding-region
variations, showed no difference between RA patients
and control subjects (Table 2), and the allelic frequencies were typical of results obtained serologically in
studies of Caucasian populations (29). The absence of
significantly elevated risk of B3 genotype (Table 3)
suggests that the association of homozygous C, genotype is not due to a rogue V, segment or region.
The distribution of combinations of C, and B3
Km(1 3 3 )
(n = 79)
(n = 54)
Control subjects
(n = 107)
genotypes showed a trend toward fewer heterozygotes
of C, or B3 in the RA group compared with the control
group, but this did not achieve statistical significance
(2 = 10.6, 6 do. There was also a trend toward
increased frequency of the homozygous genotype for
both C, 5-kb and B3 2.2-kb alleles in the RA group
(Table 3). The frequency of combined homozygosity
of both C, and B3 was higher in RA patients. The
relative risks for homozygous C, and homozygous
B3/C, were similar, but the 2 values were much
higher with the combined B3/C, homozygous state.
The attributable risks of combined B3/C, homozygosity and DR4 were similar (36% and 40%, respectively).
The homozygous genotype at B3, Km, and C, was
also more frequent in RA.
B3 and C, genotypes in seronegative RA. As
previously reported, all 16 RA patients who had negative slide agglutination test results for serum RF had
the homozygous C, 5-kb genotype (19); in this serologic subgroup of RA, the number with B3 genotypes
2.212.2 kb was 12, the number with 2.2/3.5 kb was 2,
and the number with 3.513.5 kb was 2. There was a
significant difference in the B3/C, genotype frequenTable 3. Relative risk of B3, Km, and C, genotypes in rheumatoid
Homozygous C, versus heterozygous C,
Homozvnous 8 3 versus heterozvaous 8 3
HomoGgous Km(3) versus
other Km genotype
Homozygous B31Km
Homozygous B3 2.2-kb/Km(3)
Homozygous W C ,
Homozygous Km(3)/C, 5-kb
Homozygous B3 2.2-kb/CK5-kb versus
other B31C, genotype
Homozygous B3lC, versus
heterozygous B3 or C,
Homozygous B3/Km/C,
Homozygous B3 2.2-kblKm(3)lC, 5-kb
* Relative risk (RR), versus controls, was determined according to
the method of Woolf (28). NS = not significant.
Table 4. Relative risk of €33 and C, genotypes in RA, according to
RF subgroup*
Slide-negative RA
Homozygous B3 2.2-kb/C, 5-kb
versus other genotype
Homozygous B3/C, versus
heterozygous B3 or C,
SHCA-negative RA
Homozygous B3 2.2-kb/C, 5-kb
versus other genotype
Homozygous B3/C, versus
heterozygous B3 or C,
* Slide-negative rheumatoid arthritis (RA) represents RA associated
with a negative result on slide agglutination test for serum rheumatoid factor (RF)(similar to a negative result on the latex test).
Sensitized human cell agglutination (SHCAbnegative RA represents RA associated with positive findings on slide test, but negative
findings on tube-dilution assay for serum RF, using human erythrocytes coated with anti-RhD antibody (Ripley). Relative risk (RR),
versus controls, was determined according to the method of Woolf
(28). NS = not significant.
cies among the seronegative RA, seropositive RA, and
control groups
= 23.1, 12 df, P < 0.025), with a
trend toward fewer heterozygous B3/CKindividuals in
the seronegative group compared with the controls (2
= 12.4, 5 df, P < 0.05). An additional 4 patients with
positive slide test results for serum RF but negative
tube-dilution assay results for serum RF had homozygous B3 2.2-kb/CK5-kb genotypes.
From unrelated studies of sera submitted for
clinical testing for RF, the R F level in sera with
positive slide-agglutination test results but negative
tube-dilution assay results is known to be low (30). For
further analyses, the group with negative slide test
results and the group with positive slide test results but
negative tube-dilution assay results were combined to
form an RA subgroup with low levels of serum RF.
Among the control group and the groups of RA patients categorized by serum R F levels, there were
fewer heterozygotes (2= 22.7, 12 df, P < 0.05). The
homozygous B3 2.2-kb/CK 5-kb genotype was more
common in the RA subgroup with low levels of serum
RF (Table 4). The homozygous B3/CKgenotype conferred more than twice the risk than did the homozygOuS B3 2.2-kb/CK5-kb.
B3, Km, and C, genotypes in DR subgroups. In
the DRCnegative RA subgroup (Table 5), there were
more patients with homozygous C, genotypes. There
was a trend toward more homozygous B3 and Km(3)
genotypes in the DR4-negative RA subgroup. There
was also a strong trend toward more Km(3)-bearing
chromosomes among DR4-negative RA patients (2=
6.2 for a difference among DRCnegative RA, DR4positive RA, and controls, 2 df, P < 0.05; relative risk
of Km(3) chromosome 3.8, 2 = 3.76, P < 0.1).
The distribution of combined B3 and C, genotypes between DR4-positive and DR4-negative control
groups was not different, and the controls were therefore combined. Among the DRCpositive RA, DR4negative RA, and control groups, there was a trend
toward fewer heterozygous individuals in the DR4negative RA subgroup (among the 3 groups 2 = 21.1,
12 df, P < 0.05; and between DR4-negative RA and the
controls ,$ = 17.6, 6 df, P < 0.01). The major
differences were that the DR4-negative RA subgroup
had more individuals with the homozygous B3/CK
genotype and fewer with the heterozygous genotype at
either or both restriction sites. There was an increased
frequency of the combined homozygous genotype for
C, 5-kb and B3 2.2-kb. The homozygous genotype for
both Km and C, was also more frequent (among the 3
groups 2 = 21.2, 12 df, P < 0.05), particularly the
Km(3) and C, 5-kb alleles.
B3 and C, haplotypes in RA. Haplotype analysis
was complicated by uncertainty for 4 RA and 5 DJR/
normal subjects who were doubly heterozygous at B3
and C,; the linkage phase of the C, and B3 alleles
could not be determined (that is, whether the respective alleles were cis or truns to each other). Because
most parents and siblings of the double heterozygotes
were unavailable for study, family studies to determine linkage phase could not be done. Regardless of
whether it was assumed that the C, 5-kb allele is on the
Table 5. Relative risk for B3 and C, genotypes in the DR4negative rheumatoid arthritis patient subgroup*
Hornozygous C, versus heterozygous C,
Hornozygous C, 5-kb versus other genotype
Homozygous B3 versus heterozygous B3
Homozygous B3 2.2-kb
Homozygous Km(3) versus other genotype
Hornozygous B3/Krn
Homozygous 8 3 2.2-kb/Km(3)
Homozygous B3 2.2-kb/C, 5-kb versus
other B3/C, genotype
Homozygous B3/C, versus
heterozygous B3 or C,
Hornozygous K d C ,
Homozygous Km(3)/C, 5-kb versus other
Homozygous B3 2.2-kb/Km(3)/Cn5-kb
versus other genotype
Homozygous B3/Km/C, versus
other genotype
3.9 <0.05
8.2 (0.005
3.9 12.7
4.8 10.9
4.2 9.8
3.0 9.4
3.7 12.3
* Relative risk (RR), versus controls, was determined according to
the method of Woolf (28). NS = not significant.
haplotype with the B3 2.2-kb allele or the 3.5-kb allele,
there was no significant difference in haplotype frequency between RA patients and controls, or among
RA patients and controls subgrouped according to the
presence or absence of DR4. Similarly, when the RA
and control groups were combined and the numbers of
specific B3/C, haplotypes were projected based on the
same assumptions, there was no statistically significant support for allelic association between B3 and C,
(assuming C, 5-kb with B3 2.2-kb 2 = 2.5; and
assuming C, 5-kb with B3 3.5-kb 2 = 2.6). In the
DR4-negative subgroup, the projected relative risk of
the B3 2.2-kb/C, 5-kb haplotype, assuming C, 5-kb
with B3 2.2-kb, was 1.9; assuming C, 3.7-kb with B3
2.2-kb, the projected relative risk was 2.1.
CDIA palymorphisms in RA. The possibility
that another polymorphic marker near C, might demonstrate an association with RA was considered.
There was no difference between 134 RA patients and
100 control subjects in the frequency of Dru I polymorphisms. The CDSA genotypes in the RA patients
and the control group of DJD patients and normal
subjects were as follows: 3.313.3 kb in 79 RA and 51
control subjects, 3.3/2.7 kb in 49 RA and 45 control
subjects, and 2.7/2.7 kb in 6 RA and 4 control subjects.
The allelic frequencies detected were almost identical
to those previously reported (3.3-kb was 0.76, 2.7-kb
was 0.24) (24).
The results of the present study indicate that
the homozygous B3/C, genotype confers risk for rheumatoid arthritis, particularly in HLA-DR4 negative
individuals. The use of C,, Km, and B3 polymorphisms allows definition of a segment of DNA that is
-30 kb long (extending from the polymorphic Bgl I1
site near B3 to the polymorphic Sac I site telomeric to
C,), which when present in a homozygous genotype,
that is, by recessive mechanism, confers a significantly
elevated risk for RA.
The possibility that the apparent disease association described is artifactual was considered; however, the statistical findings suggest that the apparent
difference is not random. Because the genotypes are
reproducible and the digestions were complete, as
assessed by reexamination of the same blots using a
monomorphic probe, misclassification seems unlikely,
The possibility that the different frequency of B3/C,
genotypes might be related to confounding factors in
genetic background was also a consideration. T cell
receptor (TCR) C, polymorphisms (located at human
chromosome 7q 35) detected by Kpn I show no difference between RA and DJD/normal subjects (for allelic
frequencies 2 = 0.93, P not significant) (31). The
allelic frequencies were similar to those previously
reported (32), and these observations confirm those
made by others using TCR C, and Bgl I1 (33,34). In
consideration of the similar frequencies of CDSA and
TCR C, alleles in RA patients and controls, and the
similarity of the DR4 frequencies to those in other US
white RA patient and control populations (6), no
significant differences in polymorphisms at other loci
were detected that would suggest differences in genetic background that are not disease-related. Therefore, the B3/C, genotype differences are most likely
due to disease association.
The mechanism of association with the homozygous B3/C, genotype is not known. The possibility of a rogue V, segment or region, a disease-related
difference among the variable segments of immunoglobulin kappa, was considered, but because the disease risk was not significant with either the B3 marker
alone or the associated Km allotype, there is no
evidence for such a disease-related region. The diseaserelated sequence might be reflected at another polymorphic marker genetically near C,, namely, CDSA;
however, there were no differences in the subgroups
Although 1% recombination represents an average of about 1 million basepairs, because of short
regions in which recombination occurs frequently (hot
spots), physical distance in basepairs does not necessarily correlate with genetic distance measured in
percent recombination (35). Because a small frequency of genetic recombination (less than 0.5%)
interferes with linkage disequilibrium (36), and thus by
inference, disease-association studies, the significant
association with C, and apparent lack of association
with the B3 or CDSA markers may be due to recombination between C,, B3, and CDSA. For the human
immunoglobulinheavy-chain region located on human
chromosome 14, the recombination frequency between variable-region markers and allotypic markers
of the IgG heavy chain has been estimated at 4% (36).
Physical mapping shows a hot spot between the most
V,-proximal constant segment C, and all of the C,
segments (37). Therefore, hot spots of recombination
exist among immunoglobulin gene segments other than
kappa. The putative disease sequence must be quite
close to the polymorphic Sac I site detected near C,.
The apparent linkage equilibrium among B3, C,, and
CDSA in unrelated persons suggests that the diseaseassociated segment is inherited on more than one
CDSNBYC, haplotype.
RA patients appear to have abnormal regulation
of bursa-derived lymphocytes (B cells). The synovial
tissue of persons with RA is characterized by the
presence of an inflammatory cell infiltrate of which a
significant fraction are B cells (median values 1617%)
(38,39). When cells released from synovial tissues of
persons with seropositive RA were compared with
those from persons with seronegative RA, the frequency of cells spontaneously producing RF was
much higher in seropositive than in seronegative patients (40).Explants of synovial tissue produce immunoglobulin in amounts similar to those generated by
lymphoid organs, but only a small fraction of immunoglobulin has RF activity (41,42). RA is often marked by
a polyclonal elevation of plasma immunoglobulin and
large amounts of R F in plasma, synovial fluid, and
synovial tissue (43).
The reason for the abnormal location and activation of B cells is not clear. Models of autoimmune
diseases suggest possible mechanisms for the occurrence of autoantibodies such as rheumatoid factors. In
a study of autoantibody production in murine models
of systemic lupus erythematosus (44),autoantibodyproducing cells were not present in abnormal proportions. There was a generalized increase in the number
of cells producing immunoglobulin, including not only
autoantibodies, but also antibodies directed toward
conventional antigens. This suggests that factors leading to polyclonal B cell hyperactivity may be more
important to autoimmune diseases than factors relating to immunoglobulin specificity. One may speculate
that B cell hyperactivity may be based not only on
response to cytokines ( 4 3 , but also on regulatory
sequences of immunoglobulin genes. Among the possible disease-related abnormalities consistent with the
data from the present study is an abnormality of a
kappa-enhancer region, such as the one located in the
intron between J, and C,. The enhancer region interacts with trans-acting factors so as to increase the
initiation of transcription (46); an abnormal enhancer
would be expected to act on all rearranged functional
transcriptional units, contributing to a polyclonal elevation of immunoglobulin of all specificities, and might
contribute to disease susceptibility.
Therefore, studies with additional DNA polyrnorphisms within or near C, provide data consistent
with the hypothesis that the homozygous genotype of
immunoglobulin kappa confers risk for RA and suggest
that the disease-related sequence may be close to, but
telomeric from, the kappa constant segment.
The author is appreciative for the identification and
recruitment of patients by members of the Division of
Rheumatology, Allergy and Immunology, to Dr. D. 0.
McDaniel for sending DNA specimens, and to Sharon
Nedzbala and Robert Gibbs for excellent technical assistance.
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constantin, associates, kappa, increase, variables, arthritis, immunoglobulin, segmento, genotypes, risk, rheumatoid
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