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Extended haplotypes of chromosome 6 in adult rheumatoid arthritis.

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5 16
EXTENDED HAPLOTYPES OF CHROMOSOME 6 IN
ADULT RHEUMATOID ARTHRITIS
D. RAUM, Z. AWDEH, D. GLASS, G. KAMMER, M. A. KHAN, J. S. COBLYN, M. WEINBLATT,
D. HOLDSWORTH, L. STRONG, R. D. ROSSEN, E. BREWER, E. YUNIS, and C . A. ALPER
In 46 patients with rheumatoid arthritis (RA) the
allele C4B*3 occurred in 6 patients, while among 350
normal controls, it occurred 6 times (P < 0.00002).
Among 9 white and 1 black families, each of which had 2
or more members with RA, there were 36 haplotypes
associated with RA. An extended haplotype (specific
HLA-B, DR, complotype haplotypes in significant linkage disequilibrium) containing C4B*3: HLA-Bl5, DR4,
BF*S, C2*C, C4A*3, C4B*3, was found twice (P <
0.001) among whites with the disease-associated chromosomes.
In adult rheumatoid arthritis (RA) the incidence
of certain HLA antigens is increased. HLA-DR4 is
increased in both black and white patients (1-7). This
has been amply confirmed by a joint workshop (8) and
has been reviewed (9).
The major histocompatibility complex (MHC)
is a genetic system that consists of at least 5 HLA
From the Center for Blood Research; Departments of
Medicine, Pediatrics, and Pathology, Harvard Medical School; Beth
Israel Hospital; Brigham and Women's Hospital; Children's Hospital Medical Center and Dana-Farber Cancer Institute, Boston,
Massachusetts; M.D. Anderson Hospital, University of Texas at
Houston, and Veterans Administration Medical Center, Baylor
College of Medicine, Houston, Texas; Case Western Reserve University, School of Medicine, Cleveland, Ohio.
Supported by NIH grants AM26844, AI14157, AI15033,
CA19589, CA20531, CA06516, RR05410, CA32064, and AM30486;
and grants from the Irma Bender Arthritis Research Fund, the
Northeast Ohio Arthritis Foundation, the Veterans Administration
Merit Review Program, and the Kelsey Seybold Foundation No.
988. Dr. Kammer is a Deland Fellow of the American Philosophical
Society.
Address reprint requests to D. Raum, 800 Huntington
Avenue, Boston, MA 02115.
Submitted for publication June 6, 1983; accepted in revised
form January 10, 1984.
Arthritis and Rheumatism, Vol. 27, No. 5 (May 1984)
markers, 4 serum complement protein markers, and 1
red cell enzyme marker. Certain alleles of the HLA
genes occur in associaton with other alleles more often
than expected from their gene frequencies. Family
studies have suggested that this is due to nonrandom
association of specific alleles or linkage disequilibrium
(10).
There are 4 genes for 3 complement proteins in
this same chromosomal region, F W , C2, M, and
that are closely linked (no crossovers between
them have been observed in thousands of meioses),
and they are inherited and occur in populations as
haplotypes called complotypes ( I 1). Because these
genes are linked, the HLA-A, B, C , D, and DR
antigens and BF, C2, C4A, and C4B allotypes are
inherited as haplotypes, except in rare cases of crossovers during meiosis. Hence, each child receives a
haplotype from each parent.
In our studies of the alleles of loci on chromosome 6 we have found eight combinations of HLA-B,
DR BF C2 C4A, and C4B in whites, on haplotypes
which occur at frequencies significantly higher than
expected. These combinations are defined as extended
haplotypes, and each shows limited HLA-A variation.
The extended haplotypes are listed in Table 1 (12).
Two of these incorporate HLA-DR4.
It is of relevance to the present study that only 1
of these extended haplotypes, the haplotype HLAB15(W62), DR4, BF*S, C2*C, C4A*3, C4B*3 carries
the C4B*3 allele. Also, among 350 normal haplotypes
the C4B*3 allele is almost always part of this extended
haplotype. Recently, using data from random unrelated individuals with RA, it has been inferred that the
haplotype, HLA-A2, B15(W62), CW3, DR4, BF*S,
C2*C, C4A*3, C4B*3, is associated with RA (13, 14).
w,
-3
-7
-9
HAPLOTYPES OF CHROMOSOME 6 IN RA
Table 1. Extended haplotypes
HLA-B
ComDlotvDe
HLA-DR
Haplotype
frequency
B8
B7
B12 (W44)
B12 (W44)
817 (W57)
B40 (W61)
B14
B15 (W62)
SCOl
SC3 1
FC3 1
SC30
SC6 1
sco2
DR3
DR?
DR7
DR4
DR7
DRW6
DR 1
DR4
0.093
0.059
0.037
0.034
0.028
0.01 I
0.01 1
0.009
sc22
sc33
The present study demonstrates that the C4B*3 allele
is increased in RA patients selected at random, and
from studies in families identified with multiple cases
of RA, this extended haplotype has an increased
incidence in patients.
PATIENTS AND METHODS
Patients and families. Forty-six recently hospitalized
patients with classic or definite RA (15) at Brigham and
Women's Hospital were C4 allotyped. The families of 10
patients (9 white, 1 black) from Texas (16) and Ohio (17),
with classic or definite RA were complctely typed for MHC
markers. Eight of these families have been studied by Khan
and coworkers (17,18), and 1 by Rossen and coworkers (16).
Controls. The general population of control chromosomes came from 2 sources. Families recruited for reasons
other than a disease in 1 member, provided 166 control
chromosomes. An additional 184 chromosomes were obtained from families recruited because a member had a
disease, but only those chromosomes not occurring in patients were used. The frequencies of control markers from
these 2 sources were the same. For example, in normal and
nondisease chromosome populations the frequencies of the
extended haplotype B8, DR3, SCOl were 0.097 and 0.091;
those of B7, DR2, SC31 were 0.056 and 0.061; and those
of B12, DR7, FC31 were 0.042 and 0.034. The frequencies of
each allele and extended haplotype in the 2 populations were
compared. In each case these frequencies were not statistically different from one another ( P > 0.05). Hence, no bias
was introduced by combining normal and nondisease haplotypes in this study.
BF, C2, and C4 typing. Fresh or freshly frozen (at
-70°C) serum or EDTA plasma samples were subjected to
agarose gel electrophoresis at pH 8.6. and immunofixation
with goat antiserum to human factor B (Atlantic Antibodies,
Scarborough, ME) for BF typing (19). For C2 types, the
same samples were analyzed by isoelectric focusing in
polyacrylamide gels (20), and an overlay of agarose gel
containing EA and human serum diluted 1 :90 in isotonic
veronal buffered saline, pH 7.4, containing 0.1% gelatin,
IO-'M Mg++,and 1.5 x 10-4M Ca". Portions of the same
samples were treated with Closfridiirrn perfringens neuraminidase (Sigma Chemical Co., St. Louis, MO), 10 unitslml
for I5 hours at 4"C, prior to agarose gel electrophoresis at pH
517
8.6 and crossed irnmunoelectrophoresis for detection of halfnull haplotypes (21), or to agarose gel electrophoresis at pH
8.6 and immunofixation with anti-C4 (Atlantic Antibodies),
for detection of structural variants of C4A and C4B (22).
In whites, the C4 loci exhibit the most extensive
polymorphism of any serum proteins. There are three C4B
alleles with frequencies of 1% or more, and 5 or 6 common
C4A alleles. In addition, a large number of rare variants at
both loci have been identified. In an attempt to standardize
nomenclature, a joint statement formulated by almost all
active workers in the field has been issued (23). Numbers
progress from cathode to anode. Rare variants migrating
between 2 single numbered variants are given 2 numbers
beginning with that of the more basic neighbor. The second
number is assigned sequentially based on order of recognition. A new variant between 2 rare variants is given the 2
numbers of the more basic neighbor and a third sequentially
assigned number. Variants more basic than C4B 1 or C4A 1
are in the C4B 9 or C4A 9 series. The allele C4B*3 is the
same as that initially described by some workers as C4B*2.9,
and that initially called C4B*3, associated with congenital
adrenal hyperplasia, has been renamed C4B*3 1.
' The entire C4 system nomenclature is an expansion
of that originally proposed (22), and is designed to conform
to the nomenclature guidelines proposed and accepted by
the International Society of Human Genetics (24). Null
alleles are designated QO for quantity zero: C4A*QO and
C4B*Q0. Alleles. haplotypes, and genes are denoted by an
asterisk, and individual allotypes do not have an asterisk or
underline. Complotypes are given in arbitrary order as BF,
C2, C4A, C4B types and are written after the specific HLADR type to designate a given haplotype. The order of
presentation of the alleles in a designated haplotype has
nothing to do with their position on the chromosome since
these are tightly linked to HLA-DR; no crossovers have
been observed in thousands of meioses. Complotypes can be
presented in a shorthand form using the last letters, respectively, of the B F and C2 complement alleles, and the
numbers, respectively, of the C4A and C4B alleles. Thus,
SC42 represents the complotype
C4B*2.
GLO typing. Red cell lysates were spotted on cellulose acetate, and electrophoresis was performed in a 0.03M
Tris, 0.03M barbituric acid, 0.2 mM mercaptoethanol, 0.4
mM MgClz buffer at pH 8.0, at 200 volts for 1 hour, or until
albumin had run 10 cm. Plates were stained first with 0.02M
glutathione and 0.34M methylglyoxal in a 0.1M phosphate
buffer, pH 6.5, and then with 0.1 mM 3-[4,S-dimethylthiazolyl-2]-2,5-diphenyltetrazoliumbromide (MTT), 0.69 m M
2,4-dichlorophenolindophenol in a 0.1M Tris hydrochloride
buffer at pH 7.8 (25).
HLA-A, B, C, and DR typing. Routine typing was
performed using a modification of the NIH standard microlymphocytotoxicity test procedure. One hundred forty antisera were used for defining 19 A-locus, 28 B-locus, and 6 Clocus antigens. Routine HLA-DR typing was performed
using the technique of the Oxford (7th International Histocompatibility) Workshop (26). Seventy antisera (40 reference and 30 local) were used for defining 7 HLA-DR
antigens. Families 238-245 were HLA typed in Cleveland
(1 7,18).
518
RAUM ET AL
RESULTS
Of 46 patients typed for C4 alleles, the allele
C4B*3 occurred in 6. The gene frequency is 0.065.
Among 350 normal chromosomes, it occurred 6 times
(RR = 8.5, x2 = 17.62, P < 0.00002). No homozygotes
for C4B*3 were found in either population. The frequencies of other C4A and C4B alleles did not differ
from controls. Table 2 lists haplotypes found in the 10
families which were completely typed. In family 238,
the haplotype HLA-A2, CW3, B15, DR4, SC33 was
shared by all 3 members with RA. This is also true in
family 244. Another extended haplotype, HLA-(A 1
B8, DR3, SCOl, was shared by patients in family 237,
one patient in family 239, both in 241, and two in
family 243. Of other common extended haplotypes,
HLA-A2, B7, DR2, SC31 occurred once in family 238;
HLA-A2, BW44, DR7, FC31 occurred once in family
246; and HLA-A1, BW44, DR4, SC30 occurred once
in family 244. Hence, of the 33 haplotypes from
patients in white families, 9 were extended haplotypes.
Extended haplotypes are defined as specific HLA-B,
DR complotype combinations which have been found
in random populations at a frequency greater than
expected. Those detected so far are listed in Table 1 .
One or more patients shared an extended haplotype in the 8 white families in which all haplotypes
were determined. Figures I and 2 are pedigrees of
families who carry the HLA-Bl5, DR4, BF*S, C2*C,
C4A*3, C4B*3 haplotype. The 6 members of these 2
Table 2. Haplotypes of rheumatoid arthritis patients in multiple case families
Family
number*
237
Haplotype
A
C
D
238
239
240
24 1
B
C
F
G
B
D
C
A
C
D
B
A
D
242
243
244
C
A
C
B
D
C
D
F
A
B
C
D
245
246
B
A
C
A
B
D
X?
G
I
HLA-A
A2
Al
All
C
cw I
A1
A2
A2
AW24
AW31
A28
cw3
cw7
cw3
A1
Al
A2
A26
Al I
A3
A2
A2
A29
AW3I
A26
Al
A2
All
A?
A1
A2
A2
AW30
AW30
A2
Al
A2
A2
A2
A3
cw7
cw3
CW8
cw2
C W6
cw4
cw4
cw3
CW6
cw3
cw2
cw3
B
BW38
B8
B22
B8
B15
85
B7
B40
BW21
B8
B8
B40
BW44
B14
B27
B8
B W44
BW44
B14
B37
B38
B8
BW21
BW3S
BIS
BW44
B7
B15
B17
87
B 15
BW44
B8
BI5
BW44$
B40
B40
DR
DR2
DR3
DRS
DR3
DR4
DR4
DR2
DRX
DR4
DR3
DR4
DR4
DR4
DR 1
DR4
DR3
DR4
BF,C?,C4A,C4B
HFS,CZC,C4AQO,B1
BFS,C2C.C4AQO,B 1
HFS,C2C,C4A3,HI .221
scoI
sc33
s c 3I
SC3 I
SC30
s c 3I
scoI
sco I
GLO
1
Genotypes
of patients
AC,CD
2
2
BC.CF,CG
2
2
BD,DC
?
AC,AD.BD
SB42
s c 3I
AD.I)C
scn 1
SC42
AC,CB
DRW6
DRS
DR 1
DR3
DR 1
DR2
DR5
DR4
DRW6
DR4
DR4
DR5
DR5
DR7
DR4
DR 1
DRI
DR2
DR7
FC3 I
FC3 1
sco I
s c 31
SC3 1
SC30
SC30
s c 3I
sc33
FC34
FC3 1
FC3 1
FC3 I
SC30
SC42
SC42
SC3 1
s c 31
CIl.DF,CF
CD,BD,AD
BA,AC
1
2
2
2
2
2
BID.XZIB
AIB
GI1
* Pedigrees 238-244 have been referred to in previous publications (17,18) as family numbers 11, 111, I V , VI1, X , XI. and XII, respectively.
Pedigree 245 was a black family. All other pedigrees were white.
t A duplication of C4B occurs on this chromosome. The duplicated allele is rare with a mobility between B2 and B3 and is named B22.
$
Indicates location of crossover.
519
HAPLOTYPES OF CHROMOSOME 6 IN RA
A-HU-A3
B-HU-A1
CIHLA-AZ
D-HLA-AZ
E'HU-AZa
F-HL4-M
,
B S , D R2.
,
B8 , D R 3 ,
, 0 5 3 , B 1 5 , D R4,
, W3, 840 , DRS,
9
,
SC31
SCOl
SC33
SC42
W 4 , BU35, D W , S C 3 1
BS , D R4, S C 3 1
C-HLA-AWZ4,
H-HU-AZ
0 5 7 , B7 ,
BU46,
BUZZ,
840 ,
B7 ,
,
I-HLA-IJ ,
J-HU-AZ
, CU3,
c/F-Hu-AZ
, CU7,
DRZ,
DR2,
DR6,
DRS,
DR2,
SC31
SC31
FC
SC30
SC31
Figure 1. Family 238 with 3 individuals who have rheumatoid
arthritis (RA) and an additional individual havingjuvenile RA (JRA).
Each cames haplotype C with HLA-B15, DR4, SC33. This family
was previously referred to as I1 (17,W.
families with RA all shared the C4B*3-bearing haplotype. Since the gene frequency of C4B*3 in the normal
control population was 0.017, we calculated by the
Poisson distribution that finding two C4B*3 chromosomes among 33 RA-associated chromosomes, or two
C4B*3 propositi among 9 propositi, was highly significant ( P < 0.02 and P < 0.004).
DISCUSSION
An increase in a rare allele of the Q@ locus is
demonstrated in patients with RA. The C4B*3 allele is
in linkage disequilibrium with HLA-DR4. Family
studies show that in both instances in which it was
demonstrated, it was part of an extended haplotype
HLA-B15, DR4, BF*S, C2*C, C4A*3, and C4B*3.
The haplotype, which was inherited by the family
members with disease, is rare in normal individuals,
occurring in 6 of 350 control chromosomes from 267
individuals. Although the numbers are small, there
appears to be an increased frequency of this haplotype
in the disease population. Strictly parallel data from
other studies are not available, but Strom and Moller
in an investigation of 5 families, each with 2 or more
members with RA, noted 2 haplotypes containing
HLA-B15, DR4 among 15 identified in those with
disease (27). Those authors did not report complement
polymorphisms. Dry11 and colleagues have reported an
increased frequency of the haplotype HLA-A2, CW3,
B15, BF*S, DR4 in a preliminary report of data from
81 families with an RA proband (28).
Possible reasons for the association of MHC
alleles with disease states include both trivial causes
and pathogenetic mechanisms. Trivially, these could
arise by population stratification or recent intermixing
of 2 distinct populations. For instance, a population
carrying 1 group of MHC alleles on 1 chromosome and
a disease trait like thalassemia on a separate chromosome, when mixed with a population carrying neither
that set of MHC alleles nor the thalassemia trait, will
result in an association between the first group of
MHC alleles and thalassemia. Alternatively, associations of MHC alleles with diseases may arise by
linkage of MHC genes to disease susceptibility genes.
The particular associations could then be due to either
a specific MHC allele being implicated in the pathogenetic process, or to linkage disequilibrium of the
disease susceptibility gene with a specific MHC allele.
If the allele itself leads to susceptibility, it is expected
that the associated allele will not show profound
linkage disequilibrium with alleles of other loci on the
same 6th chromosome and that the associated allele
will be found in all racial groups.
We have recently demonstrated this for HLAB27 in which the distribution of complotypes suggests
that HLA-B27, or a gene very near to HLA-B27, must
participate in the pathogenesis of the B27-associated
spondylarthropathies (unpublished observations). If
the MHC allele shows linkage disequilibrium with a
susceptibility gene, the latter could be unrelated to the
MHC system as in hemochromatosis or congenital
adrenal hyperplasia. In this situation there could be a
strong familial linkage pattern but a lack of striking
allelic associations as in hemochromatosis, or strong
associations but with an extended haplotype.
The finding of an increased frequency of 1 or
more extended haplotypes in patients suggests that
such associations arose by a mechanism other than
linkage disequilibrium with a gene closely associated
with 1 MHC locus or another. This is the case in saltlosing, 2 1-hydroxylase deficiency congenital adrenal
hyperplasia in which an extended haplotype, rare in
I
RA
A
C'
A=HLA-AZ,
B-HLA-Al,
B
/C
A
/C
CW, B15
A
/C
, DR5 , SC30
BW44, DR4
, SC30
B
4
C-HLA-A2,
R
B
10
A
ID
B7
,
DRW6, SC31
, SC33
WHLA-IU, CW3. .B15 , D R 4
Figure 2. Family 244 with 3 individuals who have rheumatoid
arthritis (RA). Each cames haplotype D with HLA-B15, DR4,
SC33. This family was previously referred to as XI1 (17,18).
520
normal controls, is found in over 20% of patient
chromosomes (29). Moreover, an association may
arise because a susceptibility gene is an Ir or Ia gene
and is part of the MHC, as may be the case for insulindependent diabetes mellitus (IDDM) or RA. In this
case, examination of haplotypes is critical in determining the cause of the association. If an immune response gene is postulated to be very close to HLADR, then we would expect weaker association of the
disease with HLA-B, HLA-A, and glyoxalase. However, if entire haplotypes are found which are associated with the disease, then the disease susceptibility
gene could be anywhere along the extended segment,
and the cause of the association might be something
other than simple linkage disequilibrium of susceptibility genes with HLA-DR alleles.
We have recently demonstrated that IDDM
shows several extended haplotypes which explain a
large portion of all previously observed associations
(30). The haplotypes include HLA-A1, B8, DR3,
SCO1, GL02; HLA-B18, DR3, FlC30;and
HLAB15, DR4, SC33. There is a paucity of other extended
haplotypes such as HLA-A2, B7, DR2, SC31 among
diabetic patients. Similarly, in juvenile rheumatoid
arthritis (JRA) an association with a haplotype can be
shown in patients who have HLA-DR4 or HLA-DR5
(31). We have demonstrated here a similar finding in
classic adult rheumatoid arthritis in which a large
proportion of the association with HLA-B15, or C4B 3
is actually explained by an association with an extended haplotype. However, the majority of HLA-DR4
alleles in an RA population are not accounted for by
the presence of the haplotypes HLA-B15, DR4, SC33
and HLA-BW44, DR4, SC30.
The cause of these extended haplotypes is still
in doubt. However, we have proposed that, in addition
to other previously recognized mechanisms for the
generation and maintenance of such haplotypes (selection for immune response or other advantageous
genes, recent mutation, and others), features similar to
those exhibited by murine t-mutants may be important
(1 1,321. Two such features, a positive transmission
bias from the male and crossover suppression for a
large segment of the human 6th chromosome, are
sufficient to explain a number of phenomena and
characteristics of the major histocompatibility complex in humans. These features may result in a genetic
“black hole” (i.e., deleterious mutations may fall in,
but they may not get out again), resulting in the
accumulation of several deleterious mutations on 1
extended haplotype. This would account for the com-
RAUM ET AL
mon occurrence of HLA-B15, DR4, SC33 in both
IDDM and RA. The presence of extended haplotypes
provides at least a partial explanation for the observed
linkage disequilibria in different human populations,
and for much of the observed HLA allele-disease
associations (including the “protective” effects of
certain alleles). The extent to which this is so in RA is
a matter for further investigation.
ACKNOWLEDGMENTS
We thank Ms Deborah Marcus, Catherine Ramaika,
and Rosanne Stein for expert technical assistance, and Diane
Sullivan for preparation of this manuscript.
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