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HLA gene frequencies in children and adults with systemic onset juvenile rheumatoid arthritis.

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146
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HLA GENE FREQUENCIES IN CHILDREN AND
ADULTS WITH SYSTEMIC ONSET
JUVENILE RHEUMATOID ARTHRITIS
MARC L . MILLER, STEPHEN AARON, JEAN JACKSON, PATRICIA FRASER, LLOYD CAIRNS,
SUSAN HOCH, YVES BOREL, MARTIN LARSON. and DAVID N. GLASS
The HLA genetic region was studied in 51 patients with systemic onset juvenile rheumatoid arthritis:
35 with childhood onset and 16 with adult onset (adult
Still’s disease). HLA genotypes were established by
including family members, 261 of whom were also typed
in the study. The most marked difference between
patients and controls involved the HLA-DR4 gene,
which occurred with a frequency of 0.348 in the childhood onset patients and 0.170 in the controls (x2 = 8.97,
P = 0.0028, adjusted P = 0.017). In contrast, the adult
onset patients showed a marginal increase in HLA-DR7,
but were similar to controls with respect to HLA-DR4.
HLA-Bw35 was increased in children with systemic
onset disease, in accordance with earlier findings. The
results suggest that patients with systemic onset juvenile
rheumatoid arthritis have complex HLA associations
which are different in childhood onset and adult onset
disease.
~
~
_
_
_
From the Department of Rheumatology and Immunology,
Brigham and Women’s Hospital, the Department of Immunology,
Children’s Hospital Medical Center, the Department of Medicine
and Pediatrics, Harvard Medical School, and the Department of
Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
Supported by the Easter Seal Society, the Gebbie Foundation, the Leeder Foundation, the Lions Clubs of Massachusetts, the
New England Peabody Home for Crippled Children, and by NIH
grants AM-30486, CRUAM-05577, and Multipurpose Arthritis Center grant AM-20580.
Marc L. Miller, MD; Stephen Aaron, MD: Fellow of the
Canadian Arthritis Society; Jean Jackson, MD; Patricia Fraser, MD;
Lloyd Cairns, MD: Fellow of the New Zealand Arthritis Foundation; Susan Hoch, MD; Yves Borel, MD; Martin Larson, ScD;
David N. Glass, MD.
Address reprint requests to David N . Glass, MD, Brigham
and Women’s Hospital, 75 Francis Street, Boston, MA 021 15.
Submitted for publication November 14, 1983; accepted in
revised form August 24, 1984.
Arthritis and Rheumatism, Vol. 28, No. 2 (February 1985)
Since the first report of the influence of HLAB27 in juvenile rheumatoid arthritis (JRA) (l), all
clinically distinct forms of JRA have been associated
with HLA antigens. Considerable agreement about
HLA genetics exists in relation to pauciarticular and
polyarticular onset disease ( 2 ) , but there is less consensus about the HLA antigens associated with systemic onset JRA (2). In an earlier study (3), we
reported an increased frequency of HLA-Bw35 in
patients with systemic onset disease, but HLA-DR
alleles were not examined. An association with HLABw35 has been found in patients with the adult onset
form of the disease (adult Still’s disease) (4) and in
some (5,6), but not all series of patients with onset
during childhood (7-11). Most subsets of JRA have
stronger associations with HLA-DR, or HLA haplotypes including HLA-DR (2,12), than with HLA-A or
B alleles. Accordingly, HLA typing, including typing
for HLA-DR, was carried out in patients with systemic onset JRA and their families to ascertain diseaseassociated genes.
PATIENTS AND METHODS
Patients. Fifty-one white patients (24 female, 27
male) with systemic onset JRA were studied, as were 261 of
their relatives. Thirty-five of the probands had disease onset
during childhood and 16 as adults (i.e., after their sixteenth
birthday). Of the 35 subjects with childhood onset, 16 were
reported in an earlier study (3). The patients met the
American Rheumatism Association criteria for systemic
onset JRA (13). All but 5 had a fever of 2103”F, and all had
arthritis at some time in the course of the disease. Forty-two
patients had documented evidence of the rash typically
associated with the disease. An additional study criterion
was the availability and consent of enough family members
to establish the possible HLA genotypes.
HLA TYPE IN JRA
Probands and family members were typed for HLAA, B, C, and DR antigens in the Tissue Typing Laboratory of
the Department of Rheumatology and Immunology, The
Brigham and Women’s Hospital, Boston.
Family trees were constructed and haplotype assignments made for each locus when an informative assortment
of alleles was demonstrated. If an assignment could not be
made for a particular polymorphism, that haplotype was not
considered in calculating the gene frequencies for the locus.
The denominator used to calculate gene frequencies varied,
therefore, with polymorphisms being lower for some than for
others.
Control haplotypes. Controls consisted of 398 haplotypes that were established in families with a rheumatic
disease proband, but were not inherited by the proband. No
haplotype was counted twice, and 1 potential control haplotype that was in recombination with a proband’s haplotype
was excluded. This method of establishing control gene
frequency and control haplotype frequencies using the proband’s family has been compared with a method in which
haplotype frequencies are derived from families without an
affected member. Very comparable results have been obtained between the 2 methods (14). Control gene frequencies
for HLA-DR were also compared with HLA-DR data for
North American whites from the 8th International Histocompatibility Workshop ( 1 5 ) , and no significant differences
were found by the application of chi-square statistics (12).
Cells. Peripheral blood mononuclear leukocytes
(MNL) were obtained by density gradient centrifugation
through Ficoll-Paque (Pharmacia Fine Chemicals, Piscataway, NJ).
HLA-A, B, and C typing. HLA-A, B, and C typing
for 39 specificities was carried out by microdroplet complement-dependent cytotoxicity (16). HLA-A, B, and C antisera were kindly supplied by the National Institute for
Allergy and Infectious Diseases, NIH, Bethesda.
HLA-DR-typing. HLA-DR specificities were typed
by complement-dependent cytotoxicity on a nylon-wool B
cell-enriched MNL population (17,18). All preparations
studied were evaluated by complement-dependent cytotoxicity with a polyvalent rabbit anti-Ia serum kindly supplied
by Dr. J . Strominger (Biological Laboratories, Harvard
University), and were found to contain 70% Ia-bearing
MNL.
The antisera used to type for HLA-DR antigens were
either obtained locally or were the gifts of laboratories
worldwide. Antisera tested in both the 8th (15) and 9th (19)
International Histocompatibility Workshops were included.
Statistical methods. Gene frequencies (counts) for
the control series were compared separately with those of
childhood onset probands and adult onset probands by chisquare analyses of R x 2 tables (20,21). The number of
genes. R, depended on which HLA locus was being considered: A, B , C, or DR. Genes with <5% frequency were
pooled with those that could not be serologically defined; the
genes so pooled are labeled “other” in the tables.
Each control versus proband comparison yields a
chi-square statistic with R - 1 degrees offreedom (do to test
the distribution of genes in the 2 groups, but does not
indicate which specific gene frequencies differed. For this
we assessed individual contributions to chi-square, each
147
with 1 degree of freedom, computed as the sum in a specific
row of (0 - E)*/E for probands and controls. Ignoring the
“other” genes, there are R - 1 independent contributions
that can be evaluated. This avoids a common problem of
correlated tests in HLA analysis (22,23). However, several
individual tests were performed, so an adjusted P value
(P*[R - 11) was computed for each test to keep the “error
rate” at an acceptable level.
The relative risk (RR), or odds ratio, was computed
using Woolfs formula (24) for specific genes that had large
chi-square contributions.
RESULTS
HLA-A, B, C, and D frequencies are shown in
Tables 1, 2, 3, and 4, respectively.
Gene frequencies: childhood onset disease. Analyses of HLA gene frequencies comparing childhood
onset probands with controls gave the following results: HLA-A locus x2 = 5.91, 6 df, P = 0.43; HLA-B
locus x2 = 19.60, 10 df, P = 0.033; HLA-C locus x’ =
9.40,4 df, P = 0.052; HLA-DR locus x’ = 12.45,6 df,
P = 0.053.
The individual genes differing most between
probands and controls were HLA-Bw35, HLA-Bw44,
and HLA-DR4. The frequency of HLA-Bw44 was
0.235 in probands, compared with 0.128 in controls
(RR = 2.09, x2 = 4.64, P = 0.031, adjusted P = 0.31),
while the frequency of HLA-Bw35 was 0.191 in probands and 0.093 in controls (RR = 2.30, xz = 5.22, P =
0.022, adjusted P = 0.22). In the HLA-DR series
genes, HLA-DR4 occurred with a frequency of 0.348
in probands and 0.170 in controls (RR = 2.60, x2 =
8.97, P = 0.0028, adjusted P = 0.017).
Gene frequencies: adult onset diseases. The
results for individual HLA loci in adult onset probands
versus controls were: HLA-A locus x2 = 3.68, 6 df, P
= 0.72; HLA-B locus x2 = 16.38, 10 df, P = 0.089;
HLA-C locus x2 = 2.66, 4 df, P = 0.62; HLA-DR
locus x2 = 9.77, 6 df, P = 0.14.
Table 1. HLA-A gene frequencies in patients with childhood onset
and adult onset juvenile rheumatoid arthritis and control family
members
Gene
Childhood
onset
(n = 67)
Adult
onset
(n = 30)
Controls
(n = 392)
A1
A2,A28
A3
A9,A23,A24
AlO,A25,A26
All
Other A
0.164
0.418
0.090
0.090
0.060
0.090
0.090
0.167
0.267
0.233
0.167
0.033
0.067
0.067
0.153
0.301
0.135
0.143
0.087
0.066
0.115
148
MILLER ET AL
Table 2. HLA-B gene frequencies in patients with childhood
onset and adult onset juvenile rheumatoid arthritis and control
family members
Gene
Childhood
onset
(n = 68)
Adult
onset
(n = 30)
Controls
(n = 398)
0.015
0.067
0.133
0.167
0.067
0.2001
0.033
0.000
0.067
0.100
0.067
0.100
0.083
0.153
0.095
0.128
0.048
0.050
0.073
0.058
0.093
0.068
0.151
B5 (BwSl,Bw52)
B7
B8
B12 (Bw44)
B14
B15 (Bw62)
B17
818
Bw35
Bw40,Bw41 (B41)
Other B
* xz = 4.64, P
0. I32
0.118
0.235*
0.015
0.074
0.029
0.044
0.191$
0.059
0.088
= 0.031, P*lO = 0.31.
= 0.0009, P*10 = 0.009.
= 0.022, P*10 = 0.22.
7 xz = 11.07, P
t x*
= 5.22, P
HLA-B 14 was found with a frequency of 0.200
in probands and 0.048 in controls (RR = 4.96, x2 =
1 I .07, P = 0.0009, adusted P = 0.009), and the HLADR7 gene was present with a frequency of 0.286 in
probands and 0.135 in controls (RR = 2.57, xz = 4.08,
P = 0.043, adjusted P = 0.26). The HLA-DR4 gene
frequency was not increased in the adult onset patients.
DISCUSSION
The increased frequency of the HLA-DR4 gene
in children with systemic onset JRA is a new finding
which suggests that this disease represents an additional form of arthropathy which can be included with
those already associated with this major histocompatibility complex product (rheumatoid arthritis, polyarticular JRA, and psoriatic arthritis) (2). Two other
groups of investigators have observed higher levels of
HLA-DR4 in children with systemic onset JRA than in
control series, but in neither study did the data reach
acceptable levels of statistical significance (10,l I).
Table 3. HLA-C gene frequencies in patients with childhood
onset and adult onset juvenile rheumatoid arthritis and control
family members
Gene
-
cw2
cw3
cw4
cw5
Other C
-
Childhood
onset
(n = 60)
Adult
onset
(n = 23)
0.000
0.150
0.200
0.050
0.600
0.043
0.087
0.174
0.000
0.696
Control
(n = 331)
0.060
0.097
0.106
0.069
0.668
Those authors limited their studies to the disease
probands, and therefore could not give the data the
additional strength of numbers that determination of
gene frequencies allows in the present study. Since 6
of our patients are homozygous for HLA-DR4, the
family studies permitting calculation of exact gene
frequencies are of considerable advantage, especially
given that the number of patients available is limited.
The increase in HLA-Bw44 may result from its linkage disequilibrium with HLA-DR4 (25).
The increase in the frequency of HLA-DR4 in
this series, obtained by comparison with locally defined controls as described above, was based on a
control gene frequency of 0.170. This compares with
the 0.148 value for the gene frequency of HLA-DR4
found in the 8th International Histocompatibility
Workshop (15). In contrast to the children, the adults
with systemic onset JRA did not have an increased
frequency of HLA-DR4.
The increase in HLA-Bw35 is consistent with
the results of earlier studies ( 3 - 3 , including one study
which used some of the same subjects reported here
(3). Not all series have shown an increase in HLABw35 antigens, but studies (one in a small series of
adults [6] and one in childhood onset patients [9]) have
shown an association between HLA-DRS and systemic onset JRA; HLA-DRS is in linkage disequilibrium
with HLA-Bw35. It is also noteworthy that the HLABw35,Cw4 haplotype, with and without HLA-DR5, is
increased in young children with pauciarticular onset
JRA (12). The HLA-Bw44,DRS haplotype, which is
also found in early onset pauciarticular JRA (12), was
not present in any of the systemic onset patients in this
study.
Of the other HLA antigens, HLA-B14 and
HLA-DR7 are increased in frequency in patients with
Table 4. HLA-DR gene frequencies in patients with childhood
onset and adult onset juvenile rheumatoid arthritis and control
family members
Gene
DR 1
DR2
DR3
DR4
DR5
DR7
Other DR
* x2 = 8.97, P
t xz = 4.08, P
Childhood
onset
(n = 66)
Adult
onset
(n = 28)
Controls
(n = 364)
0.106
0.143
0.107
0.071
0.071
0.214
0.286t
0.107
0.154
0.115
0. I70
0.115
0.135
0.195
0.121
0.091
0.348*
0.091
0.136
0.106
= 0.0028, P*6 = 0.017.
= 0.043, P*6 = 0.26.
0.115
HLA TYPE IN JRA
the adult onset form of the disease, but not in the
childhood onset patients. HLA-I314 has not, to our
knowledge, previously been associated with JRA.
There is an earlier report of an association between
HLA-DR7 and systemic onset childhood JRA, and
HLA-DR7 is also associated with psoriatic arthritis
(7,2627). The numbers of adult patients available for
study are small, and these associations should be
considered as needing further confirmation, as should
those in the childhood onset group. This is true
particularly since at least two other studies, one from
Quebec (4) and the other from England (28), have not
found an association with HLA-DR7 in adult onset
patients.
As with HLA-DR4, the HLA-DR7 association
reported in this series is based on a comparison with
locally defined controls. It is noteworthy that the
control gene frequency for HLA-DR7 used as the
basis for comparing disease and non-disease populations, 0.135, is also very comparable with the 0.126
value obtained for North American whites in the 8th
International Histocompatibility Workshop ( 1 5).
The HLA genes associated with this group of
patients are not unique to systemic onset JRA, having
been associated with other arthropathies including
other forms of JRA. From this it could be argued that
the HLA region effect is limited to the articular
features of this illness, and not to its systemic effects.
A more complete understanding of this question will
evolve when the HLA haplotypes associated with all
forms of JRA have been more fully documented.
However, it can be concluded, much in agreement
with our earlier study ( 3 ) , that systemic onset JRA is a
genetically heterogeneous entity, at least with respect
to HLA type, and that this heterogeneity extends to
differences between the adult and childhood onset
forms of the disease.
ACKNOWLEDGMENTS
The assistance of Agnes Maier in the preparation of
this manuscript is gratefully acknowledged. The cooperation
of the following physicians in referring patients is very much
appreciated: Drs. Ronald Anderson, Arthur Hall, L. Fernandez Herlihy, Michael Kane, Lewis Landsberg, Arthur Morgan, Raymond Partridge, Martin Solomon, Tom Taylor, and
Michael Weinblatt.
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I49
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