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Major histocompatibility complex associations with primary antiphospholipid syndrome.

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124
CONCISE COMMUNICATION
Major histocompatibility complex associations with
primary antiphospholipid syndrome
The antiphospholipid syndrome is characterized by
venous and arterial thromboses, recurrent fetal loss, thrombocytopenia, and the presence of autoantibodies to cardiolipin (aCL) and other negatively charged phospholipids (1).
While this syndrome is mainly seen in patients with systemic
lupus erythematosus (SLE), it is also seen in a group of
patients who do not manifest any of the major clinical or
serologic features of SLE, a condition referred to as a
primary antiphospholipid syndrome (PAPS) (2). Recent
studies have shown an association between the presence of
aCL and HLA-DR7 (3) as well as DR4 ( 4 3 , and a negative
association with DR3, in different populations. Both HLADR4 and DR7, which are coded for by the DRBl gene, are in
strong linkage disequilibrium with the DRw53 allele of the
DRB4 gene (6), suggesting a predisposing role for DRw53 in
aCL positivity. Two recent studies have documented an
association between PAPS and DRw53 (7) and DQw7 (8).
To investigate the relative contributions of the major
histocompatibility complex (MHC) class I1 and class I11
genes to aCL positivity, we determined the DR and DQ
genotypes and MHC class I11 gene polymorphisms in 13
English patients with PAPS and in 69 racially and geographically matched adult control subjects. Patients with PAPS
conformed to the criteria we proposed in 1989 (1). They
presented essentially with thromboses (venous/arterial),
which often were recurrent, and/or with recurrent fetal loss.
They did not have any of the typical clinical or serologic
features of SLE. The lupus anticoagulant was measured
according to the method of Exner et a1 (9) and the aCL
according to our previously described method (10). Twelve
of the 13 patients had both the lupus anticoagulant and aCL;
the remaining patient had only the lupus anticoagulant. All
patients with positive aCL had moderate to high elevations
of IgG aCL, which in 2 of them, was accompanied by low
levels of IgM aCL.
HLA-DR and DQB alleles were identified by restriction fragment length polymorphism (RFLP) analysis, using
Taq I-digested DNA with complementary DNA probes for
the DRB and DQB genes, and sequence-specific oligonucleotide probing of DNA fragments amplified by the polymerase chain reaction, as described previously (11). MHC class
111 gene polymorphisms were identified by Taq I RFLP
analysis using probes for the complement component C4 and
steroid 21-hydroxylase genes (12). (The DRB, DQB, C4, and
21-hydroxylase gene probes were kindly donated by J. L.
Bidwell, UK Transplant Service, Bristol, A. Jonsson, Swedish University of Agricultural Sciences, Uppsala, and R. D.
Campbell, Oxford University.)
Significant differences in genotype frequencies in
patients and controls in this study were limited to the HLA
class I1 region of the MHC. The frequencies of the DRB and
DQB alleles in patients and controls are shown in Table 1.
Using these techniques, DRl cannot be distinguished from
DRBr, DRw52a cannot be distinguished from DRwSZc, and
some DR7 polymorphisms cannot be distinguished from
DR9; so, the frequencies of these alleles were combined.
Two significant differences in HLA class I1 allele
frequencies in these patients were noted. HLA-DR4 was
present in 10 of 13 patients compared with 25 of 69 controls
(2= 7.704; P < 0.01), and DRw53 was present in 12 of 13
patients compared with 44 of 69 controls (2= 4.115; P <
0.05). Due to the small number of patients tested, these
comparisons d o not remain significant after correction for
multiple testing. The one patient negative for DRw53 had
only the lupus anticoagulant, but was aCL negative. HLADR3 was absent in all patients, and the frequencies of
HLA-DRw52 a or c and DRw52 b were reduced; however,
neither decrease was statistically significant.
N o significant associations between any DQB alleles
Table 1. HLA-DR and DQB allele frequencies (% positive) in 13 patients with primary
antiphospholipid syndrome (PAPS) and in 69 healthy control subjects
DRB allele
PAPS
patients
Control
subjects
DQB
allele
PAPS
patients
Control
subjects
DRllDRBr
DR2 (DRwlS)
DR2 (DRwl6)
DR3 (DRwl7)
DR4
DR5 (DRw11)
DR5 (DRw 12)
DRw6 (DRw 13)
DRw6 (DRw 14)
DR7/DR9
DRw8
DRwlO
DRw52 a/c
DRw52 b
DRw53
15.4
15.4
0
0
76.9*
0
7.7
23.1
1.7
38.5
1.7
0
23.1
15.4
92.3t
23.2
27.5
2.9
23.2
36.2
7.2
2.9
14.5
5.8
31.9
7.2
1.4
27.5
34.8
63.8
DQB I *050 I
0502
0503
0601
0602
0603
0401
15.4
0
7.7
0
15.4
15.4
1.7
15.4
53.8
46.2
23.1
0
0402
0
24.6
I .4
5.8
0
27.5
5.8
7.2
42.0
30.4
29.0
11.6
0
4.3
* P < 0.01. relative
t P < 0.05, relative
risk = 5.8, versus controls.
risk = 6.8, versus controls.
Arthritis and Rheumatism, Vol. 35, No. 1 (January 1992)
0604
020 1
0301
0302
0303
CONCISE COMMUNICATION
125
or C4 or 21-hydroxylase gene polymorphisms and PAPS
were found. DR3, DRw52a, and deletion of the C4A gene,
which are strongly associated with SLE in Caucasoid and
black populations, were decreased in our patients, which is
further evidence for a different immunogenetic predisposition as compared with definite SLE. DR4 is generally linked
with DQB1*0301 (DQw7) or DQB1*0302 (DQw8) in Caucasoids (13). The frequencies of both these alleles are slightly
raised in patients compared with controls, indicating that the
high incidence of DR4 is not due to an increase in the
frequency of one particular DR4 haplotype.
Although the frequency of DQw7 is increased, confirming the report by Arnett et al @), our findings suggest
that this increase is due to linkage disequilibrium between
DR4-DRw53 and DQw7, and that the DR locus is more
strongly associated with PAPS than is the DQB locus.
Furthermore, the highest relative risk for PAPS is conferred
by the DRw53 allele, which was present in all aCL-positive
patients, suggesting that this allele may play a direct role in
mediating an autoimmune response to phospholipids. These
are preliminary data and must be interpreted with caution
because of the small number of patients tested; however, the
data are consistent with a role for the DRB4 gene in the
expression of aCL.
R. A. Asherson, MD, FACP, FCP(SA)
The Rayne Institute, St. Thomas’ Hospital
D. G. Doherty, MSc
D. Vergani, MD, PhD
King’s College Hospital
M. A. Khamashta, MD, PhD
G. R. V. Hughes, MD, FRCP
The Rayne Institute, St. Thomas’ Hospital
London, U K
1. Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RHWM,
Machin SJ, Barquinero J, Out HH, Harris EN, Vilardeu-Torres
M, Hughes GRV: The “primary” antiphospholipid syndrome:
major clinical and serological features. Medicine (Baltimore)
68:36&374, 1989
2. Asherson RA: A “primary” antiphospholipid syndrome. J
Rheumatol 15: 1742-1746, 1988
3. Savi M, Ferraccioli GF, Neri TM, Zanelli P, Dall’Aglio PP,
Tincani A, Balestrieri G, Carella G, Cattaneo R: HLA-DR
antigens and anticardiolipin antibodies in northern Italian systemic lupus erythematosus patients. Arthritis Rheum 31: 15681570, 1988
4. McHugh NJ, Maddison PJ: HLA-DR antigens and anticardiolipin antibodies in patients with systemic lupus erythematosus
(letter). Arthritis Rheum 32:162%1624, 1989
5. McNeil HP, Gavaghan TP, Krilis SA, Geczy AF, Chesterman
CN: HLA-DR antigens and anticardiolipin antibodies. Clin Exp
Rheumatol8:425-427, 1990
6. Bidwell JL: DNA-RFLP analysis and genotyping of HLA-DR
and DQ antigens. Immunol Today 9:18-23, 1988
7. Goldstein B, Smith CD, Sengar DPS: MHC class I1 studies of
primary antiphospholipid antibody syndrome and of serum
antiphospholipid antibodies in systemic lupus erythematosus
(abstract). Arthritis Rheum 33 (suppl9):S125, 1990
8. Arnett FC, Olsen ML, Anderson KL, Reveille JD: Molecular
analysis of major histocompatibility complex alleles associated
with the lupus anticoagulant. J Clin Invest 87:1490-1495, 1991
9. Exner T, Rickard KA, Kronenberg H: Studies on phospholipids
in the action of a lupus coagulation inhibitor. Pathology 7:319328, 1975
10. Gharavi AE, Harris EN, Asherson RA, Hughes GRV: Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 46:1-6,1987
11. Doherty Mi,Donaldson PT: HLA-DRB and DQB typing by a
combination of serology, restriction fragment length polymorphism analysis and oligonucleotide probing. Eur J Immunogenetics 18: 1 11-124, 1991
12. Schneider PM, Carroll MC, Alper CA, Rittner C, Whitehead
AS, Yunis EJ, Colten HR: Polymorphism of the human complement C4 and steroid 21-hydroxylase genes: restriction fragment length polymorphism revealing structural deletions, homoduplications, and size variants. J Clin Invest 78:650-657,
1986
13. Todd JA, Bell JI, McDevitt HO: HLA-DQ beta gene contributes
to susceptibility and resistance to insulin-dependent diabetes
mellitus. Nature 329599404. 1987
Erratum
In the article by Walz-LeBlanc et al in the October 1991 issue of Arthritis and Rheumatism (Walz-LeBlanc
BAE, Reynolds WJ, MacFadden DK: Allopurinol sensitivity in a patient with chronic tophaceous gout: success
of intravenous desensitization after failure of oral desensitization. Arthritis Rheum 34:1329-1331, 1991), Dr.
LeBlanc’sdegrees and affiliations were listed incorrectly.The footnote listing this information should have read
as follows: “Barbara A. E. Walz-LeBlanc, MD, FRCP(C): former Rheumatology Fellow, Toronto Western
Hospital (currently Geoff Carr Lupus Fellow, Wellesley Hospital, Toronto).” We regret the error.
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