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Gm allotypes in white patients with systemic lupus erythematosus.

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828
BRIEF REPORT
Gm ALLOTYPES IN WHITE PATIENTS WITH SYSTEMIC LUPUS
ERYTHEMATOSUS
PETER H. SCHUR, JANARDAN P. PANDEY, and JOSEPH A. FEDRICK
There is increasing evidence that genetic factors may play some role in the pathogenesis of systemic lupus erythematosus (SLE). The observations that
support this hypothesis include: an increased concordancy of SLE in identical twins (1); an increased
frequency of SLE and autoimmune phenomena in
relatives of SLE patients (2); an increased frequency
of certain sixth chromosomal markers, including
IILA-B8, HLA-DR3, and HLA-DR2, C2 deficiency,
C4 deficiency, and parental HLA haplotype sharing
(3-7); and decreased levels of red blood cell receptors
for C3b (8). Based on mathematic considerations,
Winchester (9) has suggested that there are 4 genes
involved in the pathogenesis of SLE (9). A number of
recent studies have suggested that immunoglobulin
genes may also contribute to the expression of SLE
among Japanese, Australians, and black Americans
(10-12). With these observations and with the knowledge that different ethnic groups have a distinct array
of Gm phenotypes, we examined a group of white
American SLE patients to determine whether there
-
From the Robert B. Brigham Division of Rheumatology and
Immunology, Brigham and Women’s Hospital, Harvard Medical
School, Boston, Massachusetts, and the Department of Basic and
Clinical Immunology and Microbiology, Medical University of
South Carolina, Charleston, South Carolina.
Supported in part by NIH grants AM-11414, AM-05577,
AM-20580. AI-18727, AI-18940, and by grants from the Lupus
Foundation of America.
Peter H. Schur, MD; Janardan P. Pandey, MD; Joseph A.
Fednck, MD.
Address reprint requests t o Peter H. Schur, MD, Department of Rheumatology, Brigham and Women’s Hospital, 75 Francis
Street. Boston, MA 02115.
Submitted for publication October 9, 1984; accepted in
revised form January 18, 1985.
Arthritis and Rheumatism, Vol. 28, No. 7 (July 1985)
was an association between Gm and Km phenotypes
and the presence of SLE or any features thereof.
PATIENTS AND METHODS
Patients. The study population consisted of 104
white SLE patients from the New England region of
the United States; this population has been previously
described (3). All of the patients had antinuclear
antibodies and fulfilled at least 4 of the American
Rheumatism Association criteria for the classification
of SLE (13). All patients had been HLA typed (3).
Controls. Normal controls consisted of laboratory personnel, physicians, and allied health professionals employed at the Brigham and Women’s Hospital who had been HLA typed (for other purposes) and
who lived in the same communities as the patients.
Ig allotyping. Serum samples (diluted 1 : 16)
from patients and controls were typed for IgG (Gm)
and kappa light chain (Km) allotypes by our standard
hemagglutination inhibition assay, using reagents
shown in Table 1, which have been described elsewhere (14). We used the notations for human allotypic
determinants recommended by the World Health Organization (15). All subjects were typed for the following markers: Glm(1, 2, 3 , 17), G3m(5, 6, 13, 21), and
Km( 1).
Clinical and laboratory associations. Patients
were examined for possible associations with the
following clinical symptoms: arthralgialarthritis, skin
lesions including butterfly rashes and discoid lesions,
pleurisy, pericarditis, Raynaud’s phenomenon, alopecia, seizures, photosensitivity, and mouth ulcers, as
well as sex and age at onset of disease. We also sought
possible associations with the presence of the follow-
BRIEF REPORTS
829
Table 1. Reagents used in Gm and Km allotyping
Alphameric*
Numeric
Agglutinator
Anti-D
1
2
3
17
5
6
13
14
21
Pan
2135
Aus
Pon
Har
And
Gib
Beu
L37A 16
Bar
Bar
Jac
Bar
Hun
Ada
RH
RH
Bar
Cla
Roe
Gm antigen
a
X
f
z
bl
c3
b3
b4
g
Km antigen
1
1
* Nomenclature from the World Health Organization meeting, Rou-
were corrected for the number of comparisons made,
i.e., 5, all of these comparisons remained significant.
There was no apparent association between
Km(1) and the occurrence of SLE.
There was no apparent association between any
Gm or Km marker and the clinical, laboratory, and
immunologic factors examined. There was no apparent interactive effect of Gm and HLA (A, B, and DR
markers) by relative risk (chi-square) and log linear
analyses.
DISCUSSION
en, France, July 1974.
ing laboratory indicators: positive LE cells, falsepositive VDRL serology, positive Coombs’ test, rheumatoid factors, urinary abnormalities, antibodies to
DNA, Sm, and RNP, elevated blood urea nitrogen
levels, decreased platelets, leukopenia, anemia, and
decreased serum complement levels.
Statistical analysis. Associations, relative risks
(3), and interactive effects were calculated using chisquare analysis, Wilcoxon test, t-test, and log linear
analysis, using the SAS program on an IBM 4341
machine and the Loglin 1.6 log linear analysis program
on a DEC-VAX 11780 machine.
RESULTS
The distribution of Gm phenotypes in the SLE
patients was different from that of controls (Table 2).
This was true for all Gm phenotypes as a group (x2 =
15.2:,P = 0.004), as well as for the decreased frequency of Gm 3;5,13 (x2 = 10.4; P = 0.001) and for the
increased frequency of Gm 1,3,17;5,13,21 (x2 = 12.3,
P = 0.0005) in the patient group. When these P values
Table 2. Frequency of Gm phenotypes in systemic lupus
erythematosus patients and normal controls
Phlenotype
1,17;2! I
1,2,17;21
3;5,1:1
1.3.175.13.2 1
1,2,3,17;5,13,21
*P
tP
=
0.001.
= o.Ooo5.
Patients
(n = 104),
no. (%)
5 (4.8)
2 (1.9)
33 (31.7)
52 (50.0)
12 (11.5)
Controls
(n = 70),
no. (%)
1 (1.4)
2 (2.9)
40 (57. I)*
17 (24.3)t
10 (14.3)
Relative
risk
-
-
0.36
3.2
-
The decreased frequency of Gm 3;5,13 and
increased frequency of Gm 1,3,17;5,13,21 in SLE
patients, compared with the control population, suggests that the former is associated with resistance to
the disease and the latter with disease susceptibility.
The most probable genotype of the Gm 3;5,13 pheno3
that of the Gm 1,3,17;5,13,21
type is ~ ~ 3 : 5 , 1 3 / 3 : 5 , 1and
Our observations can be
phenotype is G1121717:21/3;5713.
explained by postulating a recessive disease-resistant
gene in linkage disequilibrium with the Gm 3;5,13
haplotype and a dominant disease-susceptible gene in
linkage disequilibrium with the Gm 1,17;21 haplotype.
Our observations are compatible with those
described by others (10-12) in that we have found an
association between Gm and SLE; however, as expected, the Gm phenotypes involved in disease
expression in white SLE patients are different from
those in SLE patients of other ethnic groups. Moreover, unlike the findings among Australian subjects
(1 l), we found no evidence of an additive effect of Gm
and HLA in a person’s susceptibility to SLE. This
may be due to a greater genetic heterogeneity in whites
in the United States than in their Australian counterparts.
Acknowledgments. We thank Drs. A. G. Steinberg,
E. van Loghem, and J. P. Salier for generously providing
certain reagents used in the allotyping assays.
REFERENCES
1. Block SR, Winfield JB, Lockshin MD, D’Angelo WA,
Christian CL: Studies of twins with systemic lupus
erythematosus: a review of the literature and presentation of 12 additional sets. Am J Med 59533-552, 1975
2. Arnett FC, Shulman LE: Studies in familial systemic
lupus erythematosus. Medicine (Baltimore)55:313-322,
1976
3. Schur PH, Meyer I, Garovoy M, Carpenter CB: Associations between systemic lupus erythematosus and the
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263-275, 1982
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Rheum 25:1031-1040, 1982
Glass D, Raum D, Gibson D, Stillman JS, Schur PH:
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58:853-861, 1976
Dawkins RL, Christiansen FT, Kay PH, Garlepp M,
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associations with complotypes, supratypes and haplotypes. Immunol Rev 705-23, 1983
Schur PH, Carpenter CB: Sharing of HLA haplotype by
parents of patients with systemic lupus erythematosus.
Arthritis Rheum 26:1104-1110, 1983
Wilson JG, Wong WW, Schur PH, Fearon DT: Mode of
inheritance of decreased C3b receptors on erythrocytes
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Winchester RJ: Genetic aspects, The Clinical Manage-
BRIEF REPORTS
ment of Systemic Lupus Erythematosus. Edited by PH
Schur. New York, Grune & Stratton, 1983, pp 17-27
10. Nakao Y, Matsumoto H, Miyazaki T, Nishitani H,
Takatsuki K, Kasukawa S, Nakayama S, Izumi S, Fujita
T, Tsuji K: IgG heavy chain allotypes (Gm) in autoimmune diseases. Clin Exp lmmunol 42:20-26, 1980
11. Whittingham S, Mathews JD, Schanfield MS, Tait BD,
Mackay IR: HLA and Gm genes in systemic lupus
erythematosus. Tissue Antigens 2150-57, 1983
12. Fedrick JA, Pandey JP, Chen Z, Fudenberg HH, Ainsworth SK, Dobson RL: Gm allotypes in blacks with
systemic lupus erythematosus. Hum Immunol 8: 117181, 1983
13. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ,
Rothfield NF, Schaller JG, Tala1 N , Winchester RJ: The
1982 revised criteria for the classification of systemic
lupus erythematosus. Arthritis Rheum 25: 1271-1277,
1982
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HH: Gm and Km frequencies in a Portuguese population. Hum Genet 61:154-156, 1982
15. WHO Group: Review of the notation for the allotypic
and related markers of human immunoglobulins. Eur J
Immunol 6599-601, 1976
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