Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: A Disintegrin and Metalloprotease 33 (ADAM33) is a member of a family of genes that encode membrane-anchored proteins with a disintegrin and a metalloprotease domain, and is located on chromosome 20p13. Recently, the polymorphisms in Adam33 have been found to be associated with asthma. Among the rheumatic diseases, systemic lupus erythematosus (SLE) is a prototypic Th2-mediated autoimmune disease like allergic disorders. To assess whether genetic functional variants of ADAM33 are associated with susceptibility to SLE or development of specific phenotypes in patients with SLE.
Methods: We have identified 48 SNPs, and nine SNPs were selected with regard to the LD pattern. Genotyping for g.10918G>C, g.12433T>C and g.13506C>G in the ADAM33 gene was conducted with PCR-RFLP methods, and genotyping for g.-330C>T, g.517 A>G, g.8227 G>A, g.9511 G>T, g.12462 C>T, g.12988 C>A polymorphisms was performed by single-base extension (SBE), using the ABI PrismR SNaPshotTM Multiplex kit (Applied Biosystems). We conducted an association study for ADAM33 polymorphisms in 190 SLE patients, 469 healthy controls, and 390 rheumatoid arthritis (RA) patients as a disease control. Haplotype analyses of related variants were performed as well.
Results: Significant associations of ADAM33 polymorphisms with susceptibility to SLE were found at g.8227 G>A, g.12988 C>A, and g.13506 C>G (P value were all below 0.001) (Table 1). Polymorphisms at g.8227 G>A was associated with the ANA titers among SLE patients (P = 0.012). In addition, we analysed the haplotype, and found a positive association of susceptibility to SLE with the major haplotype CGCG (P = 3.5E-11) (Table 2). There was no association between ADAM33 polymorphisms and RA as expected.
Conclusion: ADAM33 polymorphisms were strongly associated with susceptibility to SLE and the development of specific clinical manifestations.
Table 1. Genotype and allele analyses of the polymorphisms of Adam33 gene in SLE patients and healthy controls
|
Positiona |
Genotype /Allele |
Control n (%) |
<>SLE
<>n (%) |
<>Odds ratiob
(95% CI) |
<>P |
|
g.-330C>T |
CC |
426 (90.8) |
168 (88.4) |
1.00 |
0.347 |
|
CT |
43 (9.2) |
22 (11.6) |
1.30(0.75-2.24) |
||
|
TT |
0 (0.0) |
0 (0.0) |
– |
||
|
C |
895 (95.4) |
358 (94.2) |
1.00 |
0.399 |
|
|
T |
43 (4.6) |
22 (5.8) |
1.28(0.75-2.17) |
||
|
g.517 A>G |
AA |
165 (38.4) |
62 (32.6) |
1.00 |
0.392 |
|
AG |
201 (46.7) |
97 (51.1) |
1.29(0.88-1.88) |
||
|
GG |
64 (14.9) |
31 (16.3) |
1.29(0.77-2.17) |
||
|
A |
531 (61.7) |
221 (58.2) |
1.00 |
0.256 |
|
|
G |
329 (38.3) |
159 (41.8) |
1.16(0.91-1.49) |
||
|
g.8227 G>A |
GG |
300 (64.1) |
122 (65.2) |
1.00 |
> 0.0001
|
|
GA |
168 (35.9) |
59 (31.6) |
0.86(0.60-1.24) |
||
|
AA |
0 (0.0) |
6 (3.2) |
– |
||
|
G |
768 (82.1) |
303 (81.0) |
1.00 |
0.692 |
|
|
A |
168 (17.9) |
71 (19.0) |
1.07(0.79-1.46) |
||
|
g.9511 G>T |
GG |
390 (84.2) |
156 (87.6) |
1.00 |
0.093 |
|
GT |
71 (15.4) |
19 (10.7) |
0.67(0.39-1.15) |
||
|
TT |
2 (0.4) |
3 (1.7) |
3.75(0.62-22.66) |
||
|
G |
851 (91.9) |
331 (93.0) |
1.00 |
0.563 |
|
|
T |
75 (8.1) |
25 (7.0) |
0.86(0.54-1.37) |
||
|
g.10918 G>C |
GG |
275 (59.4) |
98 (61.3) |
1.00 |
0.271 |
|
GC |
172 (37.1) |
52 (2.5) |
0.85(0.58-1.25) |
||
|
CC |
17 (3.7) |
10 (6.2) |
1.65(0.73-3.23) |
||
|
G |
722 (77.8) |
248 (77.5) |
1.00 |
0.938 |
|
|
C |
206 (22.2) |
72 (22.5) |
1.02(0.75-1.38) |
||
|
g.12433 T>C |
TT |
391 (85.2) |
178 (92.7) |
1.00 |
0.025
|
|
TC |
66 (14.4) |
13 (6.8) |
0.43(0.23-0.81) |
||
|
CC |
2 (0.4) |
1 (0.5) |
1.10(0.10-12.19) |
||
|
T |
848 (92.4) |
369 (96.1) |
1.00 |
0.013
|
|
|
C |
70 (7.6) |
15 (3.9) |
0.49(0.28-0.87) |
||
|
g.12462 C>T |
CC |
380 (84.5) |
177 (93.2) |
1.00 |
0.009
|
|
CT |
68 (15.1) |
12 (6.3) |
0.38(0.20-0.72) |
||
|
TT |
2 (0.4) |
1 (0.5) |
1.07(0.10-11.92) |
||
|
C |
828 (92.0) |
366 (96.3) |
1.00 |
0.005
|
|
|
T |
72 (8.0) |
14 (3.7) |
0.44(0.25-0.79) |
||
|
g.12988 C>A |
CC |
327 (70.2) |
170 (92.4) |
1.00 |
> 0.0001
|
|
CA |
134 (28.8) |
14 (7.6) |
0.20(0.11-0.36) |
||
|
AA |
5 (1.0) |
0 (0.0) |
– |
||
|
C |
788 (84.5) |
354 (96.2) |
1.00 |
> 0.0001
|
|
|
A |
144 (15.5) |
14 (3.8) |
0.22(0.12-0.38) |
||
|
g.13506 C>G |
CC |
193 (43.3) |
91 (49.5) |
1.00 |
> 0.0001
|
|
CG |
207 (46.4) |
48 (26.1) |
0.49(0.33-0.73) |
||
|
GG |
46 (10.3) |
45 (24.4) |
2.08(1.28-3.36) |
||
|
C |
593 (66.5) |
230 (62.5) |
1.00 |
0.193 |
|
|
G |
299 (33.5) |
138 (37.5) |
1.19(0.92-1.53) |
a Calculated from the translation start site.
b Logistic regression analyses were used for calculating OR (95% CI; confidence interval)
Table 2. The haplotype frequencies by Adam33 polymorphisms in both SLE patients and controls
|
Haplotype |
g.-330 C>G |
g.8227 G>A |
g.12988 C>A |
g.13506 C>G |
Frequencya |
Chi-square |
Pb |
|
|
Control |
SLE |
|||||||
|
Ht 1 |
C |
G |
C |
G |
0.482 |
0.272 |
43.88 |
3.5E-11
|
|
Ht 2 |
C |
G |
C |
C |
0.259 |
0.484 |
56.53 |
5.5E-14
|
|
Ht 3 |
C |
A |
A |
G |
0.088 |
0.014 |
21.21 |
4.1E-6
|
|
Ht 4 |
C |
A |
C |
G |
0.057 |
0.043 |
0.915 |
0.339 |
|
Ht 5 |
G |
G |
C |
C |
0.030 |
0.022 |
0.517 |
0.472 |
|
Ht 6 |
C |
G |
A |
G |
0.027 |
0.003 |
6.655 |
0.010
|
|
others |
– |
– |
– |
– |
0.057 |
|
– |
– |
Disclosure:
S. C. Shim,
None;
M. K. Lim,
None;
D. Sheen,
None;
H. Park,
None.
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