ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2684

Association of Adam33 Polymorphisms with Systemic Lupus Erythematosus

Seong-Wook Kang1, Seung-Taek Song1, Su-Jin Yoo2, Mi-Kyoung Lim3, Dong-Hyuk Sheen4, In-Seol Yoo5, Jinhyun Kim1 and Seung-Cheol Shim1, 1Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, South Korea, 2Rheumatology, Chungnam National University School of Medicine, Daejeon, South Korea, 3Rheumatology, Eulji University Hospital, Daejeon, South Korea, 4Department of Internal Medicine, Eulji University Hospital, Daejeon, South Korea, 5Departmen of Internal medicine, Chungnam National University School of Medicine, Daejeon, South Korea

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis: T and B Cell Signaling and Genetic Variants

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 Prism SNaPshot 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). 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). 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 Adam33gene 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)

aCalculated from the translation start site.

bLogistic regression analyses were used for calculating OR (95% CI; confidence interval)

 

Table 2. The haplotype frequencies by Adam33polymorphisms 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. W. Kang,
None;

S. T. Song,
None;

S. J. Yoo,
None;

M. K. Lim,
None;

D. H. Sheen,
None;

I. S. Yoo,
None;

J. Kim,
None;

S. C. Shim,
None.

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