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Abstract Number: 2278

Single Nucleotide Polymorphisms (SNPs) of Integrin-á-M (ITGAM) Are Associated with Susceptibility to Systemic Lupus Erythematosus (SLE) in an Asian Lupus Cohort

Weng-Giap Law1, Kok Ooi Kong2, Bernard Pui Lam Leung1, Chack-Yung Yu3, Yeong W. Song4, Yun Deng5, Hiok-Hee Chng2, Betty P. Tsao6 and Hwee-Siew Howe7, 1Rheumatology, Allergy & Immunology, Tan Tock Seng Hospital, Singapore, Singapore, 2Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore, Singapore, 3Department of Pediatrics, 7Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, OH, 4Seoul National University, Seoul, South Korea, 5Division of Rheumatology, Department of Medicine, David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, 6Medicine/Rheumatology, UCLA School of Medicine, Los Angeles, CA, 7Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore, Singapore

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Integrins, polymorphism and systemic lupus erythematosus (SLE)

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Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: SLE is a systemic autoimmune disease where lupus nephritis (LN) is a major cause of morbidity and mortality. Integrin-a-M (ITGAM) is critical for the adherence of neutrophils to stimulated endothelium and phagocytosis of complement coated particles. Recently, a variant of exon 3 (rs1143679) of ITGAM was found to be associated with susceptibility to SLE and LN in several ethnic groups including oriental Chinese and Thai populations. Our aim was to examine the potential association of ITGAM SNPs in our local SLE patients.

Methods: Custom-designed arrays were employed to study 201 SNPs covering the approximately 140kb of the ITGAM-ITGAX region in 293 Singapore SLE patients vs. 243 Asian controls. All patients satisfied the 1997 ACR revised SLE criteria. In total 147 SNPs of ITGAM-ITGAX were included in analysis. Significance difference in allelic frequencies of each SNP was examined by gPLINK 1.062 software with Bonferroni adjustment for multiple testing corrections.

Results: 13 SNPs spanning from 5’ upstream of ITGAM to intron 5 of ITGAX showed significant association (p<3.4×10-4). The strongest association was detected at rs4561481 in the 5’ upstream of ITGAM (OR=1.77 [1.34-2.32], p=4.2×10-5). The previously identified functional SNP of ITGAM (rs1143679, R77H) in European ancestry and African-American populations has shown a strong association for the risk allele (A). However, we observed a low frequency of the risk allele (A) in our patients (1.4% in SLE vs 0.2% in controls; p=0.039, OR=6.7 [0.83-53.42]), and its association with disease susceptibility did not remain significant after Bonferroni correction. To localize the underlying causal variant, linkage equilibrium (LD) analysis was examined among these 13 SNPs which were located in a strong LD block (r2=0.92-1.0), and the conditional association could not be applied to further distinguish the independent association in our SLE cohort.

Signficiant Disease Association of 13/15 ITGAM SNPs from a Singapore SLE Cohort

 

 

Test

Frequency

 

 

SNP

BP

Allelle

SLE

Control

P value

OR (95%CI)

rs4561481

31167054

G

0.338

0.224

4.2E-05

1.77 (1.34-2.32)

rs8051304

31167513

C

0.336

0.224

5.4E-05

1.75 (1.33-2.30)

rs889551

31167923

A

0.323

0.216

1.0E-04

1.73 (1.31-2.28)

rs4889640

31171768

C

0.336

0.228

1.1E-04

1.71 (1.30-2.24)

rs889549

31174452

C

0.335

0.226

9.5E-05

1.72 (1.31-2.26)

rs11645526

31175740

A

0.335

0.228

1.3E-04

1.70 (1.29-2.23)

rs8057320

31177052

C

0.335

0.229

1.5E-04

1.70 (1.29-2.22)

rs7193943

31178564

G

0.336

0.228

1.1E-04

1.71 (1.30-2.24)

rs11865830

31179046

G

0.335

0.222

4.9E-05

1.76 (1.34-2.31)

rs3764327

31180630

T

0.335

0.228

1.3E-04

1.70 (1.29-2.23)

rs7196256

31181031

T

0.335

0.229

1.5E-04

1.70 (1.29-2.22)

rs3815801

31184438

C

0.331

0.226

1.5E-04

1.69 (1.29-2.22)

rs2359661

31188648

A

0.345

0.239

1.5E-04

1.68 (1.28-2.20)

rs1143679*

31184312

A

0.014

0.002

3.9E-02

6.66 (0.83-53.42)

rs41477949*

31194928

T

0.021

0.008

9.8E-02

2.53 (0.81-7.89)

(n=293 Singapore SLE vs 243 controls), *p value = Not significant after bonferroni correction.

Conclusion: All the 13 SNPs of ITGAM were associated with increased susceptibility to SLE. The most significant SNP was rs4561481, but not the previously identified functional SNP of ITGAM (rs1143679), suggesting contribution of other ITGAM variants to SLE in our cohort.

Acknowledgement: This study was funded by NKF Research Grant (NKFRC/2008/07/33) and BMRC grant 01/1/28/18/016. We thank the TTSH lupus study group for patient recruitment and sample contribution.


Disclosure:

W. G. Law,
None;

K. O. Kong,
None;

B. P. L. Leung,
None;

C. Y. Yu,
None;

Y. W. Song,
None;

Y. Deng,
None;

H. H. Chng,
None;

B. P. Tsao,
None;

H. S. Howe,
None.

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