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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/single-nucleotide-polymorphisms-snps-of-integrin-a-m-itgam-are-associated-with-susceptibility-to-systemic-lupus-erythematosus-sle-in-an-asian-lupus-cohort/