Objective Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αM (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.
Methods The authors examined several markers in the ICAM1–ICAM4–ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case–control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene–gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.
Results The A-allele of ICAM1–ICAM4–ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88×10−10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32×10−46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10−5).
Conclusion These findings are the first to suggest that an ICAM–integrin-mediated pathway contributes to susceptibility to SLE.
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KK and EEB contributed equally to this work and are joint first authors. CK, RPK and SCB contributed equally to this work and are joint corresponding authors.
Funding The work was supported by grants from US NIH (AI063622, AI071651, AI082714, AI083194, AI094377, AI24717, AR042460, AR043274, AR043814, AR044804, AR048940, AR052300, AR053483, AR058554, AR060366, AR43727, AR62277, CA141700-01, GM063483, HD07463, K08-AI083790, K24-AR002138, M01-RR00079, N01-AR-6-227, P01-AR49084, P30-DK42086, P30-AR055385, P60-AR049459 P60-AR053308, P60-2-AR30692, PO1-AR49084, PR094002, R01-AR33062, R21-AI070304, RR015577, RR020143, UL1RR024999, UL1RR025005, UL1RR025741, UL1RR029882 and 5UL1RR025777), the Lupus Foundation of America, the Alliance for Lupus Research, a Kirkland Scholar Award, the US Department of Veterans Affairs, the Korean Healthcare Technology Research and Development Project (A111218-11-GM01), the Korea Research Program for New Drug Target Discovery (20090083335), the National Research Foundation of Korea (2010-0014162), the Lupus Research Institute Novel Research Grant, the Alliance for Lupus Research Target Identification in Lupus Grant, the Arthritis National Research Foundation Eng Tan Scholar Award, the ESF in the framework of the Research Networking Programme European Science Foundation—The Identification of Novel Genes and Biomarkers for Systemic Lupus Erythematosus (BIOLUPUS) 07-RNP-083, the Swedish Research Council, the Swedish Association against Rheumatism, the Swedish International Development Agency, the Gustaf Vth 80th-Jubilee Foundation, the Instituto de Salud Carlos III (PS09/00129) partly financed by the FEDER funds of the European Union, and a grant from the Consejería de Salud de la Junta de Andalucía.
Competing interests None.
Patient consent Obtained.
Ethics approval The study was approved by the Institutional Review Board of all participating institutions.
Provenance and peer review Not commissioned; externally peer reviewed.
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