Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Variation in the ICAM1-ICAM4-ICAM5 Locus Is Associated with Systemic Lupus Erythematosus Susceptibility in Multiple Ancestry Populations.
Kim1, Kwangwoo, Brown, Elizabeth E., on behalf of PROFILE, , Choi3, Chan-Bum, Alarcon-Riquelme, Marta E., on behalf of BIOLUPUS, , Kelly5, Jennifer A.
Korea Advanced Institute of Science and Technology, Daejeon, South Korea
Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH
University of Alabama at Birmingham, Birmingham, AL
Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
Oklahoma Medical Research Foundation, Oklahoma City, OK
David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA
Wake Forest School of Medicine, Winston-Salem, NC
Systemic lupus erythematosus (SLE, OMIM 152700) is a chronic autoimmune disease with etiology that includes genetic and environmental factors. ITGAM, integrin alpha M (complement component 3 receptor 3 subunit), a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. However, the independent and joint effects of common variation in the genes that encode ITGAM and ICAM have not been previously evaluated.
We examined 12 directly typed and 58 imputed loci in the ICAM1-ICAM4-ICAM5 locus spanning ~22 kb on chromosome 19p13, a single locus in ITGAM and 347 ancestry informative markers using customized arrays based on the Illumina iSelect platform in a total of 17,481 unrelated SLE affecteds and controls from four divergent ancestry backgrounds (European, African, Hispanic, Asian). All participants were of self-reported sex and race/ethnicity. Affecteds had a minimum of four of eleven 1997 American College of Rheumatology revised criteria for the classification of SLE. We estimated allele frequencies in SLE affecteds relative to controls using logistic regression based on additive models and adjusted for population substructure.
The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM-1, 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 1.111.22; P=4.8×10-10) as did the ITGAM rs11436679-A allele (ORmeta=1.67, 95% CI 1.551.79; P=3.32×10-46). Carriers of both ICAM rs30930330-AA and ITGAM rs1143679-AA were significantly more likely to develop SLE compared to carriers without at-risk alleles at both loci (OR=4.08, 95% CI 2.097.98; P=3.91×10-5), supporting a synergistic receptor-ligand interaction.
These findings are the first to provide evidence to support the contribution of the ICAM locus alone and an ICAM-integrin mediated pathway to SLE susceptibility.
To cite this abstract, please use the following information:
Kim, Kwangwoo, Brown, Elizabeth E., on behalf of PROFILE, , Choi, Chan-Bum, Alarcon-Riquelme, Marta E., on behalf of BIOLUPUS, , et al; Variation in the ICAM1-ICAM4-ICAM5 Locus Is Associated with Systemic Lupus Erythematosus Susceptibility in Multiple Ancestry Populations. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1681