Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Large-Scale Mapping of Systemic Lupus Erythematosus (SLE) Variants across Different Ethnicities Reveals That the IRF5-TNPO3 Region Is the Strongest Common Risk Factor.
Vyse8, Timothy J., Ramos3, Paula S., Kaufman2, Kenneth M., Kelly2, Jennifer A., Gallant7, Caroline, Delgado6, Angelica, Chung10, Sharon A.
Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, San Francisco, CA
UCLA School of Medicine, Los Angeles, CA
UCSF-Box 0500, San Francisco, CA
Univ of OK Hlth Sci Ctr, Oklahoma City, OK
Arthritis and Immunology Program, Oklahoma Medical Research Foundation
Dept Biostatistical Sciences, Wake Forest University Health Sciences
Dept Medicine, University of Alabama at Birmingham, Birmingham, AL
Dept of Genetics and Pathology, Uppsala University, Uppsala, Sweden
Dept of Genetics and Pathology, Uppsala University
Dept of Genetics and Pathology, Uppsala University, Sweden
Faculty of Medicine, Imperial College, London, UK
Keck School of Medicine, University of Southern California, Los Angeles, CA
Genome-wide association studies (GWAS) have been extremely successful at identifying important SLE risk factors. Nevertheless, in spite of being more prevalent in African Americans, Hispanics and Asians, the majority of GWAS have been performed in Caucasians. Recent GWAS in Asians have been reported, but there is still a paucity of large-scale data on the genetics of SLE in non-European populations. As such, the specific genetic variants predisposing to SLE and their overlap with European ancestry risk factors are largely unknown. This study is aimed at elucidating the patterns of disease association across different ethnicities. We conducted a trans-ethnic study called Lupus Large Association Study 2 (LLAS2) consisting of 8436 SLE cases and 7554 controls of European (3977 cases and 3538 controls), African American (1679 cases and 1934 controls), Asian (1272 cases and 1270 controls) and Hispanic and Native American ancestries (1508 cases 812 controls). We selected 7069 candidate SNPs from the SLEGEN European ancestry genome-wide association study (GWAS)(Harley et al, 2008) and genotyped them on an Illumina custom array; approximately 400 ancestry informative markers were included and principal components analysis and admixture estimates were computed. We computed ethnic-specific case-control association analyses adjusting for admixture and trans-ethnic meta-analysis using the weighted inverse normal approach. Analyses were repeated adjusting for ethnic-specific tags for HLA-DR2 and DR3, and the results were comparable in non-HLA regions. Strongest associated SNP in the region is reported. The most significant trans-ethnic variation is located in the IRF5-TNPO3 region (rs4728142, P=4.77×1060), followed by STAT4 (rs11889341, P=4.66×1053), HLA (rs3131379 in MSH5, P=1.17×1052), ITGAM (rs9888739, P=5.38×1031), BLK (rs13277113, P=4.79×1029), PTTG1 (rs2431697, P=6.55×1024), TNIP1 (rs960709, P=7.22×1021), UBE2L3 (rs2298429, P=1.98×1015), NMNAT2 (rs12146097, P=9.64×1014), and TNFSF4 (rs10798269, P=5.69×1012). Some regions are dominated by the European association (HLA, ITGAM, PTTG1 and NMNAT2), others by two or more ethnicities (IRF5-TNOP3, STAT4, BLK, TNIP1, UBE2L3, TNFSF4). Some regions share a similar pattern of association between two (IRF5-TNOP3, ITGAM) or more (STAT4, BLK, PTTG1, TNIP1, UBE2L3, NMNAT2) ethnic groups, while in others it is apparently discordant (HLA, TNFSF4). This is the first report of large-scale trans-ethnic mapping in SLE. This study shows that the IRF5-TNPO3 region is the strongest SLE trans-ethnic risk factor, and helps elucidate common versus ethnic-specific risk factors for SLE.
To cite this abstract, please use the following information:
Vyse, Timothy J., Ramos, Paula S., Kaufman, Kenneth M., Kelly, Jennifer A., Gallant, Caroline, Delgado, Angelica, et al; Large-Scale Mapping of Systemic Lupus Erythematosus (SLE) Variants across Different Ethnicities Reveals That the IRF5-TNPO3 Region Is the Strongest Common Risk Factor. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2145