EGAGenomicsCase-ControldbGaPEGA study phs000122.v1.p1http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000122.v1.p1dbGaPEGArestrictedhttps://ega-archive.org/studies/phs000122.v1.p1<h4>Background</h4>Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci.<h4>Methods</h4>We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.<h4>Results</h4>Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)).<h4>Conclusions</h4>We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.Hom Geoffrey G, Graham Robert R RR, Modrek Barmak B, Taylor Kimberly E KE, Ortmann Ward W, Garnier Sophie S, Lee Annette T AT, Chung Sharon A SA, Ferreira Ricardo C RC, Pant P V Krishna PV, Ballinger Dennis G DG, Kosoy Roman R, Demirci F Yesim FY, Kamboh M Ilyas MI, Kao Amy H AH, Tian Chao C, Gunnarsson Iva I, Bengtsson Anders A AA, Rantapää-Dahlqvist Solbritt S, Petri Michelle M, Manzi Susan S, Seldin Michael F MF, Rönnblom Lars L, Syvänen Ann-Christine AC, Criswell Lindsey A LA, Gregersen Peter K PK, Behrens Timothy W TWfalseWhole Genome Association Study of Systemic Lupus Erythematosus<p>The goal of this collaborative study was to identify new genetic risk factors for Systemic Lupus Erythematosus (SLE). To do this
we conducted a genome-wide scan by combining the resources and expertise from a number of SLE researchers to establish a large
sample set comprising 1311 SLE cases and 3340 controls. The SLE case samples were genotyped from the following collections: 338
subjects from the Autoimmune Biomarkers Collaborative Network (ABCoN), an NIH/NIAMS funded repository, 141 subjects from the
Multiple Autoimmune Disease Genetics Consortium (MADGC), 613 subjects from the University of California San Francisco (UCSF) Lupus
Genetics, and 335 subjects from the University of Pittsburgh Medical Center (UPMC), plus 8 samples collected at The Feinstein
Institute for Medical Research.</p>
<p>A total of 3583 control samples were examined in the association analyses. As part of this project, 1861 control samples were
selected and then genotyped from the New York Cancer Project (NYCP), based on self-described ethnicity, gender and age.
In addition, genotype data from 1722 control samples (all self-described North Americans of European descent) were obtained from
the publicly available iControlDB database (<a href="http://www.illumina.com/pages.ilmn?ID=231" target="_blank">http://www.illumina.com/pages.ilmn?ID=231</a>).
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