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Int. J. Mol. Sci. 2018, 19(8), 2331;

Trans-Ethnic Mapping of BANK1 Identifies Two Independent SLE-Risk Linkage Groups Enriched for Co-Transcriptional Splicing Marks

GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Government, PTS, 18016 Granada, Spain
Unit of Chronic Inflammatory Diseases, Institute for Environmental Medicine, Karolinska Institutet, 171 67 Solna, Sweden
Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23284, USA
Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA
Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Hospital for Special Surgery, New York, NY 10021, USA
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Cincinnati Children’s Hospital Medical Center, OH and US Department of Veterans Affairs Medical Center, Cincinnati, OH 45229, USA
School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35205, USA
Arthritis and Clinical Immunology and Clinical Pharmacology Programs, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
Author to whom correspondence should be addressed.
Received: 21 June 2018 / Revised: 31 July 2018 / Accepted: 6 August 2018 / Published: 8 August 2018
(This article belongs to the Special Issue B Cells and Immunological Tolerance)
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BANK1 is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 (BANK1). To increase the SNP density, we used imputation followed by univariate and conditional analysis, combined with a haplotypic and expression quantitative trait locus (eQTL) analysis. The data from Europeans showed that the associated region was restricted to a minimal and dependent set of SNPs covering introns two and three, and exon two. In AA, the signal found in the Europeans was split into two independent effects. All of the major risk associated SNPs were eQTLs, and the risks were associated with an increased BANK1 gene expression. Functional annotation analysis revealed the enrichment of repressive B cell epigenomic marks (EZH2 and H3K27me3) and a strong enrichment of splice junctions. Furthermore, one eQTL located in intron two, rs13106926, was found within the binding site for RUNX3, a transcriptional activator. These results connect the local genome topography, chromatin structure, and the regulatory landscape of BANK1 with co-transcriptional splicing of exon two. Our data defines a minimal set of risk associated eQTLs predicted to be involved in the expression of BANK1 modulated through epigenetic regulation and splicing. These findings allow us to suggest that the increased expression of BANK1 will have an impact on B-cell mediated disease pathways. View Full-Text
Keywords: autoimmune disorders; systemic lupus erythematosus; genetics; BANK1; transethnic genetic studies autoimmune disorders; systemic lupus erythematosus; genetics; BANK1; transethnic genetic studies

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Martínez-Bueno, M.; Oparina, N.; Dozmorov, M.G.; Marion, M.C.; Comeau, M.E.; Gilkeson, G.; Kamen, D.; Weisman, M.; Salmon, J.; McCune, J.W.; Harley, J.B.; Kimberly, R.; James, J.A.; Merrill, J.; Montgomery, C.; Langefeld, C.D.; Alarcón-Riquelme, M.E. Trans-Ethnic Mapping of BANK1 Identifies Two Independent SLE-Risk Linkage Groups Enriched for Co-Transcriptional Splicing Marks. Int. J. Mol. Sci. 2018, 19, 2331.

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