1. Two Functional Lupus-Associated BLK Promoter Variants Control Cell-Type- and Developmental-Stage-Specific Transcription
- Author
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Joan T. Merrill, R. Hal Scofield, Anne M. Stevens, Diane L. Kamen, Nan Shen, Jennifer A. Kelly, Michelle Petri, Gary S. Gilkeson, Edward K. Wakeland, Carl D. Langefeld, Hye Soon Lee, Kenneth M. Kaufman, Chaim O. Jacob, Robert P. Kimberly, Carol F. Webb, Graham B. Wiley, Xana Kim-Howard, Joel M. Guthridge, Swapan K. Nath, Kathy L. Sivils, Jeffery Edberg, Betty P. Tsao, Harry Sun, Robert R. Graham, Susan A. Boackle, John B. Harley, Elizabeth E. Brown, Xiaoxia Qian, Marta E. Alarcón-Riquelme, Rosalind Ramsey-Goldman, Timothy J. Vyse, Lindsey A. Criswell, Luis M. Vilá, Isaac T.W. Harley, Beth L. Cobb, Judith A. James, John D. Reveille, Timothy W. Behrens, Young Bin Joo, Susan R. Macwana, Celi Sun, Patrick M. Gaffney, So Young Bang, Christopher J. Lessard, Timothy B. Niewold, Jiyoung Choi, Barry I. Freedman, Nicolas Dominguez, Adam Adler, Sang Cheol Bae, and Rufei Lu
- Subjects
Male ,Transcription, Genetic ,Electrophoretic Mobility Shift Assay ,Medical and Health Sciences ,Transcription (biology) ,2.1 Biological and endogenous factors ,Lupus Erythematosus, Systemic ,Genetics(clinical) ,Aetiology ,Promoter Regions, Genetic ,Genetics (clinical) ,Genetics ,Genetics & Heredity ,Systemic lupus erythematosus ,Single Nucleotide ,Biological Sciences ,src-Family Kinases ,Pair 8 ,Female ,Transcription ,Human ,Chromosomes, Human, Pair 8 ,Lupus ,Locus (genetics) ,Biology ,Autoimmune Disease ,Polymorphism, Single Nucleotide ,Chromosomes ,Article ,Promoter Regions ,Genetic ,Clinical Research ,medicine ,Humans ,Electrophoretic mobility shift assay ,Genetic Predisposition to Disease ,Allele ,Progenitor cell ,Polymorphism ,Alleles ,Lupus erythematosus ,Lupus Erythematosus ,Inflammatory and immune system ,Haplotype ,Systemic ,medicine.disease ,Stem Cell Research ,Molecular biology ,Haplotypes - Abstract
Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.
- Published
- 2014