Two Functional Lupus-Associated BLK Promoter Variants Control Cell-Type- and Developmental-Stage-Specific Transcription

详细信息    查看全文

• 作者：Joel M. Guthridge¹ ; ³³ ; ^{guthridgej@omrf.org" class="auth_mail} ; Rufei Lu¹ ; ² ; ³³ ; Harry Sun³ ; Celi Sun¹ ; Graham B. Wiley¹ ; Nicolas Dominguez¹ ; Susan R. Macwana¹ ; Christopher J. Lessard¹ ; Xana Kim-Howard¹ ; Beth L. Cobb⁴ ; Kenneth M. Kaufman⁴ ; ⁵ ; Jennifer A. Kelly¹ ; Carl D. Langefeld⁶ ; Adam J. Adler¹ ; Isaac T.W. Harley⁷ ; Joan T. Merrill⁸ ; Gary S. Gilkeson⁹ ; Diane L. Kamen⁹ ; Timothy B. Niewold¹⁰ ; Elizabeth E. Brown¹¹ ; ¹² ; Jeffery C. Edberg¹³ ; Michelle A. Petri¹⁴ ; Rosalind Ramsey-Goldman¹⁵ ; John D. Reveille¹⁶ ; Luis M. Vilá ; ¹⁷ ; Robert P. Kimberly¹³ ; Barry I. Freedman¹⁸ ; Anne M. Stevens¹⁹ ; Susan A. Boackle²⁰ ; Lindsey A. Criswell²¹ ; Tim J. Vyse²² ; Timothy W. Behrens³ ; Chaim O. Jacob²³ ; Marta E. Alarcó ; n-Riquelme¹ ; ²⁴ ; ³⁵ ; Kathy L. Sivils¹ ; Jiyoung Choi²⁵ ; Young Bin Joo²⁵ ; So-Young Bang²⁵ ; Hye-Soon Lee²⁵ ; Sang-Cheol Bae²⁵ ; Nan Shen²⁶ ; Xiaoxia Qian²⁶ ; Betty P. Tsao²⁷ ; R. Hal Scofield¹ ; ³¹ ; ³² ; John B. Harley⁴ ; ⁵ ; Carol F. Webb²⁸ ; ²⁹ ; Edward K. Wakeland³⁰ ; Judith A. James¹ ; ² ; ³¹ ; Swapan K. Nath¹ ; ³⁴ ; Robert R. Graham³ ; ³⁴ ; Patrick M. Gaffney¹ ; ³⁴
• 刊名：The American Journal of Human Genetics
• 出版年：3 April, 2014
• 年：2014
• 卷：94
• 期：4
• 页码：586-598
• 全文大小：1143 K

文摘

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.