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Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus

Authors :
Rosalind Ramsey-Goldman
Edward K. Wakeland
Chaoying Liang
Benjamin E. Wakeland
Courtney G. Montgomery
Marta E. Alarcón-Riquelme
Sang Cheol Bae
Young Bin Joo
Indra Adrianto
Adrienne H. Williams
Christopher J. Lessard
Anne M. Stevens
Javier Martin
Jeffrey C. Edberg
Susan A. Boackle
Robert P. Kimberly
Jennifer A. Kelly
Shaofeng Wang
Gary S. Gilkeson
Michelle Petri
Timothy B. Niewold
Patrick M. Gaffney
Stuart B. Glenn
Luis M. Vilá
Timothy J. Vyse
Bernardo A. Pons-Estel
Carl D. Langefeld
Betty P. Tsao
Barry I. Freedman
Jae Hoon Kim
Mary E. Comeau
Graciela S. Alarcón
John B. Harley
Kathy L. Moser
Graham B. Wiley
Elizabeth E. Brown
Kenneth M. Kaufman
John D. Reveille
Joel M. Guthridge
Miranda C. Marion
Julie T. Ziegler
Judith A. James
Adam Adler
Juan-Manuel Anaya
Diane L. Kamen
Joan T. Merrill
R. Hal Scofield
Chaim O. Jacob
Lindsey A. Criswell
Source :
Repositorio EdocUR-U. Rosario, Universidad del Rosario, instacron:Universidad del Rosario
Publication Year :
2012

Abstract

Objective Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-?B signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-?B pathway. Methods We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. Results We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. Conclusion Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis. Copyright © 2012 by the American College of Rheumatology.

Details

Language :
English
Database :
OpenAIRE
Journal :
Repositorio EdocUR-U. Rosario, Universidad del Rosario, instacron:Universidad del Rosario
Accession number :
edsair.doi.dedup.....3fbf37edb372686c2661f104f87fc8b2