Association of Two Independent Functional Risk Haplotypes in TNIP1 With Systemic Lupus Erythematosus

被引：68

作者：

Adrianto, Indra

Wang, Shaofeng

Wiley, Graham B.

Lessard, Christopher J. ^{[2
]}

Kelly, Jennifer A.

Adler, Adam J.

Glenn, Stuart B.

Williams, Adrienne H. ^{[3
]}

Ziegler, Julie T. ^{[3
]}

Comeau, Mary E. ^{[3
]}

Marion, Miranda C. ^{[3
]}

Wakeland, Benjamin E. ^{[4
]}

Liang, Chaoying ^{[4
]}

Kaufman, Kenneth M. ^{[5
,6
]}

Guthridge, Joel M.

Alarcon-Riquelme, Marta E. ^{[7
]}

Alarcon, Graciela S. ^{[8
]}

Anaya, Juan-Manuel ^{[9
]}

Bae, Sang-Cheol ^{[10
]}

Kim, Jae-Hoon ^{[10
]}

Joo, Young Bin ^{[10
]}

Boackle, Susan A. ^{[11
]}

Brown, Elizabeth E. ^{[8
]}

Petri, Michelle A. ^{[12
]}

Ramsey-Goldman, Rosalind ^{[13
]}

Reveille, John D. ^{[14
]}

Vila, Luis M. ^{[15
]}

Criswell, Lindsey A. ^{[16
]}

Edberg, Jeffrey C. ^{[8
]}

Freedman, Barry I. ^{[3
]}

Gilkeson, Gary S. ^{[17
]}

Jacob, Chaim O. ^{[18
]}

James, Judith A. ^{[2
]}

Kamen, Diane L. ^{[17
]}

Kimberly, Robert P. ^{[8
]}

Martin, Javier ^{[19
]}

Merrill, Joan T.

Niewold, Timothy B. ^{[20
]}

Pons-Estel, Bernardo A. ^{[21
]}

Scofield, R. Hal ^{[22
,23
]}

Stevens, Anne M. ^{[24
,25
]}

Tsao, Betty P. ^{[26
]}

Vyse, Timothy J. ^{[27
]}

Langefeld, Carl D. ^{[3
]}

Harley, John B. ^{[5
,6
]}

Wakeland, Edward K. ^{[4
]}

Moser, Kathy L. ^{[2
]}

Montgomery, Courtney G.

Gaffney, Patrick M. ^{[1
]}

机构：

[1] Oklahoma Med Res Fdn, Arthritis & Clin Immunol Res Program, Oklahoma City, OK 73104 USA

[2] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA

[3] Wake Forest Sch Med, Winston Salem, NC USA

[4] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA

[5] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA

[6] Cincinnati VA Med Ctr, Cincinnati, OH USA

[7] Univ Granada, Pfizer, Granada, Spain

[8] Univ Alabama Birmingham, Birmingham, AL USA

[9] Univ Rosario, Bogota, Colombia

[10] Hanyang Univ Hosp Rheumat Dis, Seoul, South Korea

[11] Univ Colorado Denver, Sch Med, Aurora, CO USA

[12] Johns Hopkins Univ, Sch Med, Baltimore, MD USA

[13] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

[14] Univ Texas Hlth Sci Ctr, Houston, TX USA

[15] Univ Puerto Rico Med Sci, San Juan, PR USA

[16] Univ Calif San Francisco, San Francisco, CA 94143 USA

[17] Med Univ S Carolina, Charleston, SC USA

[18] Univ So Calif, Los Angeles, CA USA

[19] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain

[20] Univ Chicago, Chicago, IL 60637 USA

[21] Sanatorio Parque, Rosario, Santa Fe, Argentina

[22] Univ Oklahoma, Hlth Sci Ctr, Oklahoma Med Res Fdn, Oklahoma City, OK USA

[23] Oklahoma City VA Med Ctr, Oklahoma City, OK USA

[24] Univ Washington, Seattle, WA 98195 USA

[25] Seattle Childrens Res Inst, Seattle, WA USA

[26] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[27] Kings Coll London, London WC2R 2LS, England

来源：

ARTHRITIS AND RHEUMATISM | 2012年 / 64卷 / 11期

基金：

瑞典研究理事会; 英国惠康基金;

关键词：

NF-KAPPA-B; GENOME-WIDE ASSOCIATION; DNA-SEQUENCING DATA; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; TNFAIP3; ADMIXTURE; VARIANT; DISEASE; 6Q23;

D O I：

10.1002/art.34642

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-kappa B signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-kappa 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.

引用

页码：3695 / 3705

页数：11

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