Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

被引：216

作者：

Adrianto, Indra ^{[1
]}

Wen, Feng ^{[1
]}

Templeton, Amanda ^{[2
]}

Wiley, Graham ^{[1
]}

King, Jarrod B. ^{[2
]}

Lessard, Christopher J. ^{[1
,2
]}

Bates, Jared S. ^{[1
]}

Hu, Yanqing ^{[2
]}

Kelly, Jennifer A. ^{[1
]}

Kaufman, Kenneth M. ^{[1
,2
,3
]}

Guthridge, Joel M. ^{[1
]}

Alarcon-Riquelme, Marta E. ^{[1
,4
]}

Anaya, Juan-Manuel ^{[5
]}

Bae, Sang-Cheol ^{[6
]}

Bang, So-Young ^{[6
]}

Boackle, Susan A. ^{[7
]}

Brown, Elizabeth E. ^{[8
]}

Petri, Michelle A. ^{[9
]}

Gallant, Caroline ^{[10
]}

Ramsey-Goldman, Rosalind ^{[11
]}

Reveille, John D. ^{[12
]}

Vila, Luis M. ^{[13
]}

Criswell, Lindsey A. ^{[14
]}

Edberg, Jeffrey C. ^{[15
]}

Freedman, Barry I. ^{[16
]}

Gregersen, Peter K. ^{[17
]}

Gilkeson, Gary S. ^{[18
]}

Jacob, Chaim O. ^{[19
]}

James, Judith A. ^{[1
,2
]}

Kamen, Diane L. ^{[18
]}

Kimberly, Robert P. ^{[15
]}

Martin, Javier ^{[20
]}

Merrill, Joan T. ^{[21
]}

Niewold, Timothy B. ^{[22
,23
]}

Park, So-Yeon ^{[6
]}

Pons-Estel, Bernardo A. ^{[24
]}

Scofield, R. Hal ^{[1
,2
]}

Stevens, Anne M. ^{[25
,26
]}

Tsao, Betty P. ^{[27
]}

Vyse, Timothy J. ^{[28
,29
]}

Langefeld, Carl D. ^{[30
]}

Harley, John B. ^{[3
,31
]}

Moser, Kathy L. ^{[1
,2
]}

Webb, Carol F. ^{[32
]}

Humphrey, Mary Beth ^{[2
]}

Montgomery, Courtney Gray ^{[1
]}

Gaffney, Patrick M. ^{[1
]}

机构：

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

[2] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Oklahoma City, OK 73190 USA

[3] US Dept Vet Affairs Med Ctr, Oklahoma City, OK USA

[4] Ctr Genom & Oncol Res GENyO, Granada, Spain

[5] Univ Rosario, Ctr Autoimmune Dis Res CREA, Bogota, Colombia

[6] Hanyang Univ Hosp Rheumat Dis, Dept Rheumatol, Seoul, South Korea

[7] Univ Colorado Denver, Div Rheumatol, Aurora, CO USA

[8] Univ Alabama, Dept Epidemiol, Birmingham, AL USA

[9] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[10] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, Uppsala, Sweden

[11] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA

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

[13] Univ Puerto Rico, Dept Med, Div Rheumatol, San Juan, PR 00936 USA

[14] Univ Calif San Francisco, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA 94143 USA

[15] Univ Alabama, Dept Med, Birmingham, AL 35294 USA

[16] Wake Forest Univ Hlth Sci, Dept Internal Med, Winston Salem, NC USA

[17] N Shore Long Isl Jewish LIJ Hlth Syst, Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY USA

[18] Univ S Carolina, Div Rheumatol, Charleston, SC USA

[19] Univ So Calif, Dept Med, Los Angeles, CA USA

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

[21] Oklahoma Med Res Fdn, Clin Pharmacol Res Program, Oklahoma City, OK 73104 USA

[22] Univ Chicago, Rheumatol Sect, Chicago, IL 60637 USA

[23] Univ Chicago, Gwen Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA

[24] Sanat Parque, Rosario, Santa Fe, Argentina

[25] Univ Washington, Dept Pediat, Div Rheumatol, Seattle, WA 98195 USA

[26] Seattle Childrens Res Inst, Ctr Immun & Immunotherapies, Seattle, WA USA

[27] Univ Calif Los Angeles, Dept Med, Div Rheumatol, Los Angeles, CA 90024 USA

[28] Kings Coll London, Div Genet & Mol Med, London WC2R 2LS, England

[29] Kings Coll London, Div Immunol Infect & Inflammatory Dis, London WC2R 2LS, England

[30] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA

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

[32] Oklahoma Med Res Fdn, Immunobiol & Canc Res Program, Oklahoma City, OK 73104 USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 03期

基金：

美国国家卫生研究院; 新加坡国家研究基金会; 英国惠康基金; 瑞典研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; AFRICAN-AMERICANS; RHEUMATOID-ARTHRITIS; ENZYME A20; ADMIXTURE; HAPLOTYPE; RISK; 6Q23; MAP; POLYMORPHISMS;

D O I：

10.1038/ng.766

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 x 10(-8), odds ratio = 1.70) and Korean (P = 8.33 x 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-kappa B subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

引用

页码：253 / U102

页数：8

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