Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations

被引：71

作者：

Bates, J. S. ^{[1
]}

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

Leon, J. M. ^{[1
]}

Nguyen, T. ^{[1
]}

Battiest, L. J. ^{[1
]}

Rodgers, J. ^{[1
]}

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

James, J. A. ^{[4
]}

Gilkeson, G. S. ^{[5
]}

Kelly, J. A. ^{[1
]}

Humphrey, M. B. ^{[2
]}

Harley, J. B. ^{[1
]}

Gray-McGuire, C. ^{[1
]}

Moser, K. L. ^{[1
]}

Gaffney, P. M. ^{[1
]}

机构：

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

[2] Univ Oklahoma, Heath Sci Ctr, Dept Pathol, Oklahoma City, OK USA

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

[4] Oklahoma Med Res Fdn, Clin Immunol Res Program, Oklahoma City, OK 73104 USA

[5] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA

来源：

GENES AND IMMUNITY | 2009年 / 10卷 / 05期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

systemic lupus erythematosus; TNFAIP3; imputation; meta-analysis; GENOME-WIDE ASSOCIATION; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; REVISED CRITERIA; ENZYME A20; ERYTHEMATOSUS; VARIANTS; ITGAM; 6Q23; CLASSIFICATION;

D O I：

10.1038/gene.2009.31

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

TNFAIP3 encodes the ubiquitin-modifying enzyme, A20, a key regulator of inflammatory signaling pathways. We previously reported association between TNFAIP3 variants and systemic lupus erythematosus (SLE). To further localize the risk variant(s), we performed a meta-analysis using genetic data available from two Caucasian case-control datasets (1453 total cases, 3381 total control subjects) and 713 SLE trio families. The best result was found at rs5029939 (P = 1.67 x 10(-14), odds ratio = 2.09, 95% confidence interval 1.68- 2.60). We then imputed single nucleotide polymorphisms (SNPs) from the CEU Phase II HapMap using genotypes from 431 SLE cases and 2155 control subjects. Imputation identified 11 SNPs in addition to three observed SNPs, which together, defined a 109 kb SLE risk segment surrounding TNFAIP3. When evaluating whether the rs5029939 risk allele was associated with SLE clinical manifestations, we observed that heterozygous carriers of the TNFAIP3 risk allele at rs5029939 have a twofold increased risk of developing renal or hematologic manifestations compared to homozygous non-risk subjects. In summary, our study strengthens the genetic evidence that variants in the region of TNFAIP3 influence risk for SLE, particularly in patients with renal and hematologic manifestations, and narrows the risk effect to a 109 kb DNA segment that spans the TNFAIP3 gene. Genes and Immunity (2009) 10, 470-477; doi: 10.1038/gene.2009.31; published online 23 April 2009

引用

页码：470 / 477

页数：8

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