Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4.
Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4.
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跨著名研究精细地图SLE敏感性基因座TNFSF4。
DOI：
10.1371/journal.pgen.1003554
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Vyse TJ
中科院分区：
文献类型：
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作者：
Manku H;Langefeld CD;Guerra SG;Malik TH;Alarcon-Riquelme M;Anaya JM;Bae SC;Boackle SA;Brown EE;Criswell LA;Freedman BI;Gaffney PM;Gregersen PA;Guthridge JM;Han SH;Harley JB;Jacob CO;James JA;Kamen DL;Kaufman KM;Kelly JA;Martin J;Merrill JT;Moser KL;Niewold TB;Park SY;Pons-Estel BA;Sawalha AH;Scofield RH;Shen N;Stevens AM;Sun C;Gilkeson GS;Edberg JC;Kimberly RP;Nath SK;Tsao BP;Vyse TJ
我们以前建立了一个80 kb的单倍型上游TNFSF 4作为易感基因座的自身免疫性疾病系统性红斑狼疮。SLE相关等位基因与炎症性疾病有关，包括动脉粥样硬化和缺血性中风。在欧洲人中，TNFSF 4致病变异体由于跨越该地区的等位基因表现出强烈的连锁不平衡而仍然难以捉摸。使用跨祖先方法对基因座进行精细定位，使用17，900例SLE和对照受试者，包括美洲印第安人/西班牙裔人（1348例，717例对照），非裔美国人（AA）（1529，2048）和欧洲人和东亚人的更好动力队列，我们发现所有种族中的风险等位基因的强关联; AA关联在非裔美国人Gullah中复制（152，122）。相关性的最佳证据来自两个相邻的标记：rs 2205960-T（P = 1.71×10−34，OR = 1.43[1.26-1.60]）和rs 1234317-T（P = 1.16×10−28，OR = 1.38[1.24-1.54]）。 对所有测试人群的精细重组率的推断发现，除了非洲裔美国人之外，所有人都有80 kb的风险和非风险单倍型。在该人群中，重组的衰减相当于11 kb风险单倍型，锚定在TNFSF 4近端的5′区域，并在1000个基因组1期（v3）插补后由rs 2205960-T标记。条件回归分析将rs 2205960-T作为5′风险信号，rs 1234314-C作为独立的非风险信号。我们的病例组和SLE对照组显示rs 2205960-T与自身抗体产生的强相关性。预测rs 2205960-T形成十聚体基序的一部分，与rs 2205960-G相比，其以增加的亲和力结合NF-κ Bp 65。ChIP-seq数据还表明NF-κB与LCL细胞中该位置处的DNA序列相互作用。我们的研究表明rs 2205960-T与多组SLE相关，rs 1234314-C为独立的非风险信号。rs 2205960-T与自身抗体产生和淋巴细胞减少症相关。我们的数据证实了TNFSF 4的全球信号和表达产物在SLE发病过程中淋巴细胞失调的多个阶段中的作用。我们证实了跨祖先映射在一个复杂的性状的有效性。系统性红斑狼疮（SLE/lupus）是一种复杂的疾病，其中身体的免疫细胞在一个或多个系统中引起炎症，从而引起相关的发病率。激素、环境和基因都是SLE的致病因素，在过去的几年里，SLE的遗传因素已经被牢固地确立。作为免疫系统调节因子的几个基因与疾病风险有关。我们已经确定了其中之一，肿瘤坏死家族超家族成员4（TNFSF 4）基因，作为北方欧洲人的狼疮易感基因。确定最能解释SLE风险的TNFSF 4标记的主要障碍是该人群中TNFSF 4区域相邻标记之间的强相关性（连锁不平衡，LD）。为了解决这一问题，我们在几个人群中除了欧洲组分型多态性。这些人群的混合祖先给出了一个不同的LD模式比在欧洲人中发现的，提出了一种方法，查明部分TNFSF 4区域，导致SLE易感性。非欧洲人群允许鉴定可能调节TNFSF 4表达以增加SLE易感性的多态性。
We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10−34, OR = 1.43[1.26–1.60]) and rs1234317-T (P = 1.16×10−28, OR = 1.38[1.24–1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait. Systemic lupus erythematosus (SLE/lupus) is a complex disease in which the body's immune cells cause inflammation in one or more systems to cause the associated morbidity. Hormones, the environment and genes are all causal contributors to SLE and over the past several years the genetic component of SLE has been firmly established. Several genes which are regulators of the immune system are associated with disease risk. We have established one of these, the tumour-necrosis family superfamily member 4 (TNFSF4) gene, as a lupus susceptibility gene in Northern Europeans. A major obstacle in pinpointing the marker(s) at TNFSF4 which best explain the risk of SLE has been the strong correlation (linkage disequilibrium, LD) between adjacent markers across the TNFSF4 region in this population. To address this, we have typed polymorphisms in several populations in addition to the European groups. The mixed ancestry of these populations gives a different LD pattern than that found in Europeans, presenting a method of pinpointing the section of the TNFSF4 region which results in SLE susceptibility. The Non-European populations have allowed identification of a polymorphism likely to regulate expression of TNFSF4 to increase susceptibility to SLE.