Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G.
Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G.
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DOI：
10.1136/annrheumdis-2011-200808
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发表时间：
2012-05
影响因子：
27.4
通讯作者：
Vyse TJ
中科院分区：
文献类型：
--
作者：
Fernando MM;Freudenberg J;Lee A;Morris DL;Boteva L;Rhodes B;Gonzalez-Escribano MF;Lopez-Nevot MA;Navarra SV;Gregersen PK;Martin J;IMAGEN;Vyse TJ
系统性红斑狼疮（SLE）是一种慢性多系统遗传复杂的自身免疫性疾病，其特征是产生针对核和细胞抗原的自身抗体、组织炎症和器官损伤。全基因组关联研究表明，在欧洲和中国人群中，6号染色体上主要组织相容性复合体（MHC）区域内的变异赋予SLE最大的遗传风险。然而，由于疾病相关的MHC单倍型之间的紧密连锁不平衡，许多MHC基因的高度多态性和SLE表型的异质性，致病变异仍然难以捉摸。使用定制的Illumina芯片在西班牙和菲律宾血统的SLE队列中进行了MHC区域的高密度病例对照单核苷酸多态性（SNP）研究，以便在这些单倍型多样性人群中精细映射关联信号。此外，还对这两个数据集和英国北方欧洲SLE队列进行了比较分析。共检查了1433例病例和1458例对照。使用这种跨祖SNP作图方法，在英国、西班牙和菲律宾SLE患者的MHC区域内发现了新的独立位点，并有一些相互作用的证据。这些位点包括HLA-DPB 1、HLA-G和MSH 5，它们彼此独立，且与HLA-DRB 1等位基因无关。此外，将建立的SLE相关HLA-DRB 1 *15信号细化到包含HLA-DRB 1和HLA-DQA 1的区间。与欧洲人相比，在菲律宾人群中发现MHC区域风险等位基因和单倍型的频率增加，这表明非欧洲SLE的疾病负担更大可能部分是由于这种现象。这些数据突出了使用transancestral方法绘制疾病易感性位点的有用性，特别是在像MHC这样复杂的区域，并为进一步的精细映射，重测序和转录组学分析提供了跳板。
Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype. A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined. Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon. These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis.
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影响因子：
--
作者：
Ding, Bo;Padyukov, Leonid;Lundstrom, Emeli;Seielstad, Mark;Plenge, Robert M.;Oksenberg, Jorge R.;Gregersen, Peter K.;Alfredsson, Lars;Klareskog, Lars
通讯作者：
Klareskog, Lars
影响因子：
4.5
作者：
Barcellos LF;May SL;Ramsay PP;Quach HL;Lane JA;Nititham J;Noble JA;Taylor KE;Quach DL;Chung SA;Kelly JA;Moser KL;Behrens TW;Seldin MF;Thomson G;Harley JB;Gaffney PM;Criswell LA
通讯作者：
Criswell LA
影响因子：
30.8
作者：
Marchini, Jonathan;Howie, Bryan;Donnelly, Peter
通讯作者：
Donnelly, Peter
影响因子：
9.8
作者：
Graham, RR;Ortmann, WA;Behrens, TW
通讯作者：
Behrens, TW
影响因子：
2.7
作者：
Kolte, Astrid M.;Steffensen, Rudi;Christiansen, Ole B.
通讯作者：
Christiansen, Ole B.