A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1
A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1
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DOI：
10.1183/09031936.00001711
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发表时间：
2011-11-01
影响因子：
24.3
通讯作者：
Schreiber, S.
中科院分区：
文献类型：
--
作者：
Hofmann, S.;Fischer, A.;Schreiber, S.
结节病是一种复杂的全身性炎症性疾病，病因不明，受多种遗传和环境因素的影响。为了进一步确定结节病的易感基因，基于Affyestival 100 k基因芯片数据，在381例患者和392例对照个体中进行了全基因组关联研究（GWAS）。在一个独立的研究小组（1，582名患者和1，783名对照）中选择了前25个单核苷酸多态性（SNP）进行验证。染色体6p12.1上的变异rs 10484410显著相关，验证样本中Bonferroni校正的p值为2.90x10（-2），GWAS中的标称p值为2.64x10（-4）。新基因座的广泛精细定位将信号缩小到包含基因BAG 2、C6 orf 65、KIAA 1586、ZNF 451和RAB 23的区域。在进一步的独立病例对照样本和定量mRNA表达研究中，结节病相关的非同义SNP rs 1040461的验证表明RAB 23基因是最可能的风险因素。RAB 23被认为参与了抗菌防御过程和音刺猬信号通路的调节，6p12.1位点与结节病的相关性表明该位点是一个进一步的易感因子，RAB 23是一个潜在的信号组分，可能为结节病的病理生理学研究开辟新的前景。
Sarcoidosis is a complex systemic inflammatory disease of unknown aetiology that is influenced by a variety of genetic and environmental factors.To identify further susceptibility loci for sarcoidosis, a genome-wide association study (GWAS) was conducted in 381 patients and 392 control individuals based on Affymetrix 100k GeneChip data. The top 25 single-nucleotide polymorphisms (SNPs) were selected for validation in an independent study panel (1,582 patients versus 1,783 controls).Variant rs10484410 on chromosome 6p12.1 was significantly associated, with a Bonferroni-corrected p-value of 2.90x10(-2) in the validation sample and a nominal p-value of 2.64x10(-4) in the GWAS. Extensive fine mapping of the novel locus narrowed down the signal to a region comprising the genes BAG2, C6orf65, KIAA1586, ZNF451 and RAB23. Verification of the sarcoidosis-associated nonsynonymous SNP rs1040461 in a further independent case-control sample and quantitative mRNA expression studies point to the RAB23 gene as the most likely risk factor. RAB23 is proposed to be involved in antibacterial defence processes and regulation of the sonic hedgehog signalling pathway.The identified association of the 6p12.1 locus with sarcoidosis implicates this locus as a further susceptibility factor and RAB23 as a potential signalling component that may open up new perspectives in the pathophysiology of sarcoidosis.