Medical Department, Rikshospitalet University Hospital and University of Oslo, 0027 Oslo, Norway.
Gastroenterology. 2010 Mar;138(3):1102-11. doi: 10.1053/j.gastro.2009.11.046. Epub 2009 Nov 26.
BACKGROUND & AIMS: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers.
A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls).
The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6-6.5; P = 2.6 x 10(-26); and rs2844559: OR, 4.7; 95% CI, 3.5-6.4; P = 4.2 x 10(-26) in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06-1.50; and rs3197999: OR, 1.22; 95% CI, 1.02-1.47, respectively), with circumstantial evidence supporting the G-protein-coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes.
Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC.
我们旨在通过全基因组关联分析单核苷酸多态性（SNP）标记物，来描述原发性硬化性胆管炎（PSC）的遗传易感性。
在 285 例挪威 PSC 患者和 298 例健康对照者中，对 Affymetrix SNP Array 5.0（Affymetrix，圣克拉拉，加利福尼亚州）上的 443816 个 SNP 进行了基因分型。在来自斯堪的纳维亚（137 例 PSC 病例和 368 例对照）、比利时/荷兰（229 例 PSC 病例和 735 例对照）和德国（400 例病例和 1832 例对照）的独立病例对照面板中，重新检查了在发现面板中检测到的关联。
在 6p21 染色体上 HLA-B 附近检测到最强的关联（rs3099844：比值比[OR]，4.8；95%置信区间[CI]，3.6-6.5；P = 2.6 x 10(-26)；rs2844559：OR，4.7；95% CI，3.5-6.4；P = 4.2 x 10(-26)）。在 HLA 复合物之外，在 13q31 染色体上的 rs9524260 在 4 个研究面板中的 3 个中显示出显著的关联。在胆管细胞系中，编码该基因座的糖蛋白 6 的慢病毒沉默导致促炎标志物的上调。在 15 个已确立的溃疡性结肠炎易感性基因座中，在染色体 2q35 和 3p21 上获得了显著的复制（rs12612347：OR，1.26；95%CI，1.06-1.50；rs3197999：OR，1.22；95%CI，1.02-1.47），有间接证据支持 G 蛋白偶联胆汁酸受体 1 和巨噬细胞刺激 1 分别为可能的疾病基因。
强 HLA 关联和一组参与胆汁稳态和其他炎症状态的基因是 PSC 遗传结构的关键组成部分。
