Zinovieva Elena, Kadi Amir, Letourneur Franck, Cagnard Nicolas, Izac Brigitte, Vigier Agathe, Said-Nahal Roula, Elewaut Dirk, de Vlam Kurt, Pimentel-Santos Fernando, Chiocchia Gilles, Breban Maxime
Institut Cochin, Paris Descartes University, CNRS (UMR 8104), Paris, France.
Arthritis Rheum. 2011 Jul;63(7):1853-9. doi: 10.1002/art.30377.
Our group previously identified a new susceptibility region linked to spondylarthritis (SpA) on chromosome 9q31-34. Fine mapping of this SPA2 locus allowed us to refine the peak of linkage to a 1.3-Mb interval. The objective of this study was to resequence most positional candidate genes lying in that region, to identify polymorphisms, and to examine their association with SpA.
Variants screening was performed in 30 independent patients with SpA from families with a high linkage score to the SPA2 locus and 30 control subjects. The coding regions, intron-exon boundaries, and 5'- and 3'-flanking regions of ZNF618, A1L4R1_HUMAN (AF495724), AMBP, KIF12, ORM1, ORM2, C9ORF91, ENSESTG000000230601, and TNFSF8 were resequenced to identify polymorphisms. Selected variants were genotyped in an extended French cohort (442 patients and 268 control subjects overall). Replication was performed in a combined Belgian and Portuguese cohort (433 patients and 299 control subjects).
Variants screening allowed us to identify 98 polymorphisms, 5 of which were selected for further studies, based on statistical significance. The rare intronic single-nucleotide polymorphism (SNP) rs3181357, located in TNFSF8, was significantly associated with SpA in the French and the replication cohorts (odds ratio [OR] 2.03, P = 0.009 and OR 2.26, P = 0.0014, respectively) and in the pooled analysis (OR 2.14, P = 0.0001).
Positional candidate gene screening in the SPA2 locus allowed us to identify and replicate an association between a rare SNP located in TNFSF8 and SpA. This new finding appears to be independent of an association with a haplotype near TNFSF15, which we recently reported.
我们的研究小组先前在9号染色体q31 - 34区域确定了一个与脊柱关节炎（SpA）相关的新的易感区域。对该SPA2位点进行精细定位，使我们能够将连锁峰值缩小到一个1.3兆碱基的区间。本研究的目的是对位于该区域的大多数位置候选基因进行重测序，以识别多态性，并研究它们与SpA的关联。
对来自与SPA2位点连锁评分高的家族的30例独立SpA患者和30例对照受试者进行变异筛查。对ZNF618、A1L4R1_HUMAN（AF495724）、AMBP、KIF12、ORM1、ORM2、C9ORF91、ENSESTG000000230601和TNFSF8的编码区、内含子 - 外显子边界以及5'和3'侧翼区域进行重测序以识别多态性。在一个扩大的法国队列（共442例患者和268例对照受试者）中对选定的变异进行基因分型。在比利时和葡萄牙联合队列（433例患者和299例对照受试者）中进行重复验证。
变异筛查使我们能够识别出98个多态性，基于统计学意义从中选择了5个进行进一步研究。位于TNFSF8中的罕见内含子单核苷酸多态性（SNP）rs3181357在法国队列和重复验证队列中与SpA显著相关（优势比[OR]分别为2.03，P = 0.009和OR 2.26，P = 0.0014），在汇总分析中（OR 2.14，P = 0.0001）也是如此。
在SPA2位点进行位置候选基因筛查使我们能够识别并重复验证位于TNFSF8中的一个罕见SNP与SpA之间的关联。这一新发现似乎独立于与TNFSF15附近单倍型的关联，我们最近报道过这种关联。
