Medical Department, Viborg Regional Hospital, Denmark.
BMC Med Genet. 2011 Oct 13;12:139. doi: 10.1186/1471-2350-12-139.
Differences in the genetic architecture of inflammatory bowel disease between different European countries and ethnicities have previously been reported. In the present study, we wanted to assess the role of 11 newly identified UC risk variants, derived from a recent European UC genome wide association study (GWAS) (Franke et al., 2010), for 1) association with UC in the Nordic countries, 2) for population heterogeneity between the Nordic countries and the rest of Europe, and, 3) eventually, to drive some of the previous findings towards overall genome-wide significance.
Eleven SNPs were replicated in a Danish sample consisting of 560 UC patients and 796 controls and nine missing SNPs of the German GWAS study were successfully genotyped in the Baltic sample comprising 441 UC cases and 1156 controls. The independent replication data was then jointly analysed with the original data and systematic comparisons of the findings between ethnicities were made. Pearson's χ2, Breslow-Day (BD) and Cochran-Mantel-Haenszel (CMH) tests were used for association analyses and heterogeneity testing.
The rs5771069 (IL17REL) SNP was not associated with UC in the Danish panel. The rs5771069 (IL17REL) SNP was significantly associated with UC in the combined Baltic, Danish and Norwegian UC study sample driven by the Norwegian panel (OR = 0.89, 95% CI: 0.79-0.98, P = 0.02). No association was found between rs7809799 (SMURF1/KPNA7) and UC (OR = 1.20, 95% CI: 0.95-1.52, P = 0.10) or between UC and all other remaining SNPs. We had 94% chance of detecting an association for rs7809799 (SMURF1/KPNA7) in the combined replication sample, whereas the power were 55% or lower for the remaining SNPs.Statistically significant PBD was found for OR heterogeneity between the combined Baltic, Danish, and Norwegian panel versus the combined German, British, Belgian, and Greek panel (rs7520292 (P = 0.001), rs12518307 (P = 0.007), and rs2395609 (TCP11) (P = 0.01), respectively).No SNP reached genome-wide significance in the combined analyses of all the panels.
This replication study supports an important role for the studied rs5771069 (IL17REL) SNP, but not for rs7809799 (SMURF1/KPNA7), in UC etiology in the Danish, Baltic, and Norwegian populations. Significant genetic heterogeneity was suggested for rs7520292, rs12518307, and rs2395609 (TCP11) in UC etiology between the Nordic and the other European populations.
先前已有报道称，不同欧洲国家和种族之间炎症性肠病的遗传结构存在差异。在本研究中，我们希望评估 11 个新鉴定的溃疡性结肠炎风险变异体（源自最近的欧洲溃疡性结肠炎全基因组关联研究（GWAS）（Franke 等人，2010 年））在以下方面的作用：1）与北欧国家的溃疡性结肠炎的相关性，2）北欧国家与欧洲其他地区之间的人群异质性，以及 3）最终，将部分先前的研究结果推进到全基因组显著性水平。
在丹麦样本中，11 个 SNP 进行了复制，该样本包括 560 例溃疡性结肠炎患者和 796 例对照；在德国 GWAS 研究中，9 个缺失的 SNP 在波罗的海样本中成功进行了基因分型，该样本包括 441 例溃疡性结肠炎病例和 1156 例对照。然后联合分析了独立的复制数据和原始数据，并对不同种族之间的发现进行了系统比较。采用 Pearson χ2、Breslow-Day（BD）和 Cochran-Mantel-Haenszel（CMH）检验进行关联分析和异质性检验。
rs5771069（IL17REL）SNP 与丹麦组中的溃疡性结肠炎无关。rs5771069（IL17REL）SNP 与联合的波罗的海、丹麦和挪威溃疡性结肠炎研究样本显著相关，该 SNP 由挪威组驱动（OR=0.89，95%CI：0.79-0.98，P=0.02）。rs7809799（SMURF1/KPNA7）与溃疡性结肠炎之间未发现关联（OR=1.20，95%CI：0.95-1.52，P=0.10），也未发现其他 SNP 与溃疡性结肠炎之间存在关联。在联合复制样本中，rs7809799（SMURF1/KPNA7）有 94%的机会被检测到关联，而其余 SNP 的检测机会则低于 55%。联合的波罗的海、丹麦和挪威组与联合的德国、英国、比利时和希腊组之间的 OR 异质性存在统计学显著的 PBD（rs7520292（P=0.001）、rs12518307（P=0.007）和 rs2395609（TCP11）（P=0.01））。在所有面板的联合分析中，没有 SNP 达到全基因组显著性水平。
这项复制研究支持研究的 rs5771069（IL17REL）SNP 在丹麦、波罗的海和挪威人群中对溃疡性结肠炎发病机制的重要作用，但 rs7809799（SMURF1/KPNA7）没有作用。rs7520292、rs12518307 和 rs2395609（TCP11）在北欧和其他欧洲人群的溃疡性结肠炎发病机制中存在显著的遗传异质性。
