Garcia-Etxebarria Koldo, Jauregi-Miguel Amaia, Romero-Garmendia Irati, Plaza-Izurieta Leticia, Legarda Maria, Irastorza Iñaki, Bilbao Jose Ramon
Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV-EHU), BioCruces Health Research Institute, Leioa, Spain.
Department of Pediatrics, Pediatric Gastroenterology Unit, Cruces University Hospital, University of the Basque Country (UPV-EHU), Barakaldo, Spain.
Eur J Hum Genet. 2016 Dec;24(12):1831-1834. doi: 10.1038/ejhg.2016.120. Epub 2016 Sep 21.
To identify candidate genes in celiac disease (CD), we reanalyzed the whole Immunochip CD cohort using a different approach that clusters individuals based on immunoancestry prior to disease association analysis, rather than by geographical origin. We detected 636 new associated SNPs (P<7.02 × 10) and identified 5 novel genomic regions, extended 8 others previously identified and also detected 18 isolated signals defined by one or very few significant SNPs. To test whether we could identify putative candidate genes, we performed expression analyses of several genes from the top novel region (chr2:134533564-136169524), from a previously identified locus that is now extended, and a gene marked by an isolated SNP, in duodenum biopsies of active and treated CD patients, and non-celiac controls. In the largest novel region, CCNT2 and R3HDM1 were constitutively underexpressed in disease, even after gluten removal. Moreover, several genes within this region were coexpressed in patients, but not in controls. Other novel genes like KIF21B, REL and SORD also showed altered expression in active disease. Apart from the identification of novel CD loci, these results suggest that ancestry-based stratified analysis is an efficient strategy for association studies in complex diseases.
为了确定乳糜泻（CD）的候选基因，我们采用了一种不同的方法对整个免疫芯片CD队列进行重新分析，该方法在疾病关联分析之前根据免疫血统对个体进行聚类，而不是按地理来源聚类。我们检测到636个新的关联单核苷酸多态性（P<7.02×10），鉴定出5个新的基因组区域，扩展了之前鉴定的8个区域，还检测到由一个或极少数显著单核苷酸多态性定义的18个孤立信号。为了测试我们是否能够识别推定的候选基因，我们在活动期和经治疗的CD患者以及非乳糜泻对照的十二指肠活检中，对来自新发现的顶级区域（chr2:134533564 - 136169524）、一个现已扩展的先前鉴定位点以及一个由孤立单核苷酸多态性标记的基因的几个基因进行了表达分析。在最大的新区域中，即使在去除麸质后，CCNT2和R3HDM1在疾病中仍持续低表达。此外，该区域内的几个基因在患者中共同表达，但在对照中不表达。其他新基因如KIF21B、REL和SORD在活动期疾病中也显示出表达改变。除了鉴定新的CD基因座外，这些结果表明基于血统的分层分析是复杂疾病关联研究的一种有效策略。
