Replication of markers from recent inflammatory bowel disease genome-wide association scans in a Lithuanian cohort

Abstract

INTRODUCTION. Inflammatory bowel disease (IBD), a chronic inflammatory disorder affecting the intestinal mucosa, most commonly presents as either one of the two subtypes, ulcerative colitis (UC) or Crohn disease (CD). The genetic variations conferring susceptibility to IBD has increased substantially over the past few years after the introduction of genome-wide association scans (GWAS). Although several susceptibilty loci have been replicated, some of the associations have been reported to be unique for certain ethnicities. AIM. To perform a comprehensive association analysis of genetic markers reported by the two previous GWAS studies 1,2 to further characterize the CD and UC associations in a Lithuanian case-control sample set. To our knowledge, this is the first case-control study using an Eastern-European panel of IBD patients and healthy controls. MATERIAL AND METHODS. A set of 43 SNPs from three different categories were selected: (1) the 6 SNPs reported by Rioux et al.; (2) the 12 ‘non-converging’ CD SNPs from Parkes et al. and (3) 25 SNPs - markers ‘converging’ between CD and nonautoimmune disease cases of the same study. They were genotyped in a cohort of 152 UC (mean age: 41.80±17.07) and 73 CD (mean age: 35.72±15.38) patients plus 249 unrelated healthy controls (mean age: 43.30±12.39) using ligation-based SNPlex™ genotyping (Applied Biosystems, USA) technology. The SNPs were quality-controlled for: genotyping success rate (>90%), allele frequency (>1% in healthy controls), deviation from Hardy-Weinberg equilibrium (pHWE>0.01 in the control sample). Assessment of all SNPs and single-marker association analyses were performed using the software program Haploview 4.0. RESULTS. Single-marker analyses revealed marginal associations between IBD and genetic variants from category (2) and (3): CD and rs17419032 (1q32.1; p=4.96x10-2) and rs9993022 (4q13.1; p=4.78x10-2); UC and rs10883365 (NKX2-3; p=2.67x10-2), rs17419032 (1q32.1; p=3.44x10-2), rs12529198 (LYRM4; p=3.22x10-2, OR=0.37 (95%C.I.:0.15-0.93)) and rs9895062 (STX8; p=9.64x10-3, OR=0.34 (95%C.I.:0.16-0.78)). CONCLUSION. We replicated genetic associations for CD with 4q13.1, UC with NKX2-3, LYRM4, STX8, both subtypes with 1q32.1. However, the lack of non-replication for the other loci is probably due to the small sample size and the lack of statistical power. REFERENCES. 1. Rioux, J.D. et al. Nat. Genet.39,596-604 (2007). 2. Parkes, M. et al. Nat. Genet.39,830-832 (2007).