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Replication Study of Ulcerative Colitis Risk Loci in a Lithuanian–Latvian Case–Control Sample

Skieceviciene, Jurgita PhD*; Kiudelis, Gediminas MD, PhD; Ellinghaus, Eva PhD; Balschun, Tobias PhD; Jonaitis, Laimas V. MD, PhD; Zvirbliene, Aida MD, PhD*,†; Denapiene, Goda MD, PhD§; Leja, Marcis MD, PhD; Pranculiene, Gitana MD; Kalibatas, Vytenis MD, PhD**; Saadati, Hamidreza MSc; Ellinghaus, David PhD; Andersen, Vibeke MD, PhD††,‡‡; Valantinas, Jonas MD, PhD§; Irnius, Algimantas MD, PhD§; Derovs, Aleksejs MD§§; Tamelis, Algimantas MD, PhD¶¶; Schreiber, Stefan MD, PhD; Kupcinskas, Limas MD, PhD*,†; Franke, Andre PhD

doi: 10.1097/MIB.0b013e3182a3eaeb
Original Basic Science Articles

Background: Differences between populations might be reflected in their different genetic risk maps to complex diseases, for example, inflammatory bowel disease. We here investigated the role of known inflammatory bowel disease–associated single nucleotide polymorphisms (SNPs) in a subset of patients with ulcerative colitis (UC) from the Northeastern European countries Lithuania and Latvia and evaluated possible epistatic interactions between these genetic variants.

Methods: We investigated 77 SNPs derived from 5 previously published genome-wide association studies for Crohn's disease and UC. Our study panel comprised 444 Lithuanian and Latvian patients with UC and 1154 healthy controls. Single marker case–control association and SNP-SNP epistasis analyses were performed.

Results: We found 14 SNPs tagging 9 loci, including 21q21.1, NKX2-3, MST1, the HLA region, 1p36.13, IL10, JAK2, ORMDL3, and IL23R, to be associated with UC. Interestingly, the association of UC with previously identified variants in the HLA region was not the strongest association in our study (P = 4.34 × 10−3, odds ratio [OR] = 1.25), which is in contrast to all previously published studies. No association with any disease subphenotype was found. SNP-SNP interaction analysis showed significant epistasis between SNPs in the PTPN22 (rs2476601) and C13orf31 (rs3764147) genes and increased risk for UC (P = 1.64 × 10−6, OR = 2.44). The association has been confirmed in the Danish study group (P = 0.04, OR = 3.25).

Conclusions: We confirmed the association of the 9 loci (21q21.1, 1p36.13, NKX2-3, MST1, the HLA region, IL10, JAK2, ORMDL3, and IL23R) with UC in the Lithuanian–Latvian population. SNP-SNP interaction analyses showed that the combination of SNPs in the PTPN22 (rs2476601) and C13orf31 (rs3764147) genes increase the risk for UC.

Article first published online 22 August 2013

*Institute for Digestive Research and

Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania;

Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany;

§Center of Hepatology, Gastroenterology and Dietetics, Vilnius University, Vilnius, Lithuania;

Digestive Diseases Centre GASTRO, Riga, Latvia;

Departments of Children Diseases and

**Health Management, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania;

††Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark;

‡‡Medical Department, Hospital of Southern Jutland, Aabenraa, Denmark;

§§Internal Disease Department, Riga Stradins University, Riga, Latvia; and

¶¶Department of Surgery, Academy of Medicine, Lithuanian University of Health Science, Kaunas, Lithuania.

Reprints: Jurgita Skieceviciene, PhD, Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus Street 9, Kaunas LT-44307, Lithuania (e-mail: j.sventoraityte@gmail.com).

Supported by the German Ministry of Education and Research through the National Genome Research Network (NGFN), the PopGen Biobank, and received infrastructure support through the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence “Inflammation at Interfaces”; grant of the Research Council of Lithuania (MIP-078/2011) and the European Social Fund (009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016).

The authors have no conflicts of interest to disclose.

Limas Kupcinskas and Andre Franke contributed equally to this work.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

Received June 18, 2013

Accepted July 07, 2013

© Crohn's & Colitis Foundation of America, Inc.
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