ORIGINAL ARTICLE Association of DLG5 Variants with Inflammatory Bowel Disease in the New Zealand Caucasian Population and Meta- analysis of the DLG5 R30Q Variant Brian L. Browning, PhD,* ,†,‡ Claudia Huebner, PhD,* ,‡ Ivonne Petermann, PhD,* ,‡ Pieter Demmers, BSc, ‡,§ Alan McCulloch, BSc, ‡,| Richard B. Gearry, BM, ChB, PhD, ¶ Murray L. Barclay, MD,** Andrew N. Shelling, PhD, ‡,†† and Lynnette R. Ferguson, DPhil (Oxon), DSc* ,‡ Background: Variants in the DLG5 gene have been associated with inflammatory bowel disease (IBD) in samples from some, but not all populations. In particular, 2 nonsynonymous single-nucle- otide polymorphisms (SNPs), R30Q (rs1248696) and P1371Q (rs2289310), have been associated with an increased risk of IBD, and a common haplotype (called haplotype “A”) has been associated with reduced risk. Methods: We genotyped R30Q, P1371Q, and a haplotype A tagging SNP (rs2289311) in a New Zealand Caucasian cohort of 389 Crohn’s disease (CD) patients, 406 ulcerative colitis (UC) patients, and 416 population controls. Each SNP was tested for association with disease susceptibility and clinical phenotypes. We also per- formed a meta-analysis of R30Q data from published association studies. Results: The haplotype A tagging SNP was associated with reduced risk of IBD at the 0.05 significance level (P = 0.036) with an allelic odds ratio of 0.83 (95% confidence interval [CI]: 0.69 – 0.99). Association with haplotype A was strongest (odds ratio 0.57) in UC patients with familial IBD or extraintestinal manifes- tations. The R30Q and P1371Q polymorphisms were not signifi- cantly associated with UC, CD, or IBD. Analysis of male and female data did not find any gender-specific associations. Meta-analysis gave no evidence of association of R30Q with IBD. Conclusions: Meta-analysis demonstrates that the minor allele of R30Q is not a risk factor for IBD across populations. This study provides some evidence that DLG5 haplotype A is associated with reduced risk of IBD in the New Zealand Caucasian population, but this association will need to be replicated in an independent sample. (Inflamm Bowel Dis 2007;13:1069 –1076) Key Words: DLG5, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, meta-analysis I nflammatory bowel disease (IBD; MIM 266600) comprises Crohn’s disease (CD) and ulcerative colitis (UC), and is characterized by idiopathic inflammation of the gastrointes- tinal tract leading to diarrhea, abdominal pain, and rectal bleeding. While the precise etiology of IBD remains elusive, there is strong evidence for genes playing an important role, as seen in family, 1–3 twin, 4 and linkage studies. 5,6 Early successes in identifying genetic susceptibility loci include the identification of variants in the CARD15/NOD2 (MIM 605956) gene on chromosome 16 7,8 and variants in the 5q31 region (MIM 606348) 9 that have well-replicated association with CD. 10 –14 Identification of genetic polymorphisms asso- ciated with IBD has allowed further elucidation of the biol- ogy that may lead to the development of IBD. 15 In 2004 Stoll et al 16 performed hierarchical fine map- ping of a linkage peak on chromosome 10q23 and identified multiple variants associated with UC and CD in the DLG5 gene (Drosophila Discs large Homolog 5; MIM 604090) in a German population. 17 DLG5 is widely expressed in human tissues (e.g., pla- centa, heart) including the gastrointestinal tract (small bowel, intestinal epithelial cells, and colon). 18,19 DLG5 belongs to the family of MAGUK proteins (membrane-associated guan- ylate kinase homologs) which are known to form scaffolds for proteins involved in intracellular signal transduction. 18 The protein may be involved in maintenance of epithelial Received for publication December 11, 2006; accepted March 13, 2007. From the *Discipline of Nutrition, University of Auckland, New Zealand, † Department of Statistics, University of Auckland, New Zealand, ‡ Nutrig- enomics New Zealand, §Crop and Food Research, Mosgiel, New Zealand, | AgResearch Limited, Mosgiel, New Zealand, ¶ Department of Gastroenter- ology, Box Hill Hospital, Monash University, Australia, **Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand, †† De- partment of Obstetrics and Gynaecology, University of Auckland, New Zealand. Funding sources for the case and control DNA collection are the Canter- bury Medical Research Foundation, Canterbury Liver and Digestive Dis- eases Trust, and Christchurch Gastroenterology Research Trust. Nutrigenomics New Zealand is a collaboration between AgResearch Ltd., Crop & Food Research, HortResearch, and the University of Auckland, with funding through the Foundation for Research Science and Technology. Reprints: Brian L. Browning, Discipline of Nutrition, University of Auckland, Private Bag 92019, Auckland, New Zealand (e-mail: b.browning@auckland.ac.nz). Copyright © 2007 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20157 Published online 23 April 2007 in Wiley InterScience (www.interscience. wiley.com). Inflamm Bowel Dis ● Volume 13, Number 9, September 2007 1069