Contribution of NKX2-3 Polymorphisms to Inflammatory Bowel Diseases: A Meta-Analysis of 35358 subjects

Scientific Reports, Jan 2014

Polymorphisms in NKX2-3 gene have been inconsistently associated with Crohn's disease (CD) and ulcerative colitis (UC). To generate large-scale evidence on whether NKX2-3 polymorphisms are associated with CD or UC susceptibility we have conducted a meta-analysis of 17 studies involving 17329 patients and 18029 controls. A significantly increased CD or UC risk was observed in persons carrying a G allele at rs10883365 polymorphism (A/G) compared with those with a A allele. (OR = 1.226, 95%CI: 1.177–1.277 and OR = 1.274, 95%CI: 1.175–1.382 respectively). In the subgroup analysis, a significantly increased CD risk was found in both Europeans and Asians. For rs11190140 polymorphism (C/T) and CD risk, the risk estimate for the allele contrast was OR = 1.201 (1.136–1.269). This meta-analysis provided a robust result that persons with a G or T allele may have a moderately increased risk of CD, and suggested that rs10883365 polymorphism was also a candidate gene polymorphism for UC susceptibility.

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Contribution of NKX2-3 Polymorphisms to Inflammatory Bowel Diseases: A Meta-Analysis of 35358 subjects

Abstract Polymorphisms in NKX2-3 gene have been inconsistently associated with Crohn's disease (CD) and ulcerative colitis (UC). To generate large-scale evidence on whether NKX2-3 polymorphisms are associated with CD or UC susceptibility we have conducted a meta-analysis of 17 studies involving 17329 patients and 18029 controls. A significantly increased CD or UC risk was observed in persons carrying a G allele at rs10883365 polymorphism (A/G) compared with those with a A allele. (OR = 1.226, 95%CI: 1.177–1.277 and OR = 1.274, 95%CI: 1.175–1.382 respectively). In the subgroup analysis, a significantly increased CD risk was found in both Europeans and Asians. For rs11190140 polymorphism (C/T) and CD risk, the risk estimate for the allele contrast was OR = 1.201 (1.136–1.269). This meta-analysis provided a robust result that persons with a G or T allele may have a moderately increased risk of CD, and suggested that rs10883365 polymorphism was also a candidate gene polymorphism for UC susceptibility. Introduction Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders characterized by chronic relapsing inflammation of the gastrointestinal tract that affect 0.1% of Western populations, comprising two major forms, Crohn's disease (CD) and ulcerative colitis (UC)1. In Crohn's disease the inflammation is often transmural, whereas in ulcerative colitis the inflammation is typically confined to the mucosa. Additionally, Crohn's disease can be associated with intestinal granulomas, strictures, and fistulas, but these are not typical findings in ulcerative colitis. Although our understanding of disease pathogenesis remains incomplete, accumulating evidence suggests that that IBD is a complex, multifactorial disease partly determined by a genetic predisposition2. Strong familial aggregation, twin studies, and established genetic associations3,4,5. indicate that there is a genetic component to the disease susceptibility in IBD. Recently, sequence variations associated with IBD have been reported for several genes, including NOD2, IL23R, IRGM, ATG16L1, PTPN2, and NK2 transcription factor related and locus 3 (NKX2-3)6,7,8,9,10,11. NKX2-3, located on 10q24, is a member of a family of genes that encodes transcription factors containing homeodomains and, therefore, is implicated in basic developmental functions. During development, NKX2-3 is expressed in midgut and hindgut mesoderm and spleen, as well as in pharyngeal endoderm12,13. The association between the NKX2-3 polymorphism and susceptibility of IBD was first reported in Caucasian patients14. After the first report of the association, several studies confirmed the association of tag-SNPs (rs10883365 and rs1190140) in the NKX2-3 gene with CD15,16 as well as with UC in Caucasian or Asian populations17,18,19. However, several studies could not replicate the genetic association between IBD and NKX2-3 polymorphsims15,20,21. Thus, a quantitative synthesis may help to provide clearer evidence on the association of such genetic polymorphisms with IBD. In the present study, we conducted a meta-analysis of all eligible studies to quantitatively assess the associations between three common polymorphisms (rs10883365 and rs11190140) in the NKX2-3 gene and IBD susceptibility. Results Characteristics of the included studies The combined search yielded 75 references, of which 31 were duplicate studies, 9 were reviews, 4 were about cell studies, 8 were only with abstracts, 7 reported other mutations, 1 reported other disease. Finally, a total of 15 articles were finally included. Among them, one publication15 contained data on two different subpopulations, one16 included Wellcome Trust Case Control Consortium (WTCCC) samples and replication Crohn's disease (RCD) samples, and we treated them independently. In total, 17 studies comprising 17329 cases and 18029 controls were included in the present meta-analysis11,15,16,17,18,19,20,21,22,23,24,25,26,27,28. The 17 separate studies consisted of 13 European and 4 Asian. The distribution of genotypes in the control groups of all studies was in agreement with HWE except for 1 study19. Summaries of all included studies were summarized in Table 1, and the flow chart of study selection process was shown in Figure 1. Table 1: Main Characteristics of Studies Involved in NKX2-3 polymorphism and Crohn's disease or ulcerative colitis Risk Full size table Figure 1: Study selection procedures for a meta-analysis of NKX2-3 polymorphisms and risk of CD or UC. NKX2-3: NK2 transcription factor related and locus 3; CD: Crohn's disease; UC: ulcerative colitis. Full size image Quantitative synthesisCrohn's disease The summary of meta-analysis for the NKX2-3 polymorphisms with CD is shown in Table 2, Figure 2A and Supplementary Figure S1. Regarding rs10883365 polymorphism, the results of combined analyses comprising 8699 cases and 13540 controls revealed a significantly increased risk of CD in all genetic models. In addition, (...truncated)


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XiaoCheng Lu, Linjun Tang, Kai Li, JinYu Zheng, Penglai Zhao, Yi Tao, Li-Xin Li. Contribution of NKX2-3 Polymorphisms to Inflammatory Bowel Diseases: A Meta-Analysis of 35358 subjects, Scientific Reports, 2014, Issue: 4, DOI: 10.1038/srep03924