Association of a Nkx2-3 polymorphism with Crohn's disease and expression of Nkx2-3 is up-regulated in B cell lines and intestinal tissues with Crohn's disease

Wu, Yu; Lin, Zhenwu; Kelly, Ashley A.; Hegarty, John P.; Poritz, Lisa S.; Wang, Yunhua; Li, Tongyi; Schreiber, Stefan; Koltun, Walter A.

doi:10.1016/j.crohns.2009.04.003

Cited by 21 publications

(29 citation statements)

References 26 publications

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“…Since our studies showed rs2542151 and rs2542152 were associated with CD but not UC, there may be a possible connection between the association of the two SNPs with PTPN2 up-regulation in CD. NKX2-3 is associated with IBD and up-regulated in CD patients [10]. We found that expression of NKX2-3 was increased in B cells and intestinal tissues from CD patients, and expression of PTPN2 was decreased in NKX2-3 knockdown human cells.…”

Section: Discussionmentioning

confidence: 64%

“…NKX2-3 (NK2 transcription factor related, locus 3) is an IBD-associated intestinal transcription factor [1,2] with increased levels of mRNA expression in CD patients [10]. Our cDNA microarray data showed that PTPN2 expression is down-regulated following knockdown of NKX2-3 in B cells from IBD patients [11,12] and human intestinal microvascular endothelial cells (HIMEC) [13].…”

Section: Introductionmentioning

confidence: 79%

“…Transcription factor NKX2-3 is associated with IBD and its expression is up-regulated in CD patients [10]. To confirm these results, we first examined NKX2-3 mRNA expression levels in 14 CD and 12 UC together with their non-IBD family members from B cell lines as indicated above in the PTPN2 study.…”

Section: Expression Of Nkx2-3 In B Cells and Intestinal Tissues From mentioning

confidence: 99%

“…Western blotting was performed as described previously [10]. Briefly, B cells and HIMEC were lysed with RIPA buffer (25 mM Tris-HCl, PH 7.6, 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS ) and protease inhibitor cocktail (Roche, Germany).…”

Section: Western Blottingmentioning

confidence: 99%

“…Using standard procedures, B cell lines were established for individual family members entered into our IBD patient registry [10,11]. B cell lines were cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS) at 37…”

Section: Establishment Of B Cell Linesmentioning

confidence: 99%

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PTPN2 is Associated with Crohn’s Disease and Its Expression Is Regulated by NKX2-3

Hegarty

Berg

et al. 2012

Disease Markers

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Abstract. PTPN2 is a risk gene for Crohn's disease (CD). We investigated whether PTPN2 genetic variants (rs2542151 and rs2542152) were associated with CD in a familial IBD registry. Both rs2542151 and rs2542152 are associated with CD, but not ulcerative colitis (UC). mRNA expression levels of PTPN2 were significantly increased in intestinal tissues (p = 0.0493), and nearly significantly increased in B cells (p = 0.0889) from CD patients, but not significantly altered in UC. cDNA microarray results found that PTPN2 was down-regulated by NKX2-3 knockdown in human cells. We confirmed this observation by RT-PCR analyses in NKX2-3 knockdown in B cells from IBD patients and human intestinal microvascular endothelial cells (HIMEC). In addition, we found that mRNA expression of another IBD-associated gene, NKX2-3, was increased in intestinal tissues and B cells from CD patients, but not significantly increased in UC patients. A positive correlation was observed between mRNA expression of PTPN2 and NKX2-3 in B cells and in intestinal tissues from both CD and UC patients. These results suggest that PTPN2 may have an important role in CD pathogenesis and may represent a potential diagnostic and therapeutic target for IBD.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 79%

Section: Expression Of Nkx2-3 In B Cells and Intestinal Tissues From mentioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

Section: Establishment Of B Cell Linesmentioning

confidence: 99%

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PTPN2 is Associated with Crohn’s Disease and Its Expression Is Regulated by NKX2-3

Hegarty

Berg

et al. 2012

Disease Markers

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Trees Assembling Mann‐Whitney Approach for Detecting Genome‐Wide Joint Association Among Low‐Marginal‐Effect Loci

Wei

Schaid

2012

Genetic Epidemiology

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Common complex diseases are likely influenced by the interplay of hundreds, or even thousands, of genetic variants. Converging evidence shows that genetic variants with low-marginal-effects (LME) play an important role in disease development. Despite their potential significance, discovering LME genetic variants and assessing their joint association on high-dimensional data (e.g., genome-wide association studies) remain a great challenge. To facilitate joint association analysis among a large ensemble of LME genetic variants, we proposed a computationally efficient and powerful approach, which we call Trees Assembling Mann-Whitney (TAMW). Through simulation studies and an empirical data application, we found that TAMW outperformed multifactor dimensionality reduction (MDR) and the likelihood-ratio-based Mann-Whitney approach (LRMW) when the underlying complex disease involves multiple LME loci and their interactions. For instance, in a simulation with 20 interacting LME loci, TAMW attained a higher power (power=0.931) than both MDR (power=0.599) and LRMW (power=0.704). In an empirical study of 29 known Crohn’s disease (CD) loci, TAMW also identified a stronger joint association with CD than those detected by MDR and LRMW. Finally, we applied TAMW to Wellcome Trust CD GWAS to conduct a genome-wide analysis. The analysis of 459K single nucleotide polymorphisms was completed in 40 hours using parallel computing, and revealed a joint association predisposing to CD (p-value=2.763e-19). Further analysis of the newly discovered association suggested that 13 genes, such as ATG16L1 and LACC1, may play an important role in CD pathophysiological and etiological processes.

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Genes Regulated by Nkx2-3 in Sporadic and Inflammatory Bowel Disease-Associated Colorectal Cancer Cell Lines

Lin

Pastor

et al. 2010

Dig Dis Sci

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Association of a Nkx2-3 polymorphism with Crohn's disease and expression of Nkx2-3 is up-regulated in B cell lines and intestinal tissues with Crohn's disease

Abstract: Nkx2-3 is genetically associated with CD and is up-regulated in CD, suggesting that Nkx2-3 is involved in the pathogenesis of CD.

Cited by 21 publications

References 26 publications

PTPN2 is Associated with Crohn’s Disease and Its Expression Is Regulated by NKX2-3

PTPN2 is Associated with Crohn’s Disease and Its Expression Is Regulated by NKX2-3

Trees Assembling Mann‐Whitney Approach for Detecting Genome‐Wide Joint Association Among Low‐Marginal‐Effect Loci

Genes Regulated by Nkx2-3 in Sporadic and Inflammatory Bowel Disease-Associated Colorectal Cancer Cell Lines

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