Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis.
ABSTRACT Following up on recent genome-wide association studies (GWAS) of Crohn's disease, we investigated 50 previously reported susceptibility loci in a German sample of individuals with Crohn's disease (n = 1,850) or ulcerative colitis (n = 1,103) and healthy controls (n = 1,817). Among these loci, we identified variants in 3p21.31, NKX2-3 and CCNY as susceptibility factors for both diseases, whereas variants in PTPN2, HERC2 and STAT3 were associated only with ulcerative colitis in our sample collection.
Article: Genes Differentially Regulated by NKX2-3 in B Cells Between Ulcerative Colitis and Crohn’s Disease Patients and Possible Involvement of EGR1[show abstract] [hide abstract]
ABSTRACT: Ulcerative colitis (UC) and Crohn’s disease (CD) are two related yet different forms of chronic intestinal inflammation. We investigated the genes regulated by NKX2-3 in B cells from a UC patient by cDNA microarray and compared the results to those genes regulated by NKX2-3 in B cells from a CD patient. Genes regulated by NKX2-3 in B cells from UC were mainly involved in cell growth, inflammation, and immune response. Among the genes regulated by NKX2-3 in both UC and CD, expression of 145 genes was similarly altered and 34 genes was differentially affected by NKX2-3 knockdown. EGR1 was up-regulated in NKX2-3 knockdown B cells from UC while down-regulated in NKX2-3 knockdown B cells from CD. mRNA expressions of NKX2-3 and EGR1 were increased in diseased intestinal tissues from 19 CD patients. NKX2-3 may play different roles in UC and CD pathogenesis by differential regulation of EGR1. KEY WORDS NKX2-3 –gene regulation–UC–cDNA microarray– EGR1Inflammation 04/2012; 35(3):889-899. · 1.75 Impact Factor
Article: Prevalence of genetic variants associated with inflammatory bowel disease in a healthy First Nations cohort.[show abstract] [hide abstract]
ABSTRACT: Inflammatory bowel disease is the result of both genes and environment. Canadian First Nations people, despite living in a region with a high prevalence of inflammatory bowel disease, are relatively protected from this disease. We aimed to compare the carriage of genetic variants associated with inflammatory bowel disease in healthy First Nations and white people. DNA was extracted from the venous blood of healthy First Nations (n = 340) and white (n = 285) participants from Manitoba. Genotyping was performed for 69 single nucleotide polymorphisms (SNPs) with known or suspected associations with inflammatory bowel disease. We compared the genotypes between groups by logistic regression, adjusting for multiple testing. We calculated a risk score for the NOD2 gene by adding the number of risk alleles at three important NOD2 SNPs (G908R, R702W and 3020insC). We found genetic variation between white and First Nations participants at 45 of 69 SNPs. Notably, carriage of the ATG16L1 T300A mutation was lower in First Nations participants (p = 4.1 × 10(-30)). Cumulative carriage of important NOD2 variants was significantly lower among First Nations participants (3.9% v. 15.2%; p < 0.0001 for risk score) than among white participants. Risk variants in IL23R (p = 0.014) and IL12B (p = 1.2 × 10(-16)), among others, were more prevalent among First Nations participants than among white participants. The low prevalence of variants associated with bacterial processing and handling in First Nations people may explain their relative protection from inflammatory bowel disease. Increased carriage of a number of risk variants, for example in the interleukin-23/Th17 pathway, is especially intriguing given their importance in other inflammatory diseases of high incidence in First Nations populations.Canadian Medical Association Journal 04/2012; 184(8):E435-41. · 8.22 Impact Factor
Article: Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease.[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: Pathogenesis of inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD), involves interaction between environmental factors and inappropriate immune responses in the intestine of genetically predisposed individuals. Bile acids and their nuclear receptor, FXR, regulate inflammatory responses and barrier function in the intestinal tract. METHODS: We studied the association of five variants (rs3863377, rs7138843, rs56163822, rs35724, rs10860603) of the NR1H4 gene encoding FXR with IBD. 1138 individuals (591 non-IBD, 203 UC, 344 CD) were genotyped for five NR1H4 genetic variants with TaqMan SNP Genotyping Assays. RESULTS: We observed that the NR1H4 SNP rs3863377 is significantly less frequent in IBD cases than in non-IBD controls (allele frequencies: P = 0.004; wild-type vs. SNP carrier genotype frequencies: P = 0.008), whereas the variant rs56163822 is less prevalent in non-IBD controls (allele frequencies: P = 0.027; wild-type vs. SNP carrier genotype frequencies: P = 0.035). The global haplotype distribution between IBD and control patients was significantly different (P = 0.003). This also held true for the comparison between non-IBD and UC groups (P = 0.004), but not for the comparison between non-IBD and CD groups (P = 0.079). CONCLUSIONS: We show that genetic variation in FXR is associated with IBD, further emphasizing the link between bile acid signaling and intestinal inflammation.BMC Research Notes 08/2012; 5(1):461.