Macrophage migration inhibitory factor gene polymorphisms in inflammatory bowel disease: An association study in New Zealand Caucasians and meta-analysis

AIM:To investigate the association of macrophage migration inhibitory factor(MIF)promoter polymorphisms with inflammatory bowel disease(IBD)risk.METHODS:One thousand and six New Zealand Caucasian cases and 540 Caucasian controls were genotyped for the MIF SNP-173G>C(rs755622)and the repeat polymorphism CATT5-8(rs5844572)using a predesigned TaqMan SNP assay and capillary electrophoresis,respectively.Data were analysed for single site and haplotype association with IBD risk and phenotype.Meta-analysis was employed,to assess cumulative evidence of association of MIF-173G>C with IBD.All published genotype data for MIF-173G>C in IBD were identified using PubMed and subsequently searching the references of all PubMed-identified studies.Imputed genotypes for MIF-173G>C were generated from the Wellcome Trust Case Control Consortium(and National Institute of Diabetes and Digestive and Kidney Diseases).Separate meta-analyses were performed on Caucasian Crohn’s disease(CD)(3863 patients,6031controls),Caucasian ulcerative colitis(UC)(1260 patients,1987 controls),and East Asian UC(416 patients and 789 controls)datasets using the Mantel-Haenszel method.The New Zealand dataset had 93%power,and the meta-analyses had 100%power to detect an effect size of OR=1.40 atα=0.05,respectively.RESULTS:In our New Zealand dataset,single-site analysis found no evidence of association of MIF polymorphisms with overall risk of CD,UC,and IBD or disease phenotype(all P values>0.05).Haplotype analysis found the CATT5/-173C haplotype occurred at a higher frequency in New Zealand controls compared to IBD patients(0.6 vs 0.01;P=0.03,OR=0.22;95%CI:0.05-0.99),but this association did not survive bonferroni correction.Meta-analysis of our New Zealand MIF-173G>C data with data from seven additional Caucasian datasets using a random effects model found no association of MIF polymorphisms with CD,UC,or overall IBD.Similarly,meta-analysis of all published MIF-173G>C data from East Asian datasets(416UC patients,789 controls)found no association of this promoter polymorphism with UC.

Single nucleotide polymorphism in the tumor necrosis factor-alpha gene affects inflammatory bowel diseases risk

AIM: To investigate the role that single nucleotide polymorphisms (SNPs) in the promoter of the tumour necrosis factor-alpha (TNF-α) gene play in the risk of inflammatory bowel diseases (IBDs) in a New Zealand population, in the context of international studies. METHODS: DNA samples from 388 patients with Crohn's disease (CD), 405 ulcerative colitis (UC), 27 indeterminate colitis (IC) and 201 randomly selected controls, from Canterbury, New Zealand were screened for 3 common polymorphisms in the TNF-α receptor: -238 G→A, -308 G→A and -857C→T, using a TaqmanR assay. A meta-analysis was performed on the data obtained on these polymorphisms combined with that from other published studies. RESULTS: Individuals carrying the -308 G/A allele had a significantly (OR = 1.91, χ2 = 17.36, P < 0.0001) increased risk of pancolitis, and a 1.57-fold increased risk (OR = 1.57, χ2 = 4.34, P = 0.037) of requiring a bowel resection in UC. Carrying the -857 C/T variant decreased the risk of ileocolonic CD (OR = 0.56, χ2 =4.32, P = 0.037), and the need for a bowel resection (OR = 0.59, χ2 = 4.85, P = 0.028). The risk of UC was reduced in individuals who were smokers at diagnosis, (OR = 0.48, χ2 = 4.86, P = 0.028). CONCLUSION: TNF-α is a key cytokine known to play a role in inflammatory response, and the locus for the gene is found in the IBD3 region on chromosome 6p21, known to be associated with an increased risk for IBD. The -308 G/A SNP in the TNF-α promoter is functional, and may account in part for the increased UC risk associated with the IBD3 genomic region. The -857 C/T SNP may decrease IBD risk in certain groups. Pharmaco- or nutrigenomic approaches may be desir- able for individuals with such affected genotypes.

NOD2 and ATG16L1 polymorphisms affect monocyte responses in Crohn's disease

AIM:To assess whether polymorphisms in NOD2 and ATG16L1 affect cytokine responses and mycobacterium avium subspecies paratuberculosis (MAP) survival in monocytes from Crohn's disease (CD) patients.METHODS:Monocytes were isolated from peripheral blood of CD patients of known genotype for common single nucleotide polymorphisms of NOD2 and ATG16L1.Monocytes were challenged with MAP and bacterial persistence assessed at subsequent time-points.Cytokine responses were assayed using a Milliplex multi-analyte profiling assay for 13 cytokines.RESULTS:Monocytes heterozygous for a NOD2 polymorphism (R702W,P268S,or 1007fs) were more permissive for growth of MAP (P=0.045) than those without.There was no effect of NOD2 genotype on subsequent cytokine expression.The T300A polymorphism ofATG16L1 did not affect growth of MAP in our model (P=0.175),but did increase expression of cytokines interleukin (IL)-10 (P=0.047) and IL-6 (P=0.019).CONCLUSION:CD-associated polymorphisms affected the elimination of MAP fromex vivo monocytes (NOD2),or expression of certain cytokines (ATG16L1),implying independent but contributory roles in the pathogenesis of CD.

SLC11A1 polymorphisms in inflammatory bowel disease and Mycobacterium avium subspecies paratuberculosis status

AIM: To test for association of SLC11A1 with inflammatory bowel disease (IBD) and Mycobacterium avium subspecies paratuberculosis (MAP) status in a Caucasian cohort. METHODS: Five hundred and seven Crohn's disease (CD) patients, 474 ulcerative colitis (UC) patients, and 569 healthy controls were genotyped for SLC11A1 1730G>A and SLC11A1 469+14G>C using pre-designed TaqMan  SNP assays. χ 2 tests were applied to test for association of single nucleotide polymorphisms (SNPs) with disease, and the presence of MAP DNA.RESULTS:SLC11A1 1730G>A and SLC11A 1469+14G>C were not associated with CD, UC, or IBD. The SLC11A1 1730A minor allele was over-represented in patients who did not require immunomodulator therapy (P = 0.002, OR: 0.29, 95% CI: 0.13-0.66). The frequency of the SLC11A1 469+14C allele was higher in the subset of study participants who tested positive for MAP DNA (P = 0.02, OR: 1.56, 95% CI: 1.06-2.29). No association of SLC11A1 1730G>A with MAP was observed.CONCLUSION: Although SLC11A1 was not associated with IBD, association with MAP suggests that SLC11A1 is important in determining susceptibility to bacteria implicated in the etiology of CD.