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Limited evidence for parent-of-origin effects in inflammatory bowel disease associated loci
Mitja Mitrovič, Karin Fransen, Uroš Potočnik, 2012, izvirni znanstveni članek

Opis: Background Genome-wide association studies of two main forms of inflammatory bowel diseases (IBD), Crohnʼs disease (CD) and ulcerative colitis (UC), have identified 99 susceptibility loci, but these explain only ~23% of the genetic risk. Part of the Žhidden heritabilityʼ could be in transmissible genetic effects in which mRNA expression in the offspring depends on the parental origin of the allele (genomic imprinting), since children whose mothers have CD are more often affected than children with affected fathers. We analyzed parent-of-origin (POO) effects in Dutch and Indian cohorts of IBD patients. Methods We selected 28 genetic loci associated with both CD and UC, and testedthem for POO effects in 181 Dutch IBD case-parent trios. Three susceptibility variants in NOD2 were tested in 111 CD trios and a significant finding was re-evaluated in 598 German trios. The UC-associated gene, BTNL2, reportedly imprinted, was tested in 70 Dutch UC trios. Finally, we used 62 independent Indian UC trios to test POO effects of five established Indian UC risk loci. Results We identified POO effects for NOD2 (L1007fs; OR = 21.0, P-value = 0.013) for CD; these results could not be replicated in an independent cohort (OR = 0.97, P-value = 0.95). A POO effect in IBD was observed for IL12B (OR = 3.2, P-value = 0.019) and PRDM1 (OR = 5.6, P-value = 0.04). In the Indian trios the IL10 locus showed a POO effect (OR = 0.2, P-value = 0.03). Conclusions Little is known about the effect of genomic imprinting in complex diseases such as IBD. We present limited evidence for POO effects for the tested IBD loci. POO effects explain part of the hidden heritability for complex genetic diseases but need to be investigated further.
Ključne besede: inflammatory bowel diseases, IBD, genetic locus, genetics
Objavljeno: 10.07.2015; Ogledov: 279; Prenosov: 1
.pdf Polno besedilo (495,25 KB)

High-resolution melting curve analysis for high-throughput genotyping of NOD2/CARD15 mutations and distribution of these mutations in Slovenian inflammatory bowel diseases patients
Mitja Mitrovič, Uroš Potočnik, 2011, izvirni znanstveni članek

Opis: Inflammatory bowel diseases (IBD) are usually classified into Crohn's disease (CD) and ulcerative colitis (UC). NOD2/CARD15 was the first identified CD-susceptibility gene and was confirmed as the most potent disease gene in CD pathogenesis. Three NOD2/CARD15 variants, namely two missense polymorphisms R702W (rs2066844) and G908R (rs2066845), and a frame shift polymorphism L1007fs (rs2066847), were associated with CD in Caucasian populations. High resolution melting analysis (HRMA) with saturation LCGreen dyes was previously reported as a simple, inexpensive, accurate and sensitive method for genotyping and/or scanning of rare variants. For this reasons we used qPCR-HRMA for genotyping NOD2/CARD15 variants in 588 Slovenian IBD patients and 256 healthy controls. PCR-RFLP was used as a reference method for genotyping of clinical samples. The optimization of an HRM experiment required careful design and adjustment of main parameters, such as primer concentration, MgCl_{2} concentration, probe design and template DNA concentration. Different HRMA approaches were tested and used to develop a reliable and low-cost SNP genotyping assays for polymorphisms in NOD2/CARD15 gene. Direct HRMA was the fastest and cheapest HRMA approach for L1007fs and R702W polymorphisms, yet for G908R polymorphism sufficient reliability was achieved after introduction of unlabeled probe. In association analysis, we found statistically significant association of L1007fs (p =0.001, OR=3.011, CI95%=1.494-6.071) and G908R (p=2.62 * 10^{-4}, OR=14.117, CI95%= 1.884-105.799) polymorphisms with CD patients. At least one of NOD2/CARD15 polymorphisms was found in 78/354 (22.03% (12.69%) in UC patients and in 26/256 (10.15%) in healthy controls. We have successfully implemented NOD2/CARD15 HRMA assays, which may contribute to the development of genetic profiles for risk prediction of developing CD and for differential diagnosis of CD vs. UC.
Ključne besede: high-resolution melting analysis, NOD2/CARD15, inflammatory bowel diseases
Objavljeno: 14.06.2017; Ogledov: 118; Prenosov: 0
.pdf Polno besedilo (1,72 MB)

High resolution melting curve analysis for high-throughput SNP genotyping in IL23R gene and association of IL23R with Slovenian inflammatory bowel diseases patients
Mitja Mitrovič, Uroš Potočnik, 2010, izvirni znanstveni članek

Opis: Single nucleotide polymorphism (SNP) analysis is important tool in the studies of genetic factors associated with complex diseases and with genetically influenced response to drug therapy (pharmacogenetics). Recently, a new generation of generic dsDNA binding dyes (LCGreen$^{TM}$) contributed to the development of fast and low-cost method for SNP detection and/or genotyping based on high resolution melting (HRM) analysis. The aim of our study was to develop HRM assay for IL23R gene (rs7517847) and to perform association study in Slovenian inflammatory bowel diseases (IBD) patients. We genotyped 345 Slovenian healthy controls and 295 IBD patients including 159 with Crohn's disease (CD) and 136 with ulcerative colitis (UC) for rs7517847 polymorphism in IL23R gene using standard RFLP and optimized HRM methods. In this study, we showed, that HRM is a simple, fast and reliable method for genotyping of clinical samples where homozygotes (GG and TT) were determined by Tm calling method and difference between homozygotes and heterozygotes was determined by different melting curve shape using gene scanning method. With combination of results from Tm calling and gene scanning methods, we achieved 98,6% concordance between PCR-RFLP and PCRHRM results, based on the analysis of 640 samples. We found statistically significant association of IL23R polymorphism with Slovenian Crohn's disease patients when comparing genotype and allele frequencies between CD patients and controls. Allele frequency of minor allele G was 0,46 in controls and was reduced to 0,33 in CD patients (p < 0,001, OR = 0,588). The frequency of T/T genotype carriers was higher in CD patients (50,3%) than in controls (26,7%, p = 0,002, OR = 2,558). We found weak association between IL23R polymorphism and Slovenian UC patients. Carriers of T/T genotype have higher risk for UC (p = 0,035, OR = 1,599). These results suggest IL23R plays important role in CD and UC development in Slovenian patients.
Ključne besede: SNP genotyping, high resolution melting, DNA dyes, inflammatory bowel diseases, LC Green Plus
Objavljeno: 18.08.2017; Ogledov: 84; Prenosov: 0
.pdf Polno besedilo (232,19 KB)

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