Strong Evidence of a Combination Polymorphism of the Tyrosine Kinase 2 Gene and the Signal Transducer and Activator of Transcription 3 Gene as a DNA-Based Biomarker for Susceptibility to Crohn’s Disease in the Japanese Population

OBJECTIVE: An association between susceptibility to inflammatory bowel disease (IBD) and polymorphisms of both the tyrosine kinase 2 gene (TYK2) and the signal transducer and activator of transcription 3 gene (STAT3) was examined in a Japanese population in order to identify the genetic determinants of IBD. METHODS: The study subjects comprised 112 patients with ulcerative colitis, 83 patients with Crohn's disease (CD), and 200 healthy control subjects. Seven tag single-nucleotide polymorphisms (SNPs) in TYK2 and STAT3 were detected by PCR-restriction fragment length polymorphism. RESULTS: The frequencies of a C allele and its homozygous C/C genotype at rs2293152 SNP in STAT3 in CD patients were significantly higher than those in control subjects (P = 0.007 and P = 0.001, respectively). Furthermore, out of four haplotypes composed of the two tag SNPs (rs280519 and rs2304256) in TYK2, the frequencies of a Hap 1 haplotype and its homozygous Hap 1/Hap1 diplotype were significantly higher in CD patients in comparison to those in control subjects (P = 0.023 and P = 0.024, respectively). In addition, the presence of both the C/C genotype at rs2293152 SNP in STAT3 and the Hap 1/Hap 1 diplotype of TYK2 independently contributes to the pathogenesis of CD and significantly increases the odds ratio to 7.486 for CD (P = 0.0008). CONCLUSION: TYK2 and STAT3 are genetic determinants of CD in the Japanese population. This combination polymorphism may be useful as a new genetic biomarker for the identification of high-risk individuals susceptible to CD

Three little pieces for computer and relativity

Numerical relativity has made big strides over the last decade. A number of problems that have plagued the field for years have now been mostly solved. This progress has transformed numerical relativity into a powerful tool to explore fundamental problems in physics and astrophysics, and I present here three representative examples. These "three little pieces" reflect a personal choice and describe work that I am particularly familiar with. However, many more examples could be made.Comment: 42 pages, 11 figures. Plenary talk at "Relativity and Gravitation: 100 Years after Einstein in Prague", June 25 - 29, 2012, Prague, Czech Republic. To appear in the Proceedings (Edition Open Access). Collects results appeared in journal articles [72,73, 122-124

Genetic Variation in the Familial Mediterranean Fever Gene (MEFV) and Risk for Crohn's Disease and Ulcerative Colitis

BACKGROUND AND AIMS: The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1beta processing. Pyrin has been shown to interact with the gene product of NLRP3, NALP3/cryopyrin, also an important active member of the inflammasome. The NLRP3 region was recently reported to be associated with Crohn's disease (CD) susceptibility. We therefore sought to evaluate MEFV as an inflammatory bowel disease (IBD) susceptibility gene. METHODOLOGY AND RESULTS: MEFV colonic mucosal gene expression was significantly increased in experimental colitis mice models (TNBS p<0.0003; DSS p<0.006), in biopsies from CD (p<0.02) and severe ulcerative colitis (UC) patients (p<0.008). Comprehensive genetic screening of the MEFV region in the Belgian exploratory sample set (440 CD trios, 137 UC trios, 239 CD cases, 96 UC cases, and 107 healthy controls) identified SNPs located in the MEFV 5' haplotype block that were significantly associated with UC (rs224217; p = 0.003; A allele frequency: 56% cases, 45% controls), while no CD associations were observed. Sequencing and subsequent genotyping of variants located in this associated haplotype block identified three synonymous variants (D102D/rs224225, G138G/rs224224, A165A/rs224223) and one non-synonymous variant (R202Q/rs224222) located in MEFV exon 2 that were significantly associated with UC (rs224222: p = 0.0005; A allele frequency: 32% in cases, 23% in controls). No consistent associations were observed in additional Canadian (256 CD trios, 91 UC trios) and Scottish (495 UC, 370 controls) sample sets. We note that rs224222 showed marginal association (p = 0.012; G allele frequency: 82% in cases, 70% in controls) in the Canadian sample, but with a different risk allele. None of the NLRP3 common variants were associated with UC in the Belgian-Canadian UC samples and no significant interactions were observed between NLRP3 and MEFV that could explain the observed flip-flop of the rs224222 risk allele. CONCLUSION: The differences in association levels observed between the sample sets may be a consequence of distinct founder effects or of the relative small sample size of the cohorts evaluated in this study. However, the results suggest that common variants in the MEFV region do not contribute to CD and UC susceptibility.Journal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

rs1004819 Is the Main Disease-Associated IL23R Variant in German Crohn's Disease Patients: Combined Analysis of IL23R, CARD15, and OCTN1/2 Variants

The IL23R gene has been identified as a susceptibility gene for inflammatory bowel disease (IBD) in the North American population. The aim of our study was to test this association in a large German IBD cohort and to elucidate potential interactions with other IBD genes as well as phenotypic consequences of IL23R variants. Genomic DNA from 2670 Caucasian individuals including 833 patients with Crohn's disease (CD), 456 patients with ulcerative colitis (UC), and 1381 healthy unrelated controls was analyzed for 10 IL23R SNPs. Genotyping included the NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T) and SLC22A5/OCTN2 (-207 G-->C). All IL23R gene variants analyzed displayed highly significant associations with CD. The strongest association was found for the SNP rs1004819 [P = 1.92x10(-11); OR 1.56; 95 % CI (1.37-1.78)]. 93.2% of the rs1004819 TT homozygous carriers as compared to 78% of CC wildtype carriers had ileal involvement [P = 0.004; OR 4.24; CI (1.46-12.34)]. The coding SNP rs11209026 (p.Arg381Gln) was protective for CD [P = 8.04x10(-8); OR 0.43; CI (0.31-0.59)]. Similar, but weaker associations were found in UC. There was no evidence for epistasis between the IL23R gene and the CD susceptibility genes CARD15 and SLC22A4/5. IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC

Inflammatory bowel disease: past, present, and future

Crohn’s disease and ulcerative colitis, collectively known as the inflammatory bowel diseases (IBD), are largely diseases of the twentieth century, and are associated with the rise of modern, Westernized industrial society. Although the causes of these diseases remain incompletely understood, the prevailing model is that the intestinal flora drives an unmitigated intestinal immune response and inflammation in the genetically susceptible host. A review of the past and present of these diseases shows that detailed description preceded more fundamental elucidation of the disease processes. Working out the details of disease pathogenesis, in turn, has yielded dividends in more focused and effective therapy for IBD. This article highlights the key descriptions of the past, and the pivotal findings of current studies in disease pathogenesis and its connection to medical therapy. Future directions in the IBD will likely explicate the inhomogeneous causes of these diseases, with implications for individualized therapy