Ulcerative colitis (UC) is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. We performed two distinct UC genome-wide association (GWA) studies, and analyzed these jointly with a previously published scan1, comprising, in aggregate, 2,693 patients with UC and 6,791 controls. A total of 59 SNPs from 14 independent loci attained P < 10−5. Seven of these loci exceeded genome-wide significance (P < 5 × 10−8). After testing an independent cohort of 2009 patients with UC and 1580 controls, 14 loci were significantly associated, including novel UC associations with FCGR2A, 5p15, 2p16, CARD9 and ORMDL3. In our study we confirmed association with 14 previously identified UC susceptibility loci, while an analysis of acknowledged Crohn's disease (CD) loci showed that roughly half of known CD associations are shared with UC. These data implicate approximately 30 loci for UC, providing novel insights into disease pathogenesis.

We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.

1 MEN 11420 (nepadutant) is a potent, selective and competitive antagonist of tachykinin NK2 receptors. 2 The objective of the present study was to assess the capability of the drug to antagonize the stimulatory eects of neurokinin A (NKA) on gastrointestinal motility, as well as to change the fasting migrating motor complex (MMC). 3 Thirty-four male volunteers were randomized to treatment with either placebo or MEN 11420 in a double-blinded manner. Eects of MEN 11420 (8 mg intravenously) were evaluated as changes in phases I, II and III of MMC, as well as contraction frequency, amplitude and motility index during baseline conditions and during stimulation of motility using NKA (25 pmol kg 71 min 71 intravenously). 4 NKA preceded by placebo increased the fraction of time occupied by phase II, increased contraction frequency, amplitude and motility index. 5 MEN 11420 eectively antagonized the motility-stimulating eects of NKA. MEN 11420 reduced the phase II-stimulating eect of NKA. In addition, the stimulatory eect of NKA on contraction frequency and amplitude, as well as motility index were inhibited by MEN 11420. MEN 11420 did not aect the characteristics of MMC during saline infusion. 6 Plasma levels of MEN 11420 peaked during the ®rst hour after infusion and decreased to less than half during the ®rst 2 h. 7 In conclusion, intravenous MEN 11420 eectively inhibited NKA-stimulated, but not basal gastrointestinal motility, and was well tolerated by all subjects.

Backgroundneuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02).Principal Findingswe identified one promoter SNP (rs2530547 [−103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk.Significancethese findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.