The MEP1A gene, located on human chromosome 6p (mouse chromosome 17) in a susceptibility region for inflammatory bowel disease (IBD), encodes the α-subunit of metalloproteinase meprin A, which is expressed in the intestinal epithelium. This study shows a genetic association of MEP1A with IBD in a cohort of ulcerative colitis (UC) patients. There were four single-nucleotide polymorphisms in the coding region (P = 0.0012-0.04), and one in the 3′-untranslated region (P = 2×10 −7 ) that displayed associations with UC. Moreover, meprin-α mRNA was decreased in inflamed mucosa of IBD patients. Meprin-α knockout mice exhibited a more severe intestinal injury and inflammation than their wild-type counterparts following oral administration of dextran sulfate sodium. Collectively, the data implicate MEP1A as a UC susceptibility gene and indicate that decreased meprin-α expression is associated with intestinal inflammation in IBD patients and in a mouse experimental model of IBD.

RDP58 at a dose of 200 or 300 mg, but not 100 mg, was effective in mild-to-moderate UC. RDP58 was safe and well tolerated, and its novel action makes it an attractive potential therapy.

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Background:The identification of NODZ(CARDI5) as a susceptibility gene for Crohn's disease (CD) has emphasised the role of the innate immune system in the pathogenesis of IBD. Aims: To identify genetic variants within innate immunity genes and to test for association with IBD and IBD phenotypes. Methods: Genetic variants were identified from public databases and direct sequencing. Genotyping was performed by RFLP or TETRA-ARMS PCR. Testing for association performed by casecontrol analysis (191 CD, 267 UC, and 245 controls) or by the transmission disequilibrium test (TDT)(556 IBD (294 CD and 252 UC) trios). All results stratified by phenotype and NODUIBD5 status. Results: No association seen with SNPs in PPARg, TLR (toll like receptor)3, TLR4, TLR6, TLR9. TIRAP, TREM-I and 2, P2X7, CD14 and ECSIT. There was a trend towards increased allele frequency of a promoter SNP in Myd88 (p=0.059) in mild colitics. The NOD2 702Trp is associated with UC (pd.047). particularly in IBD5+ cases (pd.0045) confirming a NODUIBDS interaction in the susceptibility to UC. A MEKKI SNP (Asp643Asn) is associated with the need for colectomy (p=0.0069). A TLR2 SNP (Arg753Gln) is associated with mild colitis (pd.0027). We combined these results with previous genetic associations with colectomy (MDR-1 SNP and HLA-DRBlr0103) to produce a 'panel' to predict colectomy in UC. Carriage of 2 or more at risk genotypes: colectomy 61 .I%. mild UC 42.2%. RR 2.16 (1.26-3.61), p=O.0044. Carriage of 3 or more at risk alleles: colcctomy 34.8% mild UC 15.4%. RR 2.89(1.53-5.45),p=0.0007. Conclusions: Polymorphisms within these genes confirm the role of the innate immune system in UC pathogenesis and may additionally help to identify individuals at risk of severe disease requiring surgery. These data may help elucidate the underlying biological mechanisms of disease, permit the individualisation of appropriate therapy and aid the development of future novel therapies.

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