Ulcerative Colitis: Hunt S

Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H, Lees CW, Onnie CM, Hanson C, Blaszczyk K, Ravindrarajah R, Hunt S, Varma D, Hammond N, Lewis G, Attlesey H, Watkins N, Ouwehand W, Strachan D, McArdle W, Lewis CM, Anonymous00026, Lobo A, Sanderson J, Jewell DP, Deloukas P, Mansfield JC, Mathew CG, Satsangi J, Parkes M. · Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. · Gastroenterology. · Pubmed #19068216 links to  free full text

Abstract: BACKGROUND & AIMS: Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. METHODS: We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. RESULTS: Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 x 10(-8); odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. CONCLUSIONS: Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis.

Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Anonymous00021, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P, Mathew CG, Parkes M, Satsangi J. · Department of Medical and Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK. · Nat Genet. · Pubmed #18438406 links to  free full text

Abstract: We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.

Cuffari C, Hunt S, Bayless T. · Division of Gastroenterology, Department of Paediatrics, The Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Gut. · Pubmed #11302961 links to  free full text

Abstract: BACKGROUND AND AIM: The immunosuppressive properties of 6-mercaptopurine and its parent compound azathioprine are mediated by their intracellular metabolism into active 6-thioguanine (6-TG) metabolites. Measurement of erythrocyte 6-TG metabolite levels has been proposed as a useful clinical tool for assessing treatment efficacy in patients with inflammatory bowel disease (IBD). AIM: The purpose of the study was to establish a therapeutic index of treatment efficacy based on measurement of erythrocyte 6-TG metabolite levels, and apply it clinically to guide therapy. METHODS: Heparinised blood was obtained from 82 adult patients with IBD on long term (more than three months) antimetabolite therapy (63 Crohn's disease; 19 ulcerative colitis). Erythrocyte 6-TG metabolite levels were measured using reverse phase high performance chromatography, and correlated with treatment efficacy. In 22 patients with refractory Crohn's disease despite long term azathioprine therapy, their dosage was increased by 25 mg/day at eight week intervals as needed. Serial erythrocyte 6-TG metabolite levels were measured at each clinic visit and correlated with treatment efficacy. RESULTS: Clinical remission, as defined by a low disease index score in patients weaned off or on a low alternate day dose (<20 mg on alternate days) of corticosteroid, was achieved in 68% of patients on long term antimetabolite therapy. Treatment efficacy correlated with erythrocyte 6-TG levels greater than 250 pmol/8x10(8) red blood cells in patients with colonic and fistulising Crohn's disease (p<0.01) but not in patients with ileocolonic disease. Eighteen of 22 patients with incompletely responsive Crohn's disease achieved disease remission by optimising their dose of azathioprine therapy. Median (range) erythrocyte 6-TG metabolite levels increased from 194 (67-688) to 303 (67-737) pmol/8x10(8) red blood cells (p<0.05). Clinical response associated well with a reduction in corticosteroid requirements. Mean (SEM) white blood cell count decreased from 8.6 (0.9) to 6.9 (0.6) x10(3)/microl with adjustment in azathioprine dosage. No patient incurred azathioprine induced leucopenia. CONCLUSION: Measurement of erythrocyte 6-TG metabolite levels is helpful in determining the adequacy of azathioprine dosage and can be used to optimise the dose of antimetabolite therapy to achieve an improved clinical response without inducing leucopenia. Patients who are clinically refractory to azathioprine therapy despite achieving high erythrocyte 6-TG levels (>250) should be considered for adjunct or alternative forms of immunosuppressive therapy or surgery.