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Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.

ABSTRACT: Background:The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). Method:To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. Results:HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10-9) and another SNP rs17188113 (OR = 0.48, p = 7.56*10-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13). Conclusion:In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

SUBMITTER: Venkateswaran S

PROVIDER: S-EPMC6350448 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.

Venkateswaran Suresh S Prince Jarod J Cutler David J DJ Marigorta Urko M UM Okou David T DT Prahalad Sampath S Mack David D Boyle Brendan B Walters Thomas T Griffiths Anne A Sauer Cary G CG LeLeiko Neal N Keljo David D Markowitz James J Baker Susan S SS Rosh Joel J Pfefferkorn Marian M Heyman Melvin B MB Patel Ashish A Otley Anthony A Baldassano Robert R Noe Joshua J Rufo Paul P Oliva-Hemker Maria M Davis Sonia S Zwick Michael E ME Gibson Greg G Denson Lee A LA Hyams Jeffrey J Kugathasan Subra S

Inflammatory bowel diseases 20180301 4

<h4>Background</h4>The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59).<h4>Method</h4>To study the genetic contribution to exclusive pediatric onset UC, a ...[more]

PMID: 29562276

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Project description:Ulcerative colitis in children can have a negative effect on quality of life (QOL).We included 16 of 31 patients who underwent colectomy for ulcerative colitis before 20 years of age between 1980 and 2005 at University of California in San Francisco Benioff Children's Hospital. A disease-specific QOL questionnaire (Inflammatory Bowel Disease Questionnaire-32), validated for adults, was used to determine QOL and an additional questionnaire addressing bowel function and reproductive health in long-term follow-up of these patients.Median age at the time of survey was 20.3 years (17.9-25.3), and time postcolectomy was 6.9 years (4.8-9.0). Mean total score was 159.7 ± 43.3 (58-210). Two patients (12.5%) had scores of ? 200, 12 (75.0%) had 101 to 199, and 2 (12.5%) had ? 100. Patients ages 18 years or younger at the time of survey showed higher QOL, particularly in emotional health (P=0.020), social function (P=0.014), and overall QOL (P=0.009). Social function scored highest of all of the systems (median 7; interquartile range 4-7). Patients with scores ? 100 had repeated episodes of pouchitis (16-30) compared with the other 14 patients (0-3). Children who were diagnosed ages 12 years or younger tended to have higher QOL (p=0.072). Years postcolectomy did not correlate to QOL. Eleven patients were sexually active. Two males had feelings of impotence and decreased libido, and 6 females experienced dyspareunia. Three women tried unsuccessfully to conceive after colectomy. One woman became pregnant 4 times, each leading to miscarriage.Younger age at time of colectomy, diagnosis, and survey show higher QOL. Highest satisfaction was found in ability to attend school, work, and social engagements. Pouchitis continued to be an issue for a small number of the patients, with 2 patients having recurring episodes that severely affected QOL. Patients reported decreased sexual activity and fertility at the time of survey due to colectomy, especially for females.

Project description:BackgroundThe incidence of ulcerative colitis (UC) is increasing, but there are few reports comparing elderly UC patients undergoing colectomy for elderly-onset UC (EO) and nonelderly-onset UC (NEO). The aim of this study was to analyze the differences between EO and NEO patients who underwent UC-related surgery.MethodsWe identified 1973 patients with UC who underwent colectomy at Hyogo College of Medicine between January 1, 1984, and December 31, 2018. Only patients aged 65 years old and older who underwent colectomy were enrolled in this study (n = 221, 11.2%), and their clinical records were retrospectively reviewed. Patients were divided into two groups according to their age at disease onset: those with onset at younger than 60 years old (NEO) and at 60 years old or older (EO).ResultsIn the 221 UC patients who underwent colectomy at 65 years old or older, there were 155 cases of EO and 66 cases of NEO. The main surgical indication in NEO patients was colitis-associated cancer/dysplasia (32/66, 47%). In contrast, refractory to medical treatment was the leading cause of surgery in EO patients (80/155, 52%). The distributions of surgical indications were different between the two groups (p < 0.01). The preoperative daily dose of steroids was significantly higher in the EO group than in the NEOgroup (0 mg vs. 10 mg, p < 0.01). The rates of immunosuppressant, infliximab (IFX) and adalimumab use did not differ significantly between the groups. Significantly more patients underwent emergency surgery in the EO group than in the NEO group (14% vs. 35%, p < 0.01). The proportions of patients with postoperative morbidity (Clavien-Dindo grade III or higher) were 17.4% (27/155) in the EO group and 13.6% (9/66) in the NEO group. There was no significant difference between the two groups (p = 0.48). The prognosis of the EO patients who underwent UC-related emergency surgery was worse than that of the NEO patients (p < 0.01). In the EO group, 8 (14.8%) of 54 patients died within 30 postoperative days, while there were no deaths in the NEO group.ConclusionAmong elderly UC patients undergoing UC-related surgery, EO patients undergoing emergency surgery had very poor outcomes, and the mortality rate was 14.8%. In such cases, it is important for physicians and surgeons to begin communication at an early stage so that the optimal surgical timeframe is not missed.

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Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.

Publications

Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.

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