Genotype imputation of the human leukocyte antigen (HLA) region is a cost-effective means to infer classical HLA alleles from inexpensive and dense SNP array data. In the research setting, imputation helps avoid costs for wet lab-based HLA typing and thus renders association analyses of the HLA in large cohorts feasible. Yet, most HLA imputation reference panels target Caucasian ethnicities and multi-ethnic panels are scarce. We compiled a high-quality multi-ethnic reference panel based on genotypes measured with Illumina’s Immunochip genotyping array and HLA types established using a high-resolution next generation sequencing approach. Our reference panel includes more than 1,300 samples from Germany, Malta, China, India, Iran, Japan and Korea and samples of African American ancestry for all classical HLA class I and II alleles including HLA-DRB3/4/5 . Applying extensive cross-validation, we benchmarked the imputation using the HLA imputation tool HIBAG, our multi-ethnic reference and an independent, previously published data set compiled of subpopulations of the 1000 Genomes project. We achieved average imputation accuracies higher than 0.924 for the commonly studied HLA-A , -B , -C , -DQB1 and -DRB1 genes across all ethnicities. We investigated allele-specific imputation challenges in regard to geographic origin of the samples using sensitivity and specificity measurements as well as allele frequencies and identified HLA alleles that are challenging to impute for each of the populations separately. In conclusion, our new multi-ethnic reference data set allows for high resolution HLA imputation of genotypes at all classical HLA class I and II genes including the HLA-DRB3/4/5 loci based on diverse ancestry populations.

Segmental colitis associated with diverticulosis (SCAD) is an inflammatory process that affects colonic luminal mucosa in segments that are also affected by diverticulosis. Its prevalence varies between 1.15% and 11.4% amongst those suffering from diverticular disease (DD). Being closely associated with DD, it is slightly commoner in males and usually presents in the sixth decade of life. Although the exact pathogenesis of SCAD is unknown, it is probably heterogeneous and includes mechanisms that also play a part in inflammatory bowel disease (IBD). The clinical presentation is non-specific and similar to that of other pathologies involving the sigmoid colon, and its diagnosis is based on endoscopic findings in correlation with histology. Currently, there are no guidelines for its management, which is usually based on the administration of salicylates and antibiotics, with surgery being reserved for refractory cases. The rarity of SCAD may be multifactorial: whereas milder forms go undiagnosed or are attributed to DD, more severe forms can be misdiagnosed as IBD. This latter distinction is an important one to make, since SCAD and IBD differ as regards their natural history and prognosis, while very often no long-term medications are required in SCAD.

Background and aims IBD can impair the patients` functional capacity with significant negative effects on their quality of life. Our aim was to determine the impact of IBD diagnosis on fitness levels and to assess the levels of engagement in physical activity and fatigue in IBD patients` pre-and post-diagnosis. Methods A prospective multi-centre cross-sectional study was performed. Patients diagnosed with IBD in the previous 18 months were recruited. Inclusion criteria included clinical remission and/or no treatment changes within the previous 6 months. Physical exercise levels were assessed by the Godin score and fatigue levels was assessed by the Functional assessment of chronic illness therapy (FACIT) score. Results 158 patients (100 CD) were recruited. Mean age was 35.1 years (95% CI ±2.0). Gender distribution was approximately equal (51.3% male). The Mean Harvey Bradshaw and Simple Clinical Colitis Activity indices were 2.25 (95% CI ±0.40) and 1.64 (95% CI ±0.49). Mean Godin score difference before and after IBD diagnosis was 6.94 (p = 0.002). Patients with UC (41.8%) were more likely than patients with CD (23.0%) to reduce their exercise levels (p=0.04). FACIT scores were lower in patients who had experienced relapses (p=0.012) and had severe disease (p=0.011). Approximately 1/3 of patients had a reduction in their activity level post-IBD diagnosis. Conclusions Patients were significantly less physically active after a diagnosis of IBD and this was more apparent in UC. Identification of risk factors associated with loss of fitness levels would help address the reduced patients` quality of life.

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Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD, and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such a delineation could not be made due to tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a trans-ethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analysed the physico-chemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids such. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.