Jeffrey Barrett, Carl Anderson and colleagues report the results of a large genome-wide association study of inflammatory bowel disease. They identify 25 new genome-wide significant loci, 3 of which contain integrin genes, and find that the associated variants at several of these loci are correlated with expression changes in response to immune stimulus. Genetic association studies have identified 215 risk loci for inflammatory bowel disease1,2,3,4,5,6,7,8, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

Fecal calprotectin (FC) is increasingly used during the diagnosis of inflammatory bowel disease (IBD), outperforming blood markers during investigation in children. Tests that reduce endoscopy rates in children with suspected gut inflammation would be beneficial. We aimed to determine the usefulness of FC in children undergoing their primary investigation for suspected IBD by systematic review and meta-analysis. An electronic search was performed with keywords relating to IBD and calprotectin in multiple electronic resources from 1946 to May 2012; a hand search was also performed. Inclusion criteria were studies that reported FC levels before the endoscopic investigation of IBD in patients less than 18 years old. Studies were evaluated using the Quality Assessment of Diagnostic Accuracy Studies tool, and a meta-analysis was performed using a hierarchical summary receiver operating curve model. Eight papers met the inclusion criteria (six prospective and two retrospective case-control studies); methodological quality was determined in detail for each study. The 8 studies presented FC levels at presentation in 715 patients, 394 pediatric IBD patients, and 321 non-IBD controls. Pooled sensitivity and specificity for the diagnostic utility of FC during the investigation of suspected pediatric IBD were 0.978 (95% confidence interval (CI), 0.947-0.996) and 0.682 (95% CI, 0.502-0.863), respectively; the positive and negative likelihood ratios were 3.07 and 0.03, respectively. FC has a high sensitivity and a modest specificity during the diagnosis of suspected pediatric IBD. Further work is required to determine the effect of FC levels on endoscopy rates and its role during the re-evaluation of those with confirmed disease.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 2022¹ and has now been identified in 35 countries². Several recent studies have suggested an association with human adenovirus (HAdV), a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), serology and in situ hybridisation (ISH), we detected recent infection with AAV2 in the plasma and liver samples of 26/32 (81%) hepatitis cases versus 5/74 (7%) of controls. Further, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsies. In keeping with a CD4+ T-cell-mediated immune pathology, the Human Leucocyte Antigen (HLA) class II DRB1*04:01 allele was identified in 25/27 cases (93%), compared with a background frequency of 10/64 (16%; p=5.49 x 10^-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a coinfection with HAdV which is required as a “helper virus” to support AAV2 replication) and HLA class II-related disease susceptibility.