Karamanolis, George

Abstract Background Patients with inflammatory bowel disease (IBD) have low vaccination rates for vaccine-preventable diseases. Fear of adverse reactions (AEs) appear to negatively affect vaccination efforts. We aimed to systemically review the risks for AEs following immunization for patients with IBD. Methods We searched PubMed and Embase until April 15, 2020, for studies evaluating the safety of vaccinations among patients with IBD. The primary outcome was the incidence of systemic and local AEs among vaccinated patients. Secondary outcome was the rate of IBD flare following immunization. We utilized a random effects meta-analysis of proportions using the DerSimonian-Laird approach to estimate the safety of immunizations. Results A total of 13 studies with 2116 patients was included in our analysis after fulfilling our inclusion criteria. Seven studies examined the influenza vaccine, 4 the pneumococcal vaccine, 1 the recombinant zoster vaccine, and 1 the hepatitis B vaccine. Follow-up of patients was up to 6 months. The majority of AEs were local, with a pooled incidence of 24% (95% CI, 9%-42%) for all vaccines. Systemic AEs were mostly mild, without resulting in hospitalizations or deaths, with a pooled incidence of 16% (95% CI, 6%-29%) for all vaccines. Flare of inflammatory bowel disease after vaccination found with a pooled incidence of 2% (95% CI, 1%-4%) and we include in the analysis data from all immunizations examined. Discussion Our study demonstrated that AEs after vaccination are mainly local or mildly systemic and do not differ significantly from the expected AE after recommended immunizations for the general population. Thus, gastroenterologists should reinforce that vaccines are safe in patients with IBD.

AbstractIrritable bowel syndrome (IBS) is a gut‐brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation‐predominant IBS (IBS‐C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta‐analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS‐C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow‐up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS‐C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

Objective IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. Design We conducted a GWA study (GWAS) of IBS in a general population sample of 11 326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. Results One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10 −6 in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. Conclusions Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.