Proton pump inhibitors and dementia risk: Evidence from a cohort study using linked routinely collected national health data in Wales, UK

Objectives: Proton pump inhibitors (PPIs) are commonly prescribed for prevention and treatment of gastrointestinal conditions or for gastroprotection from other drugs. Research suggests they are linked to increased dementia risk. We use linked national health data to examine the association between PPI use and the development of incident dementia. Methods and findings: A population-based study using electronic health-data from the Secure Anonymised Information Linkage (SAIL) Databank, Wales (UK) from 1999 to 2015. Of data available on 3,765,744 individuals, a cohort who had ever been prescribed a PPI was developed (n=183,968) for people aged 55 years and over and compared to non-PPI exposed individuals (131,110). Those with prior dementia, mild-cognitive-impairment or delirium codes were excluded. Confounding factors included comorbidities and/or drugs associated with them. Comorbidities might include head injury and some examples of medications include antidepressants, antiplatelets and anticoagulants. These commonly prescribed drugs were investigated as it was not feasible to explore all drugs in this study. The main outcome was a diagnosis of incident dementia. Cox proportional hazard regression modelling was used to calculate the Hazard ratio (HR) of developing dementia in PPI-exposed compared to unexposed individuals while controlling for potential confounders. The mean age of the PPI exposed individuals was 69.9 years and 39.8% male while the mean age of the unexposed individuals was 72.1 years and 41.1% male. The rate of PPI usage was 58.4% (183,968) and incident dementia rate was 11.8% (37,148/315,078). PPI use was associated with decreased dementia risk (HR: 0.67, 95% CI: 0.65 to 0.67, p<0.01). Conclusions: This study, using large-scale, multi-centre health-data was unable to confirm an association between PPI use and increased dementia risk. Previously reported links may be associated with confounders of people using PPI’s, such as increased risk of cardiovascular disease and/or depression and their associated medications which may be responsible for any increased risk of developing dementia

Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease

PMCID: PMC3710212This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Genomic Regions Associated with Multiple Sclerosis Are Active in B Cells

More than 50 genomic regions have now been shown to influence the risk of multiple sclerosis (MS). However, the mechanisms of action, and the cell types in which these associated variants act at the molecular level remain largely unknown. This is especially true for associated regions containing no known genes. Given the evidence for a role for B cells in MS, we hypothesized that MS associated genomic regions co-localized with regions which are functionally active in B cells. We used publicly available data on 1) MS associated regions and single nucleotide polymorphisms (SNPs) and 2) chromatin profiling in B cells as well as three additional cell types thought to be unrelated to MS (hepatocytes, fibroblasts and keratinocytes). Genomic intervals and SNPs were tested for overlap using the Genomic Hyperbrowser. We found that MS associated regions are significantly enriched in strong enhancer, active promoter and strong transcribed regions (p = 0.00005) and that this overlap is significantly higher in B cells than control cells. In addition, MS associated SNPs also land in active promoter (p = 0.00005) and enhancer regions more than expected by chance (strong enhancer p = 0.0006; weak enhancer p = 0.00005). These results confirm the important role of the immune system and specifically B cells in MS and suggest that MS risk variants exert a gene regulatory role. Previous studies assessing MS risk variants in T cells may be missing important effects in B cells. Similar analyses in other immunological cell types relevant to MS and functional studies are necessary to fully elucidate how genes contribute to MS pathogenesis

Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D

Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease. Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region. Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non–MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous “VDRE” sequence found in non–MS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells. This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention

Seasonal Distribution of Psychiatric Births in England

There is general consensus that season of birth influences the risk of developing psychiatric conditions later in life. We aimed to investigate whether the risk of schizophrenia (SC), bipolar affective disorder (BAD) and recurrent depressive disorder (RDD) is influenced by month of birth in England to a similar extent as other countries using the largest cohort of English patients collected to date (n=57,971). When cases were compared to the general English population (n=29,183,034) all diseases showed a seasonal distribution of births (SC p=2.48E-05; BAD p=0.019; RDD p=0.015). This data has implications for future strategies of disease prevention

Genetic, environmental and stochastic factors in monozygotic twin discordance with a focus on epigenetic differences

PMCID: PMC3566971This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

Recent evidence indicates that single multiple sclerosis (MS) susceptibility genes involved in interferon (IFN) signaling display altered transcript levels in peripheral blood of untreated MS subjects, suggesting that responsiveness to endogenous IFN is dysregulated during neuroinflammation. To prove this hypothesis we exploited the systematic collection of IFN regulated genes (IRG) provided by the Interferome database and mapped Interferome changes in experimental and human MS. Indeed, central nervous system tissue and encephalitogenic CD4 T cells during experimental autoimmune encephalomyelitis were characterized by massive changes in Interferome transcription. Further, the analysis of almost 500 human blood transcriptomes showed that (i) several IRG changed expression at distinct MS stages with a core of 21 transcripts concordantly dysregulated in all MS forms compared with healthy subjects; (ii) 100 differentially expressed IRG were validated in independent case-control cohorts; and (iii) 53 out of 100 dysregulated IRG were targeted by IFN-beta treatment in vivo. Finally, ex vivo and in vitro experiments established that IFN-beta administration modulated expression of two IRG, ARRB1 and CHP1, in immune cells. Our study confirms the impairment of Interferome in experimental and human MS, and describes IRG signatures at distinct disease stages which can represent novel therapeutic targets in MS