Genetic and inflammatory effects on childhood trauma and cognitive functioning in patients with schizophrenia and healthy participants.

Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants.

GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Systematic review on gene-sun exposure interactions in skin cancer.

BACKGROUND: The risk of skin cancer is determined by environmental factors like ultraviolet radiation (UVR), personal habits like time spent outdoors and genetic factors. This review aimed to survey existing studies in gene-environment (GxE) interaction on skin cancer risk, and report on GxE effect estimates. METHODS: We searched Embase, Medline (Ovid) and Web of Science (Core Collection) and included only primary research that reported on GxE on the risk of the three most common types of skin cancer: basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma. Quality assessment followed the Newcastle-Ottawa Scale. Meta-analysis was not possible because no two studies examined the same interaction. This review was registered on PROSPERO (CRD42021238064). RESULTS: In total 260 records were identified after exclusion of duplicates. Fifteen studies were included in the final synthesis-12 used candidate gene approach. We found some evidence of GxE interactions with sun exposure, notably, with MC1R, CAT and NOS1 genes in melanoma, HAL and IL23A in BCC and HAL and XRCC1 in SCC. CONCLUSION: Sun exposure seems to interact with genes involved in pigmentation, oxidative stress and immunosuppression, indicating that excessive UV exposure might exhaust oxidative defence and repair systems differentially, dependent on genetic make-up. Further research is warranted to better understand skin cancer epidemiology and develop sun exposure recommendations. A genome-wide approach is recommended as it might uncover unknown disease pathways dependent on UV radiation.

Early life stress, low-grade systemic inflammation and weaker suppression of the default mode network (DMN) during face processing in Schizophrenia.

Childhood trauma (CT) is associated with lower cognitive and social cognitive function in schizophrenia. Recent evidence suggests that the relationship between CT and cognition is mediated by both low-grade systemic inflammation and reduced connectivity of the default mode network (DMN) during resting state. This study sought to test whether the same pattern of associations was observed for DMN connectivity during task based activity. Fifty-three individuals with schizophrenia (SZ) or schizoaffective disorder (SZA) and one hundred and seventy six healthy participants were recruited from the Immune Response and Social Cognition (iRELATE) project. A panel of pro-inflammatory markers that included IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNFa), and C-reactive protein (CRP), were measured in plasma using ELISA. DMN connectivity was measured during an fMRI social cognitive face processing task. Patients showed evidence of low grade systemic inflammation and significantly increased connectivity between the left lateral parietal (LLP) cortex-cerebellum and LLP-left angular gyrus compared to healthy participants. Across the entire sample, IL-6 predicted increased connectivity between LLP-cerebellum, LLP-precuneus, and mPFC-bilateral-precentral-gyri and left postcentral gyrus. In turn, and again in the entire sample, IL-6 (but no other inflammatory marker) mediated the relationship between childhood physical neglect and LLP-cerebellum. Physical neglect scores also significantly predicted the positive association between IL-6 and LLP-precuneus connectivity. This is to our knowledge the first study that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during task based activity. Consistent with our hypothesis, exposure to trauma is associated with weaker suppression of the DMN during a face processing task, and this association was mediated via increased inflammatory response. The findings may represent part of the biological mechanism by which CT and cognitive performance are related.

Childhood trauma, IL-6 and weaker suppression of the default mode network (DMN) during theory of mind (ToM) performance in schizophrenia.

Background: Both low-grade systemic inflammation and functional connectivity of the default mode network (DMN) during rest have recently been observed to mediate the association between childhood trauma (CT) and behavioural performance on an emotion recognition task. Whether inflammation also mediates the association between CT and functional connectivity of the DMN during social cognitive task performance is unknown. Methods: 51 patients with schizophrenia (SZ) or schizoaffective disorder (SZA) and 176 healthy participants completed a theory of mind (ToM) task during fMRI. IL-6 was measured in plasma using ELISA. DMN connectivity was measured during performance of the fMRI ToM task. To examine DMN connectivity, we selected 4 a priori seeds of the DMN, i.e., the medial prefrontal cortex (PFC), right lateral parietal (LP), left LP, and posterior cingulate cortex (PCC) according to the Harvard-Oxford Cortical and Subcortical Atlas (http://www.cma.mgh.harvard.edu/fsl_atlas.html) as implemented in CONN. Results: Patients showed significantly increased DMN connectivity compared to healthy participants between each of the four seeds of the DMN and with other clusters in the brain. Across the entire sample, higher levels of IL-6 predicted increased connectivity between the mPFC and regions encompassing the cerebellum (<0.001 FWE). IL-6 mediated the association between physical neglect and weaker suppression of the posterior cingulate cortex (PCC) DMN seed -left precentral and postcentral gyrus (ßINDIRECT = .0170, CI: 0.0008 to.0506) connectivity during ToM performance. Discussion: This is the first study to our knowledge that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during ToM task performance. Consistent with our previous study that IL-6 mediated the association between early life stress exposure and reduced connectivity of the DMN during rest, here IL-6 mediated the association between early life stress and increased connectivity of the DMN during ToM based cognitive processing. These findings suggest a biological mechanism for how chronic stress impacts social cognitive processing.

The genetic backbone of ankylosing spondylitis: how knowledge of genetic susceptibility informs our understanding and management of disease.

Ankylosing spondylitis (AS) is a seronegative, chronic inflammatory arthritis with high genetic burden. A strong association with HLA-B27 has long been established, but to date its contribution to disease aetiology remains unresolved. Recent insights through genome wide studies reveal an increasing array of immunogenetic risk variants extraneous to the HLA complex in AS cohorts. These genetic traits build a complex profile of disease causality, highlighting several molecular pathways associated with the condition. This and other evidence strongly implicates T-cell-driven pathology, revolving around the T helper 17 cell subset as an important contributor to disease. This prominence of the T helper 17 cell subset has presented the opportunity for therapeutic intervention through inhibition of interleukins 17 and 23 which drive T helper 17 activity. While targeting of interleukin 17 has proven effective, this success has not been replicated with interleukin 23 inhibition in AS patients. Evidence points to significant genetic diversity between AS patients which may, in part, explain the observed refractoriness among a proportion of patients. In this review we discuss the impact of genetics on our understanding of AS and its relationship with closely linked pathologies. We further explore how genetics can be used in the development of therapeutics and as a tool to assist in the diagnosis and management of patients. This evidence indicates that genetic profiling should play a role in the clinician's choice of therapy as part of a precision medicine strategy towards disease management.

Gene-Environment Interactions in Vitamin D Status and Sun Exposure: A Systematic Review with Recommendations for Future Research.

Vitamin D is essential for good health. Dermal vitamin D production is dependent on environmental factors such as season and latitude, and personal factors such as time spent outdoors and genetics. Varying heritability of vitamin D status by season has been reported, suggesting that gene-environment interactions (GxE) may play a key role. Thus, understanding GxE might significantly improve our understanding of determinants of vitamin D status. The objective of this review was to survey the existing methods in GxE on vitamin D studies and report on GxE effect estimates. We searched the Embase, Medline (Ovid), and Web of Science (Core Collection) databases. We included only primary research that reported on GxE effects on vitamin D status using 25-hydroxyvitamin D as a biomarker. Sun exposure was the only environmental exposure identified in these studies. The quality assessment followed the Newcastle-Ottawa Scale for cohort studies. Seven studies were included in the final narrative synthesis. We evaluate the limitations and findings of the available GxE in vitamin D research and provide recommendations for future GxE research. The systematic review was registered on PROSPERO (CRD42021238081).

Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling.

OBJECTIVES: Psoriatic arthritis (PsA) has a strong genetic component, and the identification of genetic risk factors could help identify the ~30% of psoriasis patients at high risk of developing PsA. Our objectives were to identify genetic risk factors and pathways that differentiate PsA from cutaneous-only psoriasis (PsC) and to evaluate the performance of PsA risk prediction models. METHODS: Genome-wide meta-analyses were conducted separately for 5,065 patients with PsA and 21,286 healthy controls and separately for 4,340 patients with PsA and 6,431 patients with PsC. The heritability of PsA was calculated as a single-nucleotide polymorphism (SNP)-based heritability estimate (h2 SNP ) and biologic pathways that differentiate PsA from PsC were identified using Priority Index software. The generalizability of previously published PsA risk prediction pipelines was explored, and a risk prediction model was developed with external validation. RESULTS: We identified a novel genome-wide significant susceptibility locus for the development of PsA on chromosome 22q11 (rs5754467; P = 1.61 × 10-9 ), and key pathways that differentiate PsA from PsC, including NF-κB signaling (adjusted P = 1.4 × 10-45 ) and Wnt signaling (adjusted P = 9.5 × 10-58 ). The heritability of PsA in this cohort was found to be moderate (h2 SNP = 0.63), which was similar to the heritability of PsC (h2 SNP = 0.61). We observed modest performance of published classification pipelines (maximum area under the curve 0.61), with similar performance of a risk model derived using the current data. CONCLUSION: Key biologic pathways associated with the development of PsA were identified, but the investigation of risk classification revealed modest utility in the available data sets, possibly because many of the PsC patients included in the present study were receiving treatments that are also effective in PsA. Future predictive models of PsA should be tested in PsC patients recruited from primary care.

Study protocol for the St James's Hospital, Tallaght University Hospital, Trinity College Dublin Allied Researchers' (STTAR) Bioresource for COVID-19.

Background: The current coronavirus disease 2019 (COVID-19) pandemic began in Ireland with the first confirmed positive case in March 2020. In the early stages of the pandemic clinicians and researchers in two affiliated Dublin hospitals identified the need for a COVID-19 biobanking initiative to support and enhance research into the disease. Through large scale analysis of clinical, regional, and genetic characteristics of COVID-19 patients, biobanks have helped identify, and so protect, at risk patient groups The STTAR Bioresource has been created to collect and store data and linked biological samples from patients with SARS-CoV-2 infection and healthy and disease controls. Aim: The primary objective of this study is to build a biobank, to understand the clinical characteristics and natural history of COVID-19 infection with the long-term goal of research into improved disease understanding, diagnostic tests and treatments. Methods: This is a prospective dual-site cohort study across two tertiary acute university teaching hospitals. Patients are recruited from inpatient wards or outpatient clinics. Patients with confirmed COVID-19 infection as well as healthy and specific disease control groups are recruited.  Biological samples are collected and a case report form detailing demographic and medical background is entered into the bespoke secure online Dendrite database. Impact: The results of this study will be used to inform national and international strategy on health service provision and disease management related to COVID-19. In common with other biobanks, study end points  evolve over time as new research questions emerge. They currently include patient survival, occurrence of severe complications of the disease or its therapy, occurrence of persistent symptoms following recovery from the acute illness and vaccine responses.

Interleukin 6 predicts increased neural response during face processing in a sample of individuals with schizophrenia and healthy participants: A functional magnetic resonance imaging study.

BACKGROUND: Deficits in facial emotion recognition are a core feature of schizophrenia and predictive of functional outcome. Higher plasma levels of the cytokine interleukin 6 (IL-6) have recently been associated with poorer facial emotion recognition in individuals with schizophrenia and healthy participants, but the neural mechanisms affected remain poorly understood. METHODS: Forty-nine individuals with schizophrenia or schizoaffective disorder and 158 healthy participants were imaged using functional magnetic resonance imaging during a dynamic facial emotion recognition task. Plasma IL-6 was measured from blood samples taken outside the scanner. Multiple regression was used in statistical parametric mapping software to test whether higher plasma IL-6 predicted increased neural response during task performance. RESULTS: Higher plasma IL-6 predicted increased bilateral medial prefrontal response during neutral face processing compared to angry face processing in the total sample (N = 207, tmax = 5.67) and increased left insula response during angry face processing compared to neutral face processing (N = 207, tmax = 4.40) (p < 0.05, family-wise error corrected across the whole brain at the cluster level). CONCLUSIONS: These findings suggest that higher peripheral IL-6 levels predict altered neural response within brain regions involved in social cognition and emotion during facial emotion recognition. This is consistent with recent neuroimaging research on IL-6 and suggesting a possible neural mechanism by which this cytokine might affect facial emotion recognition accuracy.

Early life Adversity, functional connectivity and cognitive performance in Schizophrenia: The mediating role of IL-6.

OBJECTIVE: Exposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity. METHODS: Three-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity. RESULTS: Higher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: ßindirect -0.0234, 95% CI: -0.0573 to -0.0074; CTQ physical neglect: ßindirect = -0.0316, 95% CI: -0.0741 to -0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (ßindirect = -0.0618, 95% CI: -0.1523 to -0.285). CONCLUSION: This work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6's association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted.

A high prevalence of genetic polymorphisms in idiopathic and alcohol-associated chronic pancreatitis patients in Ireland.

BACKGROUND: Individual genetic architecture is considered central to susceptibility and progression of disease in chronic pancreatitis. The study aimed to evaluate the presence of common pancreatic gene mutations in a defined cohort of idiopathic and alcohol-induced chronic pancreatitis patients in Ireland. METHODS: The study comprised patients with idiopathic and alcohol-induced chronic pancreatitis and historic controls. Variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, cationic trypsinogen (PRSS1) gene and serine protease inhibitor kazal type-1 (SPINK1) gene, were assessed by Taqman© genotyping assay. RESULTS: Of n = 126 patients and n = 167 controls, mutations were detected in 23 (20%) and in 10 (6%) respectively (P < 0.001). The majority of mutations found were in the SPINK1 gene variant N34S (13%) which increased disease risk almost six-fold (OR 5.9). Neither CFTR severe mutation (F508del) (P = 0.649) nor mild variant (R117H) (P = 0.327) were over-represented amongst patients compared to control subjects. PRSS1 variants were not detected in either patient or control subjects. CONCLUSION: There was a significant prevalence of chronic pancreatitis-associated gene mutations in this well-phenotyped cohort. In patients with alcohol-related or idiopathic chronic pancreatitis, the possibility of genetic mutations in the SPINK 1 gene should be considered as a contributing aetiology factor.

Innate Lymphocyte Th1 and Th17 Responses in Elderly Hospitalised Patients with Infection and Sepsis.

Background: the role of innate immunity in human sepsis must be fully clarified to identify potential avenues for novel immune adjuvant sepsis therapies. Methods: A prospective observational study was performed including patients with sepsis (septic group), infection without sepsis (infection group), and healthy controls (control group) in the setting of acute medical wards and intensive care units in a 1000-bed university hospital. A total of 42 patients with sepsis, 30 patients with infection, and 30 healthy controls were studied. The differentiation states of circulating mucosal associated invariant T (MAIT) cells and Natural Killer T (NKT) cells were characterised as naive (CD45RA+, CD197+), central memory (CD45RA-, CD197+), effector memory (CD45RA-, CD197-), or terminally differentiated (CD45RA+, CD197-). The differentiation states of circulating gamma-delta T lymphocytes were characterised as naive (CD45RA+, CD27+), central memory (CD45RA-, CD27+), effector memory (CD45RA-, CD27-), or terminally differentiated (CD45RA+, CD27-). The expression of IL-12 and IL-23 receptors, the transcription factors T-Bet and RORγt, and interferon-γ and IL-17a were analysed. Results: MAIT cell counts were lower in the septic group (p = 0.002) and the infection group (p < 0.001) than in the control group. The MAIT cell T-Bet expression in the infection group was greater than in the septic group (p = 0.012). The MAIT RORγt expression in the septic group was lower than in the control group (p = 0.003). The NK cell counts differed in the three groups (p < 0.001), with lower Natural Killer (NK) cell counts in the septic group (p < 0.001) and in the infection group (p = 0.001) than in the control group. The NK cell counts increased in the septic group in the 3 weeks following the onset of sepsis (p = 0.028). In lymphocyte stimulation experiments, fewer NK cells expressed T-Bet in the septic group than in the infection group (p = 0.002), and fewer NK cells expressed IFN-γ in the septic group than in the control group (p = 0.002). The NKT cell counts were lower in the septic group than both the control group (p = 0.05) and the infection group (p = 0.04). Fewer NKT cells expressed T-Bet in the septic group than in the infection group (p = 0.004). Fewer NKT cells expressed RORγt in the septic group than in the control group (p = 0.003). Fewer NKT cells expressed IFN-γ in the septic group than in both the control group (p = 0.002) and the infection group (p = 0.036). Conclusion: The clinical presentation of infection and or sepsis in patients is linked with a mosaic of changes in the innate lymphocyte Th1 and Th17 phenotypes. The manipulation of the innate lymphocyte phenotype offers a potential avenue for immune modulation in patients with sepsis.

Prevalence of coexisting autoimmune thyroidal diseases in coeliac disease is decreasing.

BACKGROUND: Coeliac disease (CD) is associated with an increased risk of other immune-mediated conditions. Aim: To investigate the prevalence of coexistent immune-mediated diseases in CD patients, and changes in the prevalence of autoimmune thyroidal diseases over the last 50 years. METHODS: Medical record data were collected retrospectively from 749 CD patients in Ireland. Prevalence of autoimmune diseases was compared with previously published results from general populations. Patients were divided into four groups based on the year of diagnosis to analyse changes in the prevalence of autoimmune thyroidal disease over time. RESULTS: Median age at the time of CD diagnosis was 56 years (range 18-91 years). A total of 233 (31.1%) patients had a coexistent immune-mediated condition (IMC). Autoimmune thyroidal diseases were seen in 149 (19.9%) patients, hypothyroidism in 110 (14.7%), type 1 diabetes in 27 (3.6%), psoriasis in 20 (2.7%), inflammatory bowel disease in 14 (1.9%) and rheumatoid arthritis in 12 (1.6%). All conditions were more common in CD patients than in the general population. Type 1 diabetes was diagnosed mainly before CD, whereas there was no such trend in other conditions. Autoimmune thyroidal diseases became less common in female CD patients over time. CONCLUSIONS: Prevalence of autoimmune diseases is increased in adult CD patients compared with the general population. However, concomitant autoimmune thyroidal diseases became less common over time in women.

Collagens and elastin genetic variations and their potential role in aging-related diseases and longevity in humans.

Collagens and elastin are 'building blocks' of tissues and extracellular matrix. Mutations in these proteins cause severe congenital syndromes. Adverse genetic variations may accelerate the aging process in adults contributing to premature morbidity, disability and/or mortality. Favorable variants may contribute to longevity and/or healthy aging, but this is much less studied. We reviewed the association between variation in the genes of collagens and elastin and premature aging, accelerated aging, age-related diseases and/or frailty; and the association between genetic variation in those and longevity and/or healthy aging in humans. A systematic search was conducted in MEDLINE and other online databases (OMIM, Genetics Home Reference, Orphanet, ClinVar). Results suggest that genetic variants lead to aging phenotypes of known congenital disease, but also to association with common age-related diseases in adults without known congenital disease. This may be due to the variable penetrance and expressivity of many variants. Some collagen variants have been associated with longevity or healthy aging. A limitation is that most studies had <1000 participants and their criterion for statistical significance was p < 0.05. Results highlight the importance of adopting a lifecourse approach to the study of the genomics of aging. Gerontology can help with new methodologies that operationalize biological aging.

Dysregulated T helper type 1 (Th1) and Th17 responses in elderly hospitalised patients with infection and sepsis.

OBJECTIVE: The role of Th1 and Th17 lymphocyte responses in human infection and sepsis of elderly patients has yet to be clarified. DESIGN: A prospective observational study of patients with sepsis, infection only and healthy controls. SETTING: The acute medical wards and intensive care units in a 1000 bed university hospital. PATIENTS: 32 patients with sepsis, 20 patients with infection, and 20 healthy controls. Patients and controls were older than 65 years of age. Patients with recognised underlying immune compromise were excluded. METHODS: Phenotype, differentiation status and cytokine production by T lymphocytes were determined by flow cytometry. MEASUREMENTS: The differentiation states of circulating CD3+, CD4+, and CD8+ T cells were characterised as naive (CD45RA+, CD197+), central memory (CD45RA-, CD197+), effector memory (CD45RA-, CD197-), or terminally differentated (CD45RA+, CD197-). Expression of IL-12 and IL-23 receptors, and the transcription factors T-bet and RORγt, was analysed in circulating T lymphocytes. Expression of interferon- γ and IL-17A were analysed following stimulation in vitro. RESULTS: CD4+ T cells from patients with infection predominantly expressed effector-memory or terminally differentiated phenotypes but CD4+ T cells from patients with severe sepsis predominantly expressed naive phenotypes (p<0.0001). CD4+ T cells expressing IL-23 receptor were lower in patients with sepsis compared to patients with infection alone (p = 0.007). RORγt expression by CD4+ T cells was less frequent in patients with sepsis (p<0.001), whereas T-bet expressing CD8+ T cells that do not express RORγt was lower in the sepsis patients. HLA-DR expression by monocytes was lower in patients with sepsis. In septic patients fewer monocytes expressed IL-23. CONCLUSION: Persistent failure of T cell activation was observed in patients with sepsis. Sepsis was associated with attenuated CD8+Th1 and CD4+Th17 based lymphocyte response.

Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis.

OBJECTIVES: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, with a strong heritable component, affecting patients with psoriasis. Here we attempt to identify genetic variants within the major histocompatibility complex (MHC) that differentiate patients with PsA from patients with cutaneous psoriasis alone (PsC). METHODS: 2808 patients with PsC, 1945 patients with PsA and 8920 population controls were genotyped. We imputed SNPs, amino acids and classical HLA alleles across the MHC and tested for association with PsA compared to population controls and the PsC patient group. In addition we investigated the impact of the age of disease onset on associations. RESULTS: HLA-C*06:02 was protective of PsA compared to PsC (p=9.57×10-66, OR 0.37). The HLA-C*06:02 risk allele was associated with a younger age of psoriasis onset in all patients (p=1.01×10-59). After controlling for the age of psoriasis onset no association of PsA to HLA-C*06:02 (p=0.07) was observed; instead, the most significant association was to amino acid at position 97 of HLA-B (p=1.54×10-9) where the presence of asparagine or serine residue increased PsA risk. Asparagine at position 97 of HLA-B defines the HLA-B*27 alleles. CONCLUSIONS: By controlling for the age of psoriasis onset, we show, for the first time, that HLA-C*06:02 is not associated with PsA and that amino acid position 97 of HLA-B differentiates PsA from PsC. This amino acid also represents the largest genetic effect for ankylosing spondylitis, thereby refining the genetic overlap of these two spondyloarthropathies. Correcting for bias has important implications for cross-phenotype genetic studies.

Changes in Presentation of Celiac Disease in Ireland From the 1960s to 2015.

BACKGROUND & AIMS: Celiac disease is an immune-mediated enteropathy characterized with high heterogeneity in presentation among genetically predisposed individuals. In recent years, a change in the phenotypic presentation of celiac disease has been reported. We studied clinical presentation, from 1960 through 2015, in Ireland, which has a high incidence of celiac disease. METHODS: We performed a retrospective analysis of medical charts from patients diagnosed with celiac disease at 5 secondary referral centers in Ireland from 1960 through 2015 (n = 749; median age, 56 years; age range, 18-91 years). The cohort was divided into 5 groups based on year of diagnosis (≤1985, 1986-1995, 1996-2005, 2006-2010, or 2011 and later). We collected findings from clinical presentation at diagnosis; serology tests; small intestinal biopsy analyses; and patients' demographic, clinical, and family data. Presentations at diagnosis were classified according to the Oslo criteria as follows: classical (patients presenting with malabsorption), nonclassical (no signs or symptoms of malabsorption at presentation), or subclinical (below the threshold of clinical detection). The primary outcome was change in clinical presentation of celiac disease over time. RESULTS: Of the 749 patients studied, 512 were female and 237 were male (ratio of 2.2:1). Female patients were diagnosed at younger ages than male patients (42 vs 47 years, respectively; P = .004), and had more immune-mediated conditions than male patients (35.7% for female patients vs 21.5% for male patients; P < .001). For patients diagnosed as adults (after the age of 18 years), the median age of diagnosis increased from 34.0 years during the period ≤1985 to median ages of 44-46 years after 1985 (P < .002). A smaller proportion of patients presented with classical features of celiac disease after 2010 (48.4%) than ≤1985 (85.2%); the proportion of patients with nonclassical or subclinical celiac disease increased from 14.8% ≤1985 to 51.6% after 2010 (P = .006 for each). Biopsies categorized as Marsh 3c decreased, from 52.2% in the period 1996-2005 to 22.5% in the period after 2010 (P = .003). The prevalence of associated thyroid disease has decreased during the study period, from 36.6% ≤1985 to 17.1% after 2010 (P = .039), whereas body mass index at diagnosis increased from 21.5 kg/m2 ≤1985 to 24.8 kg/m2 after 2010 (P < .001). CONCLUSIONS: We found the clinical presentation of celiac disease changed significantly in Ireland from 1960 through 2015. The age of presentation in adulthood increased over this time period, as did the proportions of patients with nonclassical or subclinical disease.

Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.

Viral Bronchiolitis is Associated With Altered Cytokine Gene Expression and Lymphocyte Activation Status.

BACKGROUND: Disease severity in viral bronchiolitis is often difficult to predict at onset, and may be related to the host immune response. Recognizing the particular immunologic features of infants who develop severe disease might offer an opportunity for developing diagnostic tools to facilitate early intervention and improve outcomes. METHODS: We compared cytokine gene expression (by real-time reverse-transcriptase polymerase chain reaction), cytokine concentrations (by enzyme-linked immunosorbent assay) and the activation status of lymphocytes (by flow cytometry) in the peripheral blood of children hospitalized with moderate and severe viral bronchiolitis and a group of age-matched controls. RESULTS: Analysis was undertaken on 57 children with viral bronchiolitis and 33 controls. Interleukin-7 mRNA expression at enrollment in peripheral blood mononuclear cells differed significantly between those with moderate and severe bronchiolitis, and correlated with both the subsequent length of hospital stay and need for supplemental oxygen therapy. Serum interleukin-10 concentration also distinguished moderate from severe disease. Participants with viral bronchiolitis demonstrated a more activated γδ-T cell phenotype (Vδ1+), but a more naive TCR αß-T cell compartment compared with controls. CONCLUSIONS: Viral bronchiolitis is characterized by a distinct pattern of cytokine expression and lymphocyte activation. These changes suggest an inadequate innate response in severe disease, and may offer potential as markers of disease severity.