Explore the vast range of titles available.

Jacob George and colleagues report a genome-wide association study to hepatitis C treatment response. They report an association of common variants within the IL28B region to sustained virologic response following pegylated interferon alpha and ribavirin combined therapy in individuals with genotype 1 chronic hepatitis C. Hepatitis C virus (HCV) infects 3% of the world's population. Treatment of chronic HCV consists of a combination of PEGylated interferon-α (PEG-IFN-α) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-α/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B ( IL28B , also called IFNλ3 ; rs8099917 combined P = 9.25 × 10 −9 , OR = 1.98, 95% CI = 1.57–2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-α.

Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism ( rs12979860) in the intronic region of interferon-λ4 (IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates ( P <0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis. Tissue fibrosis is a major contributor to mortality in the developed world. Here, the authors identify a genetic variant in the intronic region of interferon-λ4 that is a strong predictor of hepatic inflammation and fibrosis, independent of liver disease aetiology

The cellular identity of pancreatic polypeptide (Ppy)-expressing γ-cells, one of the rarest pancreatic islet cell-type, remains elusive. Within islets, glucagon and somatostatin, released respectively from α- and δ-cells, modulate the secretion of insulin by β-cells. Dysregulation of insulin production raises blood glucose levels, leading to diabetes onset. Here, we present the genetic signature of human and mouse γ-cells. Using different approaches, we identified a set of genes and pathways defining their functional identity. We found that the γ-cell population is heterogeneous, with subsets of cells producing another hormone in addition to Ppy. These bihormonal cells share identity markers typical of the other islet cell-types. In mice, Ppy gene inactivation or conditional γ-cell ablation did not alter glycemia nor body weight. Interestingly, upon β-cell injury induction, γ-cells exhibited gene expression changes and some of them engaged insulin production, like α- and δ-cells. In conclusion, we provide a comprehensive characterization of γ-cells and highlight their plasticity and therapeutic potential. The cellular identity and function of the pancreatic polypeptide (Ppy)-producing γ-cells are incompletely understood. Here the authors show that these cells are heterogeneous and display adaptive plasticity to engage in insulin production following β-cell injury, but loss of the Ppy gene or γ-cells in mice does not affect weight or glycemia under basal conditions.

Background/Objectives: The association between gestational weight gain (GWG) and adverse outcomes in individuals with gestational diabetes mellitus (GDM) and obesity remains unclear. This study aimed to evaluate the relationship between total GWG and maternal, obstetric, and neonatal outcomes in patients with GDM, stratified by obesity class. Methods: This retrospective cohort included 695 pregnant individuals with GDM treated at a tertiary university hospital in Brazil between 2007 and 2021. GWG was categorized as insufficient, adequate, or excessive per National Academy of Medicine guidelines. Outcomes included maternal, obstetric, and neonatal events. Analyses were conducted for the entire cohort and stratified by obesity class (I and II/III), using multivariate regression models adjusted for maternal age, parity, and pre-pregnancy BMI. Results: The mean age was 33.6 (SD 5.7) years. GWG was insufficient in 33.2%, adequate in 28.2%, and excessive in 37.8%. Excessive GWG was associated with increased odds of cesarean delivery (OR 1.69; 95% CI 1.15–2.48) and large-for-gestational-age newborns (OR 3.29; 95% CI 1.61–6.46). As a continuous variable, GWG was positively associated with cesarean delivery (OR 1.04), LGA (OR 1.10), and birthweight (β = 0.02). Lower GWG was independently associated with reduced preeclampsia risk (OR 1.09 per kg). Insufficient GWG was not linked to increased risk of small-for-gestational-age newborns or other adverse outcomes and was associated with lower insulin requirement. Results remained consistent across obesity subgroups, except for cesarean delivery in class II/III obesity. Conclusions: In individuals with GDM and obesity, insufficient GWG was not associated with increased adverse outcomes, while excessive GWG was consistently linked to unfavorable maternal and neonatal risks. Stricter GWG control may be safe and beneficial in this population.

Background Electroconvulsive therapy (ECT) benefits patients with treatment-resistant depression (TRD), but the underlying biological processes are unclear. We conducted an epigenome-wide association study in 32 TRD patients undergoing ECT to depict ECT-associated methylation changes. Illness severity and ECT outcomes were assessed with the Montgomery–Åsberg Depression Rating Scale at baseline (T0) and 1 month after its end (T1). Methylation was profiled at T0 and T1 with the Illumina Infinium Methylation EPIC BeadChip array. Results Longitudinal T0–T1 analyses showed 3 differentially methylated probes (DMPs) with nominal p values ≤ 10 −5 , with 2 annotated in the genes CYB5B and PVRL4 . Including covariates, we found 4 DMPs for symptoms variation, annotated in FAM20C , EPB41 , OTUB1 and ADARB1 , and 3 DMPs for response status, with 2 annotated in IQCE and FAM20C . Regional analysis revealed 54 differentially methylated regions (DMRs) with nominal p value area ≤ 0.05, with 9 presenting adjusted p -value area ≤ 0.10, annotated in MCF2L , SLC25A24 , RUNX3 , MIR637 , FOXK2 , FAM180B , POU6F1 , ALS2CL and CCRL2 . Considering covariates, we found 21 DMRs for symptoms variation and 26 DMRs for response (nominal p value area ≤ 0.05), with 4 presenting adjusted p -value area ≤ 0.10 for response, annotated in SNORD34 , NLRP6 , GALNT2 and SFT2D3 . None remained significant after false discovery rate correction. Notably, ADARB1 variants are associated with suicide attempt in patients with psychiatric disorders, and SLC25A24 relates to conduct disorder. Several DMPs and DMRs are annotated in genes associated with inflammatory/immune processes. Longitudinal analyses on females (n = 22) revealed statistically significant DMRs (adjusted p value area ≤ 0.05) and trend-significant DMRs (adjusted p value area ≤ 0.07) for symptoms variation and response status, annotated in genes related to psychiatric disorders ( ZFP57 , POLD4, TRIM10, GAS7, ADORA2A, TOLLIP ), trauma exposure ( RIPOR2 ) and inflammatory/immune responses ( LAT , DLX4 , POLD4 , FAM30A, H19 ). Pathway analysis on females revealed enrichment for transcriptional activity, growth factors, DNA maintenance, and immune pathways including IRF7 and IRF2 . Conclusion Although no significant results were found for the whole cohort, the study provides insights into ECT-associated methylation changes, highlighting DMPs and DMRs related to ECT outcomes. Analyses on females revealed significant DMRs and pathways related to psychiatric disorders and inflammatory/immune processes.

In patients with inflammatory bowel diseases (IBD) undergoing biologic therapy, biomarkers of treatment response are still scarce. This study aimed to evaluate whether serum zonulin, a biomarker of intestinal permeability; soluble CD163 (sCD163), a macrophage activation marker; and a panel of serum cytokines could predict the response to biologic treatment in patients with IBD. For this purpose, we prospectively enrolled 101 patients with IBD and 19 patients with irritable bowel syndrome (IBS) as a control group; 60 out of 101 patients underwent treatment with biologics. Zonulin, sCD163, and cytokines were measured at the baseline in all patients and after 10 weeks of treatment in the 60 patients who underwent biologic therapy. We observed that zonulin levels were higher in IBD patients with active disease compared to those in remission (p = 0.035), and that sCD163 values were higher in patients with IBD compared to those with IBS (p = 0.042), but no association with therapy response was observed for either biomarker. Conversely, interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha showed a significant reduction from baseline to week 10 of treatment, particularly in responder patients. By multivariate logistic regression analysis corrected for disease (Crohn’s disease or ulcerative colitis), type of biologic drug (Infliximab, Adalimumab, Vedolizumab, or Ustekinumab) and disease activity, the reduction in IL-6 values was associated with a clinical response at 12 months of biological therapy (odds ratio (OR) = 4.75, 95% confidence interval (CI) 1.25–18.02, p = 0.022). In conclusion, the measurement of serum IL-6 in biologics-treated IBD patients may allow for the prediction of response to treatment at 12 months of therapy and thus may help with tailoring personalized treatment strategies.

Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis. Chronic Hepatitis C infection is associated with a broad spectrum of liver pathologies, ranging from inflammation to fibrosis and liver cancer. Here Thabet et al . identified a polymorphism in the gene MBOAT7 that is associated with increased hepatic inflammation and higher risk of fibrosis development and progression.

Background Noonan Syndrome (NS) is a rare multisystemic disorder with heterogeneous phenotypic manifestations. The aim of this study was to analyse rates of survival, hospitalisation, surgeries and prescriptions in children born with NS in the first 10 years of life. Methods This is a multi-centre population-based cohort study. Data on 175 liveborn children diagnosed with NS from 11 EUROCAT congenital anomaly registries were linked to healthcare databases. Each registry applied a common data model to standardise data and run common syntax scripts to produce aggregated results which were pooled using random effects meta-analyses. Results Mortality rates were high in the first year of life with 5.4% (95%CI 1.5%-10.1%) of children dying before the age of 1 year with a further 2% dying up to age 5. In the first year, 87.9% (95%CI 75.3%-94.3%) of children were hospitalized and the median Length Of hospital Stay (LOS) was 15.3 days (95%CI 9.3–21.2). After the first year, the proportion of children hospitalized remained higher than 70%, but the LOS decreased to 1.3 days per year. In the first 5 years, 65.2% of children underwent a median of two surgical procedures. The median age at first surgery was 29 weeks. The proportion of children with an antibiotic prescription increased from 53.6% at age 1 to 62.4% yearly until 4 years of age. Conclusions Children with NS have high mortality and morbidity not only in the first year of life but also up to five years of age. This study evaluated the health burden of NS and provided information for clinicians, health-care providers and families.

Background: Pathogenetic mechanisms involved in the progression of non-alcoholic fatty liver disease (NAFLD) are complex and multifactorial. We investigated oxidative stress through the measurement of selenoprotein P (SeP) in serum and we explored its relation to metabolic derangements and liver damage in a group of non-diabetic NAFLD subjects. Methods: 57 NAFLD patients underwent a double-tracer oral glucose tolerance test (OGTT). Insulin resistance (IR) components were calculated at baseline as follows: hepatic-IR = (endogenous glucose production*insulin); peripheral-IR = (glucose rate of disappearance(Rd)); adipose-tissue(AT)-IR as Lipo-IR = (glycerol rate of appearance (Ra)*insulin) or AT-IR = (free fatty acids (FFAs)*insulin). The lipid and amino acid (AA) profiles were assessed by gas chromatography–mass spectrometry. SeP levels were measured by enzyme immunosorbent assay. Results: Circulating SeP correlated with insulin (rS = 0.28), FFAs (rS = 0.42), glucose Rd (rS = −0.33) and glycerol Ra (rS = −0.34); consistently, SeP levels correlated with Lipo-IR and AT-IR (rS > 0.4). Among the AA and lipid profiles, SeP inversely correlated with serine (rS = −0.31), glycine (rS = −0.44) and branched chain AA (rS = −0.32), and directly correlated with saturated (rS = 0.41) and monounsaturated FFAs (rS = 0.40). Hepatic steatosis and fibrosis increased in subjects with higher levels of SeP. In multivariable regression analysis, SeP was associated with the degree of hepatic fibrosis (t = 2.4, p = 0.022). Conclusions: SeP levels were associated with an altered metabolic profile and to the degree of hepatic fibrosis, suggesting a role in the pathogenesis of NAFLD.

Globally, it is estimated that 56 [...]