X-box binding protein 1 (XBP1) C--116G polymorphisms in bipolar disorders and age of onset

X-box binding protein 1 (XBP1), a critical gene in the endoplasmic reticulum stress response, is located on chromosome 22q12, which has been linked with bipolar disorders in several studies. Recently, associations have been reported between a polymorphism (-116C --> G) in the promoter region of XBP1, and bipolar disorders in both case-control study and family-based association study, however, this finding is not yet confirmed by other research using independent sample populations. To replicate this finding and determine the association between onset age of bipolar disorders and the XBP1 C--116G polymorphism, we investigated the prevalence of this polymorphism in a Chinese population (153 bipolar disorder patients and 174 controls). We were unable, however, to demonstrate a significant association between the C--116G polymorphism and bipolar disorders (P = 0.674 for genotype and P = 0.436 for allele frequency) or age at onset (P = 0.563). Further, no association was demonstrated between this polymorphism and family history in bipolar disorder patients. These negative findings suggest that the XBP1 C--116G polymorphism does not play a major role in the pathogenesis of bipolar disorders in Chinese populations.     

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta?=??0.0264, p value?=?3.5?×?10^–8) in the discovery panel and was replicated in replication panel (beta?=??0.07, p value?=?0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value?=?1.4?×?10^–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

     

Cortico-thalamic dysconnection in early-stage schizophrenia: a functional connectivity magnetic resonance imaging study

European Archives of Psychiatry and Clinical Neuroscience - Studies have indicated thalamus-related network dysfunction in schizophrenia and psychotic disorders. However, whether thalamus-related...     

Elevated Galectin-3 Precedes the Development of CKD

Galectin-3, a profibrotic mediator, is linked to the development of renal fibrosis in animal models and inversely correlates with GFR in humans, but whether galectin-3 predicts incident kidney disease is unknown. Here, we assessed renal outcomes for 2450 Framingham Offspring participants who attended examination 6 (1995–1998) and had follow-up data at examination 8 (2005–2008). Renal outcomes of interest included rapid decline in renal function (≥3 ml/min per 1.73 m² per year decline in estimated GFR [eGFR]), CKD (eGFR < 60 ml/min per 1.73 m²), and albuminuria (albumin-to-creatinine ratio ≥17 mg/g in men or ≥25 mg/g in women). We used multivariable logistic regression models to evaluate associations between galectin-3 with incident renal outcomes at examination 8. During a mean follow-up of 10.1 years, GFR declined rapidly in 241 (9.2%) participants, incident CKD developed in 277 (11.3%), and albuminuria developed in 194 (10.1%). Higher plasma levels of galectin-3 were associated with rapid decline in eGFR (per 1-SD log-galectin-3; adjusted odds ratio [OR], 1.49; 95% confidence interval [CI], 1.28 to 1.73]) and a higher risk of incident CKD (OR, 1.47; 95% CI, 1.27 to 1.71), but not with the risk of incident albuminuria. The addition of galectin-3 to clinical predictors improved the C-statistic (0.837–0.845; P=0.02) but did not reach predefined thresholds for clinically significant improvements to risk prediction based on reclassification indices. In conclusion, elevated levels of plasma galectin-3 are associated with increased risks of rapid GFR decline and of incident CKD in the community, which calls for further study in higher-risk groups.CKD is a major worldwide public health problem^1–6 that may result in progressive deterioration in kidney function,⁷ substantial morbidity,^8–10 and increased mortality from both cardiovascular¹¹ and noncardiovascular causes.¹² Because of the lack of early clinical signs or symptoms and the poor sensitivity of currently available biomarkers (serum creatinine and urinary protein), CKD is typically detected at an advanced stage. However, when detected early, kidney function decline may be slowed or even reversed and these secondary complications averted.^13–15 Hence, there is a pressing clinical need for novel biomarkers that identify at-risk individuals at the earliest possible stage.Galectin-3 is a β-galactoside–binding lectin that has emerged as a key regulator of inflammation and fibrosis.¹⁶ Galectin-3 is strongly linked to the development of organ fibrosis in rodent models: Galectin-3 knockout mice are resistant to the development of fibrosis, whereas infusion of recombinant galectin-3 induces TGF-β−dependent tissue fibroblast proliferation and collagen deposition.^17,18 In addition, upregulation of galectin-3 has been implicated in fibrosis of multiple organs, including the liver,^19,20 lung,²¹ and heart.¹⁷ Galectin-3 has also been linked to the development of renal fibrosis,^22,23 as well as fibrosis attenuation via matrix remodeling,²⁴ indicating a context-dependent role.Progressive CKD is characterized by the development of tubulointerstitial fibrosis.²⁵ Galectin-3 expression and secretion by macrophages have previously been shown to promote the development of tubulointerstitial fibrosis in mouse models.²³ We believe galectin-3 merits study as a renal biomarker on the basis of this association with renal fibrosis, as well as strong cross-sectional correlations with GFR identified in studies of patients with heart failure and in the general population.^26–30 We hypothesized that higher plasma galectin-3 levels would be associated with an increased risk of incident CKD in the general population, defined as estimated GFR (eGFR) < 60 ml/min per 1.73 m² or incident albuminuria. We also considered whether galectin-3 is associated with rapid decline in kidney function, as assessed by decline in eGFR during the follow-up period. To address these questions, we assessed prospective relations of galectin-3 and these outcomes in unselected participants from the Framingham Heart Study (FHS).     

Mid-Adulthood Risk Factor Profiles for CKD

Early identification of CKD risk factors may allow risk factor modification and prevention of CKD progression. We investigated the hypothesis that risk factors are present ≥30 years before the diagnosis of CKD in a case-control study using data from the Framingham Offspring Study. Patients with incident CKD (eGFR≤60 ml/min per 1.73 m²) at examination cycles 6, 7, and 8 were age- and sex-matched 1:2 to patients without CKD at baseline (examination 5). CKD risk factors were measured at each examination cycle. Logistic regression models, adjusted for age, sex, and time period, were constructed to compare risk factor profiles at each time point between cases and controls. During follow-up, 441 new cases of CKD were identified and matched to 882 controls (mean age 69.2 years, 52.4% women). Those who ultimately developed CKD were more likely to have hypertension (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.23 to 2.51), obesity (OR, 1.71; 95% CI, 1.14 to 2.59), and higher triglyceride levels (OR, 1.43; 95% CI, 1.12 to 1.83) 30 years before CKD diagnosis, and were more likely to have hypertension (OR, 1.38; 95% CI, 1.07 to 1.79), higher triglyceride levels (OR, 1.35; 95% CI, 1.11 to 1.64), lower HDL_c (OR, 0.89; 95% CI, 0.81 to 0.97), and diabetes (OR, 2.90; 95% CI, 1.59 to 5.29) 20 years before CKD diagnosis. These findings demonstrate that risk factors for CKD are identifiable ≥30 years before diagnosis and suggest the importance of early risk factor identification in patients at risk for CKD.     

Sequencing of LRP2 Reveals Multiple Rare Variants Associated with Urinary Trefoil Factor-3

Novel biomarkers are being investigated to identify patients with kidney disease. We measured a panel of 13 urinary biomarkers in participants from the Offspring Cohort of the Framingham Heart Study. Using an Affymetrix chip with imputation to 2.5 M single-nucleotide polymorphisms (SNPs), we conducted a GWAS of these biomarkers (n=2640) followed by exonic sequencing and genotyping. Functional studies in zebrafish were used to investigate histologic correlation with renal function. Across all 13 biomarkers, there were 97 significant SNPs at three loci. Lead SNPs at each locus were rs6555820 (P=6.7×10⁻⁴⁹; minor allele frequency [MAF]=0.49) in HAVCR1 (associated with kidney injury molecule-1), rs7565788 (P=2.15×10⁻¹⁶; MAF=0.22) in LRP2 (associated with trefoil factor 3 [TFF3]), and rs11048230 (P=4.77×10⁻⁸; MAF=0.10) in an intergenic region near RASSF8 (associated with vascular endothelial growth factor). Validation in the CKDGen Consortium (n=67,093) showed that only rs7565788 at LRP2, which encodes megalin, was associated with eGFR (P=0.003). Sequencing of exons 16–72 of LRP2 in 200 unrelated individuals at extremes of urinary TFF3 levels identified 197 variants (152 rare; MAF<0.05), 31 of which (27 rare) were nonsynonymous. In aggregate testing, rare variants were associated with urinary TFF3 levels (P=0.003), and the lead GWAS signal was not explained by these variants. Knockdown of LRP2 in zebrafish did not alter the renal phenotype in static or kidney injury models. In conclusion, this study revealed common variants associated with urinary levels of TFF3, kidney injury molecule-1, and vascular endothelial growth factor and identified a cluster of rare variants independently associated with TFF3.Serum creatinine, as used in most GFR estimating equations, is the primary biomarker of CKD.¹ Creatinine has significant limitations as a biomarker. It is insensitive to early declines in kidney function, and there are important extrarenal factors that influence its concentration, thus increasing the potential for misclassification when it is used to diagnose renal disease.² As a result, novel biomarkers are being investigated that could allow earlier and more accurate diagnosis of CKD.³ It is likely, however, that these biomarkers also have non-GFR determinants, including genetic factors. For example, levels of cystatin C, a novel GFR biomarker, are known to be influenced by both nongenetic factors, such as adiposity and the metabolic syndrome,⁴ and the presence of specific genetic variants in the cystatin C-gene cluster.⁵Genome-wide association studies (GWAS) allow for the evaluation of genetic associations of biomarkers in an unbiased manner. These studies could illuminate previously unrecognized pathways for CKD pathogenesis, thus identifying new potential molecular targets for therapeutic intervention. Multiple variants have been identified in association with kidney function through GWAS,⁶ whereas a variant in CUBN encoding cubilin, a proximal tubular transport protein, has been associated with albuminuria.⁷ Recently, a GWAS identified a locus at PTGDS in association with another kidney biomarker, β-trace protein.⁸To gain additional insight into biologic pathways of renal function and kidney injury, we measured a panel of 13 urinary biomarkers in participants from the Framingham Heart Study (FHS) and performed a GWAS of their levels. Here, we report the primary results from these studies as well as follow-up work to identify whether rare variants in LRP2 are associated with levels of trefoil factor 3 (TFF3).     

Postpartum endogenous Candida endophthalmitis.

Candida albicans is the most common pathogen causing intraocular fungal infection. Postpartum endogenous Candida endophthalmitis, however, is extremely rare. We report the case of a 33-year-old postpartum woman who presented with a 5-day history of decreased vision and had a positive blood culture for C. albicans. Fundus examination showed vitreous haze and multiple pre-retinal whitish lesions with indistinct borders. Systemic investigations revealed acute renal failure and cardiomegaly. After treatment with intravenous antifungal therapy, vitrectomy, and intravitreal injection of antimycotics, systemic and intraocular infections were eradicated successfully.