Citations

Objectives Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early‐onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD‐ and schizophrenia (SCZ)‐associated risk variants is associated with an earlier AAO in BD patients. Methods A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn‐Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD‐ and SCZ‐PRSs and AAO were evaluated with regression models. Results BD‐ and SCZ‐PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

It has been postulated that catheter-based renal denervation (RDN) may lower blood pressure (BP) and improve severity of obstructive sleep apnea (OSA) in resistant hypertensive patients. The aim of our study (NCT01366625) was to investigate in a prospective randomized trial the effect of RDN on BP and clinical course of OSA. Sixty patients with true resistant hypertension coexisting with moderate-to-severe OSA (apnea/hypopnea index, ≥15) were randomly allocated to RDN group (30 patients) and to control group (30 patients). The primary end point was reduction in office systolic BP at 3 months. Secondary end points included reduction in diastolic office and ambulatory BP, change in apnea/hypopnea index and biochemical measurements at 3 months, and change in echocardiographic measurements at 6 months. There were no differences in clinical characteristics between the groups. At 3 months in the RDN group, both office and ambulatory BP were significantly reduced, and a significant decrease in OSA severity (apnea/hypopnea index, 39.4 versus 31.2 events per hour; P =0.015) was observed. Between-group difference in apnea/hypopnea index change was significant at 0.05. At 6 months in the RDN group, reductions in office and ambulatory BP were sustained and were accompanied by significant improvement in echocardiographic measures of global longitudinal strain. There were no differences in metabolic variables in follow-up in both groups. In a randomized controlled trial, RDN lowered both office and ambulatory BP in patients with resistant hypertension and OSA. This was accompanied by improvement of the clinical severity of OSA. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01366625.

AbstractThe protein phosphatase Phlpp1 is an essential enzyme for proper chondrocyte function. Altered Phlpp1 levels are associated with cancer and degenerative diseases such as osteoarthritis. While much is known about the post‐transcriptional mechanisms controlling Phlpp1 levels, transcriptional regulation of the Phlpp1 gene locus is underexplored. We previously showed that CpG methylation of the PHLPP1 promoter is lower in osteoarthritic cartilage than in normal cartilage, and indirectly correlates with gene expression. Here we further defined the effects of DNA methylation on PHLPP1 promoter activity in chondrocytes. We cloned a 1791 bp fragment of the PHLPP1 promoter (−1589:+202) and found that the first 500 bp were required for maximal promoter activity. General methylation of CpG sites within this fragment significantly blunts transcriptional activity, whereas site‐specific methyltransferases HhaI or HpaII decrease transcriptional activation by approximately 50%. We located putative FoxO consensus sites within the PHLPP1 promoter region. Inhibition of DNA methylation by incorporation of 5‐azacytidine increases Phlpp1 mRNA levels, but FoxO inhibition abolishes this induction. To determine which FoxO transcription factor mediates Phlpp1 expression, we performed overexpression and siRNA‐mediated knock down experiments. Overexpression of FoxO3a, but not FoxO1, increases Phlpp1 levels. Likewise, siRNAs targeting FoxO3a, but not FoxO1, diminished Phlpp1 levels. Last, FoxO inhibition increases glycosaminoglycan staining of cultured chondrocytes and leads to concomitant increases in FGF18 and HAS2 expression. Together, these data demonstrate that CpG methylation and FoxO3a regulate PHLPP1 expression.

ABSTRACT Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT ‐associated variants and the entire coding sequence of MAPT were analyzed. Age‐, sex‐, and ethnicity‐adjusted analyses were performed to examine the association between MAPT , PD, and rapid eye movement sleep behavior disorder. Results: MAPT‐ H2 variants were associated with PD (odds ratios: 0.62‐0.65; P = 0.010‐0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12‐2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48‐0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT ‐H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society

Abstract Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep-disordered breathing. Recent advances in -omics and behavioral science provide an opportunity to specifically address sex-based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Women’s Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Summary Ketogenic dietary therapies ( KDTs ) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre‐ KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow‐up, side events, and KDT discontinuation. It has been helpful in outlining a state‐of‐the‐art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

Key Points There was no difference in overall survival after allogeneic transplant between patients aged 55-64 years and patients ≥65 years. Age alone should not be a determinant for allogeneic transplant eligibility among older non-Hodgkin lymphoma patients.