Citations

AbstractIrritable bowel syndrome (IBS) is a gut‐brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation‐predominant IBS (IBS‐C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta‐analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS‐C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow‐up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS‐C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

Abstract Motivation Interpreting genetic variation in noncoding regions of the genome is an important challenge for personal genome analysis. One mechanism by which noncoding single nucleotide variants (SNVs) influence downstream phenotypes is through the regulation of gene expression. Methods to predict whether or not individual SNVs are likely to regulate gene expression would aid interpretation of variants of unknown significance identified in whole-genome sequencing studies. Results We developed FIRE (Functional Inference of Regulators of Expression), a tool to score both noncoding and coding SNVs based on their potential to regulate the expression levels of nearby genes. FIRE consists of 23 random forests trained to recognize SNVs in cis-expression quantitative trait loci (cis-eQTLs) using a set of 92 genomic annotations as predictive features. FIRE scores discriminate cis-eQTL SNVs from non-eQTL SNVs in the training set with a cross-validated area under the receiver operating characteristic curve (AUC) of 0.807, and discriminate cis-eQTL SNVs shared across six populations of different ancestry from non-eQTL SNVs with an AUC of 0.939. FIRE scores are also predictive of cis-eQTL SNVs across a variety of tissue types. Availability and implementation FIRE scores for genome-wide SNVs in hg19/GRCh37 are available for download at https://sites.google.com/site/fireregulatoryvariation/. Supplementary information Supplementary data are available at Bioinformatics online.

Objective The objective of this study was to assess patients’ achievement of ADA (American Diabetes Association) guideline recommendations for glycosylated hemoglobin, lipid profile, and blood pressure in a type 2 diabetes mellitus (T2DM) outpatient clinic in a low-middle income country (LMIC) setting. Methods This is a descriptive cross-sectional study with 123 ambulatory T2DM patients who are being treated at a public hospital in Lima, Peru. Data was gathered via standardized interviews, clinical surveys, and anthropomorphic measurements for each patient. Blood samples were drawn in fasting state for measures of glucose, glycosylated hemoglobin (HbA1c), and lipid profile. Laboratory parameters and blood pressure were evaluated according to ADA recommendations. Results Of the 123 patients, 81 were women and the mean age was 61.8 years. Glycemic control was abnormal in 82 (68.33%) participants, and 45 (37.50%) were unable to control their blood pressure. Lipid profile was abnormal in 73 (60.83%) participants. Only nine (7.50%) participants fulfilled ADA recommendations for glycemic, blood pressure, and lipid control. Conclusions Amongst individuals with type 2 diabetes, there was poor attainment of the ADA recommendations (HbA1c, blood pressure and LDL-cholesterol) for ambulatory T2DM patients. Interventions are urgently needed in order to prevent long-term diabetic complications.

OBJECTIVE: The World Health Organization Atlas Project identified important deficiencies in world mental and neurological health resources. These deficiencies, especially evident in low and middle-income countries, can be overcome by improving research capacity. The objective of this study is to assess the status of mental and neurological research in Latin American countries and identify the main difficulties encountered in conducting research, publishing results, and shaping health policies, interventions, and programs. METHOD: Semi-structured interviews were conducted with 34 key informants from 13 Latin American countries. RESULTS: Participants reported that production of mental and neurological research in Latin American countries is low. Lack of financial and human resources, including lack of support from government agencies, were identified as the main factors contributing to the dearth of local research. The few research projects that do take place in Latin American countries are often funded at researchers' personal expense. Few policies, interventions, or programs are generated from research results. To address these deficiencies, participants called for training in research methodology, mechanisms for identifying funding opportunities, and greater recognition of their research products. CONCLUSIONS: Researchers and stakeholders recognize the need to mobilize local and international efforts aimed at strengthening research capacity and results implementation. This will lead to an overall optimization of mental and neurological research in the region.