The trans-ancestral genomic architecture of glycemic traits.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

A Multi-tissue Transcriptome Analysis of Human Metabolites Guides Interpretability of Associations Based on Multi-SNP Models for Gene Expression.

There is particular interest in transcriptome-wide association studies (TWAS) gene-level tests based on multi-SNP predictive models of gene expression-for identifying causal genes at loci associated with complex traits. However, interpretation of TWAS associations may be complicated by divergent effects of model SNPs on phenotype and gene expression. We developed an iterative modeling scheme for obtaining multi-SNP models of gene expression and applied this framework to generate expression models for 43 human tissues from the Genotype-Tissue Expression (GTEx) Project. We characterized the performance of single- and multi-SNP models for identifying causal genes in GWAS data for 46 circulating metabolites. We show that: (A) multi-SNP models captured more variation in expression than did the top cis-eQTL (median 2-fold improvement); (B) predicted expression based on multi-SNP models was associated (false discovery rate < 0.01) with metabolite levels for 826 unique gene-metabolite pairs, but, after stepwise conditional analyses, 90% were dominated by a single eQTL SNP; (C) among the 35% of associations where a SNP in the expression model was a significant cis-eQTL and metabolomic-QTL (met-QTL), 92% demonstrated colocalization between these signals, but interpretation was often complicated by incomplete overlap of QTLs in multi-SNP models; and (D) using a "truth" set of causal genes at 61 met-QTLs, the sensitivity was high (67%), but the positive predictive value was low, as only 8% of TWAS associations (19% when restricted to colocalized associations at met-QTLs) involved true causal genes. These results guide the interpretation of TWAS and highlight the need for corroborative data to provide confident assignment of causality.

Occurrence and risk assessment of heavy metals and organochlorine pesticides in surface soils, Central Kenya.

BACKGROUND: The present study investigated pollution in surface soils of five dominant land use types in central Kenya. The mean concentration of heavy metals (Zn, Hg, Cd, Cu, Cr, As and Ni) in (mg/kg) and two organochlorine pesticides (DDTs and HCHs) (µg/kg) were determined. METHOD: Heavy metal contamination and potential ecological risk using the Nemerow pollution index and Hakanson ecological risk index respectively were used in examining pollution level. With the help of multivariate analysis sources of heavy metal pollution were identified which were mainly from anthropogenic activities. Notably, heavy metal concentration in our study was compared to other regions within the country, results showed regional variation. Total levels of DDTs, HCHs pesticide and their constituent isomers in the surface soil were determined by a gas chromatography (GC-µECD). RESULTS: Pollution level in all land use areas according to Nemerow pollution index indicated low pollution status. Notably, in all land use areas the pollution level decreased in the following order Industrial land>Peri-urban>Agriculture land>Forest>River. In addition, heavy metals had low risks values according to Hakanson ecological risk index ranging from 0.01 to 0.58, with Hg having the highest mean value of 0.58. As expected, organochlorine pesticide were higher in agricultural land use, DDTs levels were comparatively higher than HCHs levels. Results on DDTs ratio (p, p'-DDT/p, p'-DDD + p, p'-DDE) were < 1 in all land use types which showed that their residues originated from historical sources. Lower α/ γ HCH ratio in forest and peri-urban land uses however indicated current input of lindane. Correlation analysis showed significant relationship between TOC and HCHs only. CONCLUSION: When compared to recent study done in agricultural soil (Nairobi surroundings), present study of OCPs (DDTs and HCHs) concentration in central Kenya was relatively high. The quality of soil in Central Kenya was classified as considerably polluted by OCPs but low polluted by heavy metals.

Microplastics pollution in inland freshwaters of China: A case study in urban surface waters of Wuhan, China.

Microplastics have been considered as an emerging pollutant in the aquatic environment. However, research about microplastic pollution in inland freshwaters of China is insufficient. The present study investigated the levels of microplastics in surface water of 20 urban lakes and urban reaches of the Hanjiang River and Yangtze River of Wuhan, the largest city in central China. Microplastic concentrations ranged from 1660.0±639.1 to 8925±1591n/m3 for the studied waters, with the highest concentration found in Bei Lake. Microplastic abundance in lakes varied markedly in space, and negatively correlated with the distance from the city center (p<0.001), which confirmed the important role of anthropogenic factors in microplastic distribution. Urban reaches of the Hanjiang River and Yangtze River were found to have relatively lower levels of microplastics than most of the studied lakes. The major type of microplastics among the studied waters was colored plastic, with fiber being the most frequent shape. More than 80% of microplastics in number had a size of <2mm. Polyethylene terephthalate and polypropylene were the dominant polymer-types of microplastics analyzed. This study provided important reference for better understanding microplastic levels in inland freshwaters.

Monitoring of Endocrine-Disrupting Compounds in Surface Water and Sediments of the Three Gorges Reservoir Region, China.

Occurrence and distribution of eight selected endocrine-disrupting compounds (EDCs), including estrone (E1), 17α-ethinylestradiol (EE2), 17α-estradiol (αE2), 17ß-estradiol (ßE2), estriol (E3), bisphenol A (BPA), 4-nonylphenol (NP), and 4-octylphenol (OP), were investigated in surface water and sediments of the Three Gorges Reservoir region (TGRR). The mean concentrations of E1, αE2, ßE2, E3, EE2, BPA, NP, and OP were 10.3, 3.3, 3.7, 17.2, 7.8, 26.6, 10.8, and 32.3 ng L-1 respectively in surface water and 2.6, 4.1, 7.7, 2.4, 11.8, 17.4, 5.0, and 5.3 ng g-1 dry weight (dw) respectively in sediments. BPA, NP, and OP were the main EDCs in both media. Distributions of EDCs in surface water and sediments varied significantly in space but not synchronously. The higher EDCs abundance was found in the upstream water of the TGRR. EDCs concentrations in sediments had no correlations with those in water and the total organic carbon content in sediments. EDCs presented low to high risks in the water, and steroidal estrogens were the main contributors to the total estrogenic activities.

Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children.

Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.

Ready-to-use therapeutic food with elevated n-3 polyunsaturated fatty acid content, with or without fish oil, to treat severe acute malnutrition: a randomized controlled trial.

BACKGROUND: Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children's PUFA status during treatment of severe acute malnutrition. METHODS: This randomized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were randomized to receive i) RUTF with standard composition; ii) RUTF with elevated short chain n-3 PUFA; or iii) RUTF with elevated short chain n-3 PUFA plus fish oil capsules. Participants were followed-up for 3 months. The primary outcome was erythrocyte PUFA composition. RESULTS: Erythrocyte docosahexaenoic acid (DHA) content declined from baseline in the two arms not receiving fish oil. Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or standard RUTF alone: 3 months after enrollment, DHA content was 6.3% (interquartile range 6.0-7.3), 4.5% (3.9-4.9), and 3.9% (2.4-5.7) of total erythrocyte fatty acids (P <0.001), respectively, while eicosapentaenoic acid (EPA) content was 2.0% (1.5-2.6), 0.7% (0.6-0.8), and 0.4% (0.3-0.5) (P <0.001). RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers, and there were no significant differences in safety outcomes. CONCLUSIONS: PUFA requirements of children with SAM are not met by current formulations of RUTF, or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA. Clinical and growth implications of revised formulations need to be addressed in large clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT01593969. Registered 4 May 2012.