Rare Coding Variants in RCN3 Are Associated with Blood Pressure

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10− 7). CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants

Comparative Assessment of Soil-Structure Interaction Regulations of ASCE 7-16 and ASCE 7-10

This paper evaluates the consequences of practicing soil structure interaction (SSI) regulations of ASCE 7-16 on seismic performance of building structures. The motivation for this research stems from the significant changes in the new SSI provisions of ASCE 7-16 compared to the previous 2010 edition. Generally, ASCE 7 considers SSI as a beneficial effect, and allows designer to reduce the design base shear. However, literature shows that this idea cannot properly capture the SSI effects on nonlinear systems. ASCE 7-16 is the first edition of ASCE 7 that considers the SSI effect on yielding systems. This study investigates the consequences of practicing the new provisions on a wide range of buildings with different dynamic characteristics on different soil types. Ductility demand of the structure forms the performance metric of this study, and the probability that practicing SSI provisions, in lieu of fixed-base provisions, increases the ductility demand of the structure is computed. The analyses are conducted within a probabilistic framework which considers the uncertainties in the ground motion and in the properties of the soil-structure system. It is concluded that, for structures with surface foundation on moderate to soft soils, SSI regulations of both ASCE 7-10 and ASCE 7-16 are fairly likely to result in a similar and larger structural responses than those obtained by practicing the fixed-base design regulations. However, for squat and ordinary stiff structures on soft soil or structures with embedded foundation on moderate to soft soils, the SSI provisions of ASCE 7-16 result in performance levels that are closer to those obtained by practicing the fixed-base regulations. Finally, for structures on very soft soils, the new SSI provisions of ASCE 7-16 are likely to rather conservative designs.Comment: ASCE Structures Congress, Fort Worth, TX, USA, April 19-21 (2018

Inter-scan reproducibility of coronary calcium measurement using Multi Detector-Row Computed Tomography (MDCT)

Purpose: To assess inter-scan reproducibility of coronary calcium measurements obtained from Multi Detector-Row CT (MDCT) images and to evaluate whether this reproducibility is affected by different measurement protocols, slice thickness, cardiovascular risk factors and/or technical variables. Design: Cross-sectional study with repeated measurements. Materials and methods: The study population comprised 76 healthy women. Coronary calcium was assessed in these women twice in one session using 16-MDCT (Philips Mx 8000 IDT 16). Images were reconstructed with 1.5 mm slice thickness and 3.0 mm slice thickness. The 76 repeated scans were scored. The Agatston score, a volume measurement and a mass measurement were assessed. Reproducibility was determined by estimation of mean, absolute, relative difference, the weighted kappa value for agreement and the Intra-class correlation coefficient (ICCC). Results: Fifty-five participants (72.4%) had a coronary calcification of more than zero in Agatston (1.5 mm slice thickness). The reproducibility of coronary calcium measurements between scans in terms of ranking was excellent with Intra-class correlation coefficients of >0.98, and kappa values above 0.80. The absolute difference in calcium score between scans increased with increasing calcium levels, indicating that measurement error increases with increasing calcium levels. However, no relation was found between the mean difference in scores and calcium levels, indicating that the increase in measurement error is likely to result in random misclassification in calcium score. Reproducibility results were similar for 1.5 mm slices and for 3.0 mm slices, and equal for Agatston, volume and mass measurements. Conclusion: Inter-scan reproducibilility of measurement of coronary calcium using images from MDCT is excellent, irrespective of slice thickness and type of calcium parameter

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition

Chromosome Xq23 Is Associated with Lower Atherogenic Lipid Concentrations and Favorable Cardiometabolic Indices

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids

Molecular Characterization of a 21.4 Kilobase Antibiotic Resistance Plasmid from an α-Hemolytic Escherichia coli O108:H- Human Clinical Isolate

This study characterizes the 21.4 kilobase plasmid pECTm80 isolated from Escherichia coli strain 80, an α hemolytic human clinical diarrhoeal isolate (serotype O108:H-). DNA sequence analysis of pECTm80 revealed it belonged to incompatibility group X1, and contained plasmid partition and toxin-antitoxin systems, an R6K-like triple origin (ori) replication system, genes required for replication regulation, insertion sequences IS1R, ISEc37 and a truncated transposase gene (Tn3-like ΔtnpA) of the Tn3 family, and carried a class 2 integron. The class 2 integron of pECTm80 contains an intact cassette array dfrA1-sat2, encoding resistance to trimethoprim and streptothricin, and an aadA1 gene cassette truncated by the insertion of IS1R. The complex plasmid replication system includes α, β and γ origins of replication. Pairwise BLASTn comparison of pECTm80 with plasmid pE001 reveals a conserved plasmid backbone suggestive of a common ancestral lineage. Plasmid pECTm80 is of potential clinical importance, as it carries multiple genes to ensure its stable maintenance through successive bacterial cell divisions and multiple antibiotic resistance genes

Predicting the spatial and temporal dynamics of species interactions in Fagus sylvatica and Pinus sylvestris forests across Europe

The productivity and functioning of mixed-species forests often differs from that of monocultures. However, the magnitude and direction of these differences are difficult to predict because species interactions can be modified by many potentially interacting climatic and edaphic conditions, stand structure and previous management. Process-based forest growth models could potentially be used to disentangle the effects of these factors and thereby improve our understanding of mixed forest functioning while facilitating their design and silvicultural management. However, to date, the predicted mixing effects of forest growth models have not been compared with measured mixing effects. In this study, 26 sites across Europe, each containing a mixture and monocultures of Fagus sylvatica and Pinus sylvestris, were used to calculate mixing effects on growth and yield and compare them with the mixing effects predicted by the forest growth model 3-PGmix. The climate and edaphic conditions, stand structures and ages varied greatly between sites. The model performed well when predicting the stem mass and total mass (and mixing effects on these components), with model efficiency that was usually >0.7. The model efficiency was lower for growth or smaller components such as foliage mass and root mass. The model was also used to predict how mixing effects would change along gradients in precipitation, temperature, potential available soil water, age, thinning intensity and soil fertility. The predicted patterns were consistent with measurements of mixing effects from published studies. The 3-PG model is a widely used management tool for monospecific stands and this study shows that 3-PGmix can be used to examine the dynamics of mixed-species stands and determine how they may need to be managed.This article is based upon work from COST Action EuMIXFOR, supported by COST (European Cooperation in Science and Technology). Funding for the Czech Republic site was provided by the MŠMT projects COST CZ – LD14063 and LD14074. All contributors thank their national funding institutions and the forest owners for agreeing to establish the plots and to measure and analyse data from the plots. The first author was funded by a Heisenberg Fellowship (FO 791/4-1) from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG). Mário Pereira was supported by European Investment Funds by FEDER/COMPETE/POCI– Operacional Competitiveness and Internacionalization Programme, under Project POCI-01-0145-FEDER-006958 and National Funds by FCT – Portuguese Foundation for Science and Technology, under the project UID/AGR/04033/2013 as well as by project Interact-Integrative Research in Environment, Agro-Chain and Technology, NORTE-01-0145-FEDER-000017, research line BEST, co-financed by FEDER/NORTE 2020