Pleiotropic genes for metabolic syndrome and inflammation

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P <10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P <5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.Peer reviewe

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P <5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.Peer reviewe

Adaptation to climate change in small island settlements

Adaptation to climate change in small island settlements poses unique issues of access, cost, governance and cultural, historical, and ecological preservation. There is a need therefore to focus research efforts on these small coastal settlements in order to assist and support their communities to develop and implement adaptation. This article is an initial attempt to evaluate and categorise these issues for island settlements, based on case studies and general perspectives on adaptation. Six island settlement case studies are used from around the world: Cocos Islands (Australian territory); Shishmaref, USA; Broad Channel, USA; Samsø, Denmark; Ciutadella de Menorca, Spain; and Port Vila, Vanuatu. This article describes and assesses impacts, adaptations, and capacity within each of the six case studies, and outlines the relationship of the Sustainable Development Goals system to small coastal settlements in general

Ecosystems, Climate Change and Development Scenarios, Vanuatu

illustrations; mapsPort Vila is the capital and largest city of the Melanesian island nation of Vanuatu, and is situated on the southern coast of Efate, the third largest island in Vanuatu. Metropolitan Port Vila is where more than a quarter of Vanuatu’s total population live. In 2016 the population of the city was approximately 75 000 and current growth rates are as high as 8% per annum. Population growth in Port Vila is much higher than in other provinces and the city is attracting internal migrants from all other islands in Vanuatu. Most new internal migrants reside in outer urban or peri-urban settlements where they do not generally have formal access to housing or land for growing food. Tropical Cyclone Pam (TC Pam) in March 2015 was one of the most severe cyclones in living memory, causing at least 16 fatalities and more than US$360 million worth of damage. Efate was one of the worst affected islands by TC Pam because of the infrastructure and population concentration in Port Vila. Vanuatu’s experience of TC Pam, followed immediately by a severe El Niño-Southern Oscillation drought which caused widespread food shortages, highlighted the vulnerability of Vanuatu to natural hazards and other risk factors. The Pacific Ecosystem-based Adaptation to Climate Change (PEBACC) Project responds to these vulnerability challenges. The five-year Project (implemented by the Secretariat of the Pacific Regional Environment Programme (SPREP)) explores and promotes Ecosystem-based Adaptation (EbA) options for adapting to climate change in the Pacific region. EbA is the practice of strengthening ecosystems to increase people’s ability to adapt to the impacts of climate change. It draws upon knowledge of ecosystem services and is based on the premise that if ecosystems are protected, remediated, or regenerated, this leads to healthier ecosystems, more ecosystem services, and therefore greater human well-being and resilience to the impacts of climate change. The current study continues the PEBACC project in Vanuatu. It builds on an earlier PEBACC study that undertook a baseline ecosystem and socio-economic resilience analysis and mapping appraisal of the Port Vila Metropolitan area. The methodology approach adopted provided for mainly desk-top review work, supplemented by four key workshops (including one in Port Vila), interviews with Port Vila stakeholders, and brief field inspection in Port Vila." (From Executive Summary

Applying Biomimicry to Cities: The Forest as Model for Urban Planning and Design

International audienceThe idea of applying biomimicry to cities is attracting increasing attention as a way of achieving sustainability. Undoubtedly the most frequently evoked natural model in this context is the forest, though it has not yet been investigated with any great scientific rigour. To overcome this lacuna, we provide: first, a justification of the model of the forest via what we call the arguments from “fittingness”, “scale”, and “complexity”; second, an exploration of various key innovations made possible by this model in the fields of urban planning, urban water systems, urban energy and transport systems, and urban food and nutrient systems