Impaired Rho GTPase activation abrogates cell polarization and migration in macrophages with defective lipolysis

Infiltration of monocytes and macrophages into the site of inflammation is critical in the progression of inflammatory diseases such as atherosclerosis. Cell migration is dependent on the continuous organization of the actin cytoskeleton, which is regulated by members of the small Rho GTPase family (RhoA, Cdc42, Rac) that are also important for the regulation of signal transduction pathways. We have recently reported on reduced plaque formation in an atherosclerotic mouse model transplanted with bone marrow from adipose triglyceride lipase-deficient (Atgl−/−) mice. Here we provide evidence that defective lipolysis in macrophages lacking ATGL, the major enzyme responsible for triacylglycerol hydrolysis, favors an anti-inflammatory M2-like macrophage phenotype. Our data implicate an as yet unrecognized principle that insufficient lipolysis influences macrophage polarization and actin polymerization, resulting in impaired macrophage migration. Sustained phosphorylation of focal adhesion kinase [due to inactivation of its phosphatase by elevated levels of reactive oxygen species (ROS)] results in defective Cdc42, Rac1 and RhoA activation and in increased and sustained activation of Rac2. Inhibition of ROS production restores the migratory capacity of Atgl−/− macrophages. Since monocyte and macrophage migration are a prerequisite for infiltrating the arterial wall, our results provide a molecular link between lipolysis and the development of atherosclerosis

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.Academy of Finland (129293, 128315, 129330, 131593, 139635, 139635, 121584, 126925, 124282, 129378, 258753); Action on Hearing Loss (G51); Ahokas Foundation; American Diabetes Association (#7-12-MN-02); Atlantic Canada Opportunities Agency; Augustinus foundation; Becket foundation; Benzon Foundation; Biomedical Research Council; British Heart Foundation (SP/04/002); Canada Foundation for Innovation; Commission of the European Communities, Directorate C-Public Health (2004310); Copenhagen County; Danish Centre for Evaluation and Health Technology Assessment; Danish Council for Independent Research; Danish Heart Foundation (07-10-R61-A1754-B838-22392F); Danish Medical Research Council; Danish Pharmaceutical Association; Emil Aaltonen Foundation; European Research Council Advanced Research Grant; European Union FP7 (EpiMigrant, 279143; FP7/2007-2013; 259749); Finland's Slottery Machine Association; Finnish Cultural Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Foundation of Cardiovascular Research; Finnish Medical Society; Finnish National Public Health Institute; Finska Läkaresällskapet; Folkhälsan Research Foundation; Foundation for Life and Health in Finland; German Center for Diabetes Research (DZD) ; German Federal Ministry of Education and Research; Health Care Centers in Vasa, Närpes and Korsholm; Health Insurance Foundation (2012B233) ; Helsinki University Central Hospital Research Foundation; Hospital districts of Pirkanmaa, Southern Ostrobothnia, North Ostrobothnia, Central Finland, and Northern Savo; Ib Henriksen foundation; Juho Vainio Foundation; Korea Centers for Disease Control and Prevention (4845–301); Korea National Institute of Health (2012-N73002-00); Li Ka Shing Foundation; Liv och Hälsa; Lundbeck Foundation; Marie-Curie Fellowship (PIEF-GA-2012-329156); Medical Research Council (G0601261, G0900747-91070, G0601966, G0700931); Ministry of Education in Finland; Ministry of Social Affairs and Health in Finland; MRC-PHE Centre for Environment and Health;Municipal Heath Care Center and Hospital in Jakobstad; Närpes Health Care Foundation; National Institute for Health Research (RP-PG-0407-10371); National Institutes of Health (U01 DK085526, U01 DK085501, U01 DK085524, U01 DK085545, U01 DK085584, U01 DK088389, RC2-DK088389, DK085545, DK098032, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN, R01MH107666 and K12CA139160268201300050C, U01 DK062370, R01 DK066358, U01DK085501, R01HL102830, R01DK073541, PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R01 MH101820, R01MH090937, P30DK020595, R01 DK078616, NIDDK K24 DK080140, 1RC2DK088389, T32GM007753); National Medical Research Council; National Research Foundation of Korea (NRF-2012R1A2A1A03006155); Nordic Center of Excellence in Disease Genetics; Novo Nordisk; Ollqvist Foundation; OrionFarmos Research Foundation; Paavo Nurmi Foundation; Perklén Foundation; Samfundet Folkhälsan; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; South East Norway Health Authority (2011060); Swedish Cultural Foundation in Finland; Swedish Heart-Lung Foundation; Swedish Research Council; Swedish Research Council (Linné and Strategic Research Grant); The American Federation for Aging Research; The Einstein Glenn Center; The European Commission (HEALTH-F4-2007-201413); The Finnish Diabetes Association; The Folkhälsan Research Foundation; The Påhlssons Foundation; The provinces of Newfoundland and Labrador, Nova Scotia, and New Brunswick; The Sigrid Juselius Foundation; The Skåne Regional Health Authority; The Swedish Heart-Lung Foundation; Timber Merchant Vilhelm Bang’s Foundation; Turku University Foundation; Uppsala University; Wellcome Trust (064890, 083948, 085475, 086596, 090367, 090532, 092447, 095101/Z/10/Z, 200837/Z/16/Z, 095552, 098017, 098381, 098051, 084723, 072960/2/ 03/2, 086113/Z/08/Z, WT098017, WT064890, WT090532, WT098017, 098051, WT086596/Z/08/A and 086596/Z/08/Z). Detailed acknowledgment of funding sources is provided in the Additional Acknowledgements section of the Supplementary Materials

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes(1). Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel(2)) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries