Nprl3 is required for normal development of the cardiovascular system.

C16orf35 is a conserved and widely expressed gene lying adjacent to the human α-globin cluster in all vertebrate species. In-depth sequence analysis shows that C16orf35 (now called NPRL3) is an orthologue of the yeast gene Npr3 (nitrogen permease regulator 3) and, furthermore, is a paralogue of its protein partner Npr2. The yeast Npr2/3 dimeric protein complex senses amino acid starvation and appropriately adjusts cell metabolism via the TOR pathway.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.

AMP-activated protein kinase phosphorylates cardiac troponin I and alters contractility of murine ventricular myocytes.

Rationale: AMP-activated protein kinase (AMPK) is an important regulator of energy balance and signaling in the heart. Mutations affecting the regulatory γ2 subunit have been shown to cause an essentially cardiac-restricted phenotype of hypertrophy and conduction disease, suggesting a specific role for this subunit in the heart.

Objective: The γ isoforms are highly conserved at their C-termini but have unique N-terminal sequences, and we hypothesized that the N-terminus of γ2 may be involved in conferring substrate specificity or in determining intracellular localization.

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.

Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway.

The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R).

Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.

Background: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so "Mendelian randomization" studies using this variant as an instrumental variable could help test causality.

Methods And Findings: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T.

Subunit composition of AMPK trimers present in the cytokinetic apparatus: Implications for drug target identification.

AMP-activated protein kinase has been shown to be a key regulator of energy homeostasis; it has also been identified as a tumor suppressor and is required for correct cell division and chromosome segregation during mitosis. The enzyme is a heterotrimer, with each subunit having more than one isoform, each encoded by a separate gene (two α, two β and three γ isoforms). In human endothelial cells, the activated kinase subunit of AMPK in the cytokinetic apparatus is α2, the minority α subunit, which co-localizes with β2 and γ2.

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples.

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions.

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.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

Objective: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.

Genotype at the P554L variant of the hexose-6 phosphate dehydrogenase gene is associated with carotid intima-medial thickness.

Objective: The combined thickness of the intima and media of the carotid artery (carotid intima-medial thickness, CIMT) is associated with cardiovascular disease and stroke. Previous studies indicate that carotid intima-medial thickness is a significantly heritable phenotype, but the responsible genes are largely unknown. Hexose-6 phosphate dehydrogenase (H6PDH) is a microsomal enzyme whose activity regulates corticosteroid metabolism in the liver and adipose tissue; variability in measures of corticosteroid metabolism within the normal range have been associated with risk factors for cardiovascular disease.

Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy.

As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still confirm that HCM is principally a disease of the sarcomere. At the biophysical level, myofilament mutations generally enhance Ca(2+) sensitivity, maximal force production, and ATPase activity.

Common variation at the 11-β hydroxysteroid dehydrogenase type 1 gene is associated with left ventricular mass.

Background: Polymorphisms in 11-β hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) have been reported to be associated with obesity-related cardiovascular risk factors, such as type II diabetes and hypertension. Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular death associated with these factors but has significant additional heritability, the cause of which is undetermined. The 11β-HSD1 is believed to maintain tonic inhibition of the mineralocorticoid receptor in cardiomyocytes, and mineralocorticoid receptor activation is involved in the pathophysiology of LVH.

Common variation in the CD36 (fatty acid translocase) gene is associated with left-ventricular mass.

Aims: Genetic variation in the fatty acid translocase (CD36) gene has been shown in animal models to affect several risk factors for the development of left-ventricular hypertrophy, but this phenotype has not, thus far, been investigated in humans. We examined the relationship between common genetic polymorphisms in the CD36 gene and left-ventricular mass.

Methods And Results: We studied a cohort of 255 families comprising 1425 individuals ascertained via a hypertensive proband.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals.

Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity.

Methods And Results: Forty-six consecutive patients with symptomatic exercise limitation (peak Vo(2) <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55±0.

The role of vascular myoglobin in nitrite-mediated blood vessel relaxation.

Aims: This work investigates the role of myoglobin in mediating the vascular relaxation induced by nitrite. Nitrite, previously considered an inert by-product of nitric oxide metabolism, is now believed to play an important role in several areas of pharmacology and physiology. Myoglobin can act as a nitrite reductase in the heart, where it is plentiful, but it is present at a far lower level in vascular smooth muscle-indeed, its existence in the vessel wall is controversial.

Hundreds of variants clustered in genomic loci and biological pathways affect human height.

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait.