Coupling Photoresponsive Transmembrane Ion Transport with Transition Metal Catalysis.

Artificial ion transporters have been explored both as tools for studying fundamental ion transport processes and as potential therapeutics for cancer and channelopathies. Here we demonstrate that synthetic transporters may also be used to regulate the transport of catalytic metal ions across lipid membranes and thus control chemical reactivity inside lipid-bound compartments. We show that acyclic lipophilic pyridyltriazoles enable Pd(II) cations to be transported from the external aqueous phase across the lipid bilayer and into the interior of large unilamellar vesicles. In situ reduction generates Pd(0) species, which catalyze the generation of a fluorescent product. Photocaging the Pd(II) transporter allows for photoactivation of the transport process and hence photocontrol over the internal catalysis process. This work demonstrates that artificial transporters enable control over catalysis inside artificial cell-like systems, which could form the basis of biocompatible nanoreactors for applications such as drug synthesis and delivery or to mediate phototargeted catalyst delivery into cells.

Responsive Anionophores with AND Logic Multi-Stimuli Activation.

Artificial ion transport systems have emerged as an important class of compounds that promise applications in chemotherapeutics as anticancer agents or to treat channelopathies. Stimulus-responsive systems that offer spatiotemporally controlled activity for targeted applications remain rare. Here we utilize dynamic hydrogen bonding interactions of a 4,6-dihydroxy-isophthalamide core to generate a modular platform enabling access to stimuli-responsive ion transporters that can be activated in response to a wide variety of external stimuli, including light, redox, and enzymes, with excellent OFF-ON activation profiles. Alkylation of the two free hydroxyl groups with stimulus-responsive moieties locks the amide bonds through intramolecular hydrogen bonding and hence makes them unavailable for anion binding and transport. Triggering using a particular stimulus to cleave both cages reverses the hydrogen bonding arrangement, to generate a highly preorganized anion binding cavity for efficient transmembrane transport. Integration of two cages that are responsive to orthogonal stimuli enables multi-stimuli activation, where both stimuli are required to trigger transport in an AND logic process. Importantly, the strategy provides a facile method to post-functionalize the highly active transporter core with a variety of stimulus-responsive moieties for targeted activation with multiple triggers.

Molecular Machines For The Control Of Transmembrane Transport.

Nature embeds some of its molecular machinery, including ion pumps, within lipid bilayer membranes. This has inspired chemists to attempt to develop synthetic analogues to exploit membrane confinement and transmembrane potential gradients, much like their biological cousins. In this perspective, we outline the various strategies by which molecular machines─molecular systems in which a nanomechanical motion is exploited for function─have been designed to be incorporated within lipid membranes and utilized to mediate transmembrane ion transport. We survey molecular machines spanning both switches and motors, those that act as mobile carriers or that are anchored within the membrane, mechanically interlocked molecules, and examples that are activated in response to external stimuli.

Multistate Redox-Switchable Ion Transport Using Chalcogen-Bonding Anionophores.

Synthetic supramolecular transmembrane anionophores have emerged as promising anticancer chemotherapeutics. However, key to their targeted application is achieving spatiotemporally controlled activity. Herein, we report a series of chalcogen-bonding diaryl tellurium-based transporters in which their anion binding potency and anionophoric activity are controlled through reversible redox cycling between Te oxidation states. This unprecedented in situ reversible multistate switching allows for switching between ON and OFF anion transport and is crucially achieved with biomimetic chemical redox couples.

Inter-Vesicle Signal Transduction Using a Photo-Responsive Zinc Ionophore.

Transmission of chemical information between cells and across lipid bilayer membranes is of profound significance in many biological processes. The design of synthetic signalling systems is a critical step towards preparing artificial cells with collective behaviour. Here, we report the first example of a synthetic inter-vesicle signalling system, in which diffusible chemical signals trigger transmembrane ion transport in a manner reminiscent of signalling pathways in biology. The system is derived from novel ortho-nitrobenzyl and BODIPY photo-caged ZnII transporters, in which cation transport is triggered by photo-decaging with UV or red light, respectively. This decaging reaction can be used to trigger the release of the cationophores from a small population of sender vesicles. This in turn triggers the transport of ions across the membrane of a larger population of receiver vesicles, but not across the sender vesicle membrane, leading to overall inter-vesicle signal transduction and amplification.

Exploiting the Catenane Mechanical Bond Effect for Selective Halide Anion Transmembrane Transport.

The first examples of [2]catenanes capable of selective anion transport across a lipid bilayer are reported. The neutral halogen bonding (XB) [2]catenanes were prepared via a chloride template-directed strategy in an unprecedented demonstration of using XB⋅⋅⋅anion interactions to direct catenane assembly from all-neutral components. Anion binding experiments in aqueous-organic solvent media revealed strong halide over oxoanion selectivity, and a marked enhancement in the chloride and bromide affinities of the catenanes relative to their constituent macrocycles. The catenanes additionally displayed an anti-Hofmeister binding preference for bromide over the larger iodide anion, illustrating the efficacy of employing sigma-hole interactions in conjunction with the mechanical bond effect to tune receptor selectivity. Transmembrane anion transport studies conducted in POPC LUVs revealed that the catenanes were more effective anion transporters than the constituent macrocycles, with high chloride over hydroxide selectivity, which is critical to potential therapeutic applications of anionophores. Remarkably these outperform existing acyclic halogen bonding anionophores with regards to this selectivity. Record chloride over nitrate anion transport selectivity was also observed. This represents a rare example of the direct translation of intrinsic anion binding affinities to anion transport behaviour, and demonstrates the key role of the catenane mechanical bond effect for enhanced anion transport selectivity.

A Photo-responsive Transmembrane Anion Transporter Relay.

Ion transport across lipid membranes in biology is controlled by stimuli-responsive membrane channels and molecular machine ion pumps such as ATPases. Here, we report a synthetic molecular machine-like ion transport relay, in which transporters on opposite sides of a lipid bilayer membrane facilitate transport by passing ions between them. By incorporating a photo-responsive telescopic arm into the relay design, this process is reversibly controlled in response to irradiation with blue and green light. Transport occurs only in the extended state when the length of the arm is sufficient to pass the anion between transporters located on opposite sides of the membrane. In contrast, the contracted state of the telescopic arm is too short to mediate effective transport. The system acts as a stimuli-responsive ensemble of machine-like components, reminiscent of robotic arms in a factory assembly line, working cooperatively to mediate ion transport. This work points to new prospects for using lipid bilayer membranes as scaffolds for confining, orientating, and controlling the relative positions of molecular machines, thus enabling multiple components to work in concert and opening up new applications in biological contexts.

The genetics of drug efficacy: opportunities and challenges.

Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine.

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.

Lp-PLA2 activity is associated with increased risk of diabetic retinopathy: a longitudinal disease progression study.

AIMS/HYPOTHESIS: The aim of the study was to examine the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) activity levels and incident diabetic retinopathy and change in retinopathy grade. METHODS: This was a cohort study of diabetic participants with serum collected at baseline and routinely collected diabetic retinal screening data. Participants with type 2 diabetes from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort were used. This cohort is composed of individuals of white Scottish ancestry from the Tayside region of Scotland. Survival analysis accounting for informative censoring by modelling death as a competing risk was performed for the development of incident diabetic retinopathy from a disease-free state in a 3 year follow-up period (n = 1364) by stratified Lp-PLA2 activity levels (in quartiles). The same analysis was performed for transitions to more severe grades. RESULTS: The hazard of developing incident diabetic retinopathy was 2.08 times higher (95% CI 1.64, 2.63) for the highest quartile of Lp-PLA2 activity compared with the lowest. Higher Lp-PLA2 activity levels were associated with a significantly increased risk for transitions to all grades. The hazards of developing observable (or more severe) and referable (or more severe) retinopathy were 2.82 (95% CI 1.71, 4.65) and 1.87 (95% CI 1.26, 2.77) times higher for the highest quartile of Lp-PLA2 activity compared with the lowest, respectively. CONCLUSIONS/INTERPRETATION: Higher Lp-PLA2 levels are associated with increased risk of death and the development of incident diabetic retinopathy, as well as transitions to more severe grades of diabetic retinopathy. These associations are independent of calculated LDL-cholesterol and other traditional risk factors. Further, this biomarker study shows that the association is temporally sensitive to the proximity of the event to measurement of Lp-PLA2.

'Hidden identities': perceptions of sexual identity in Beijing.

This article draws upon responses given by volunteers who work in the Beijing LGBT Centre regarding perceptions of sexual identity, and how Chinese culture affects hidden or open sexual identities of Chinese lesbian and gay people in this region. The insights gained from those working carefully to create social change offers an important and original contribution to the field of gay and lesbian studies in China. The findings indicate the volunteers at the Beijing LGBT Centre are frustrated by the lack of acceptance of non-heterosexual relationships among Chinese culture and society, and by the disregard of lesbian gay and bisexual (LGB) people by the Chinese government. The findings also illustrate stigmatization of homosexuality in China is enacted in structural terms (such as in the lack of policy, legislation and positive endorsement by governmental and socio-political organizations), public expression (such as negative attitudes, beliefs or reactions towards LGB people) and internalized repression (through fear of stigmatization, and subsequent abuse due to negative societal attitudes and discrimination). Influenced by the Chinese tradition of conforming to group values, the findings from this study show that volunteers at the Beijing LGBT Centre believe LGB people in China are generally hesitant to disclose their sexual identities, and reject the idea that there had been a collective shift in Chinese culture regarding increased acceptance of LGB people. It also finds volunteers at the LGBT Centre in Beijing blame Chinese culture for its lack of acceptance of non-heterosexual relationships, and state stigmatization of homosexuality in China is due to deep-rooted cultural homophobia.

Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

The epigenetic signature of systemic insulin resistance in obese women.

AIMS/HYPOTHESIS: Insulin resistance (IR) links obesity to type 2 diabetes. The aim of this study was to explore whether white adipose tissue (WAT) epigenetic dysregulation is associated with systemic IR by genome-wide CG dinucleotide (CpG) methylation and gene expression profiling in WAT from insulin-resistant and insulin-sensitive women. A secondary aim was to determine whether the DNA methylation signature in peripheral blood mononuclear cells (PBMCs) reflects WAT methylation and, if so, can be used as a marker for systemic IR. METHODS: From 220 obese women, we selected a total of 80 individuals from either of the extreme ends of the distribution curve of HOMA-IR, an indirect measure of systemic insulin sensitivity. Genome-wide transcriptome and DNA CpG methylation profiling by array was performed on subcutaneous (SAT) and visceral (omental) adipose tissue (VAT). CpG methylation in PBMCs was assayed in the same cohort. RESULTS: There were 647 differentially expressed genes (false discovery rate [FDR] 10%) in SAT, all of which displayed directionally consistent associations in VAT. This suggests that IR is associated with dysregulated expression of a common set of genes in SAT and VAT. The average degree of DNA methylation did not differ between the insulin-resistant and insulin-sensitive group in any of the analysed tissues/cells. There were 223 IR-associated genes in SAT containing a total of 336 nominally significant differentially methylated sites (DMS). The 223 IR-associated genes were over-represented in pathways related to integrin cell surface interactions and insulin signalling and included COL5A1, GAB1, IRS2, PFKFB3 and PTPRJ. In VAT there were a total of 51 differentially expressed genes (FDR 10%); 18 IR-associated genes contained a total of 29 DMS. CONCLUSIONS/INTERPRETATION: In individuals discordant for insulin sensitivity, the average DNA CpG methylation in SAT and VAT is similar, although specific genes, particularly in SAT, display significantly altered expression and DMS in IR, possibly indicating that epigenetic regulation of these genes influences metabolism.

Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations.

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (ß ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (ß = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (ß = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (ß = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (ß = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study.

OBJECTIVE: AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival (PFS) in patients with ovarian cancer whose disease had not progressed after first-line therapy. In a sub-study, we evaluated the effect of clinically important germline BRCA1 and BRCA2 mutations on PFS. METHODS: Of 940 AGO-OVAR 16 participants, 664 had BRCA1/2 exon sequencing data (pazopanib, n=335; placebo, n=329). A Cox model was used to test the association between genetic variants and PFS. RESULTS: Ninety-seven of 664 patients (15%) carried clinically important BRCA1/2 mutations (BRCA1/2 carriers: pazopanib 14%, placebo 16%). Median PFS was longer in BRCA1/2 mutation carriers than in BRCA1/2 non-carriers in the placebo arm (30.3 vs 14.1 months, hazard ratio, 0.48; 95% confidence interval [CI]: 0.29-0.78; P=0.0031); a similar non-significant trend was noted with pazopanib (30.2 vs 17.7 months, hazard ratio, 0.64; 95% CI: 0.40-1.03; P=0.069). Among BRCA1/2 non-carriers, PFS was longer for pazopanib-treated patients than placebo-treated patients (17.7 vs 14.1 months, hazard ratio, 0.77; 95% CI: 0.62-0.97; P=0.024). Among BRCA1/2 carriers, there was no significant PFS difference between treatments, although numbers were small (pazopanib, 46; placebo, 51), resulting in a wide CI (hazard ratio, 1.36; 95% CI: 0.66-2.82). CONCLUSIONS: Patients with clinically important BRCA1/2 mutations had better prognosis. BRCA1/2 mutation status might be added as strata in future trials in primary ovarian cancer.

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

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. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Communicating BRCA research results to patients enrolled in international clinical trials: lessons learnt from the AGO-OVAR 16 study.

BACKGROUND: The focus on translational research in clinical trials has the potential to generate clinically relevant genetic data that could have importance to patients. This raises challenging questions about communicating relevant genetic research results to individual patients. METHODS: An exploratory pharmacogenetic analysis was conducted in the international ovarian cancer phase III trial, AGO-OVAR 16, which found that patients with clinically important germ-line BRCA1/2 mutations had improved progression-free survival prognosis. Mechanisms to communicate BRCA results were evaluated, because these findings may be beneficial to patients and their families. RESULTS: Communicating individual BRCA results was not anticipated during clinical trial design. Consequently, options were not available for patients to indicate their preference for receiving their individual results when they signed pharmacogenetic informed consent. Differences in local requirements, clinical practice, and opinion regarding the ethical aspects of how to convey genetic results to patients are all potential barriers to returning individual BRCA results to patients. Communicating the aggregate BRCA result from this study provided clinical investigators with a mechanism to disseminate the overall study finding to patients while taking individual circumstances, local guidelines and clinical practice into account. CONCLUSION: This study illustrates the importance of increasing the clarity and scope of informed consent and the need for patient engagement to ensure clinical trial participants can indicate their preference regarding receipt of potentially important individual pharmacogenetic results. TRIAL REGISTRATION: This study was registered in the NCT Clinical Trial Registry under NCT00866697 on March 19, 2009, following approval from participating ethics committees (Additional file 1).

Loci influencing blood pressure identified using a cardiovascular gene-centric array.

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.