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Pulse pressure, wide [keywords]
- Genome-wide analysis of gestational gene-environment interactions in the developing kidney. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Jul 8.
The G-protein coupled bradykinin B2 receptor (Bdkrb2) plays an important role in regulation of blood pressure under conditions of excess salt intake. Our previous work has shown that Bdkrb2 also plays a developmental role since Bdkrb2(-/-) embryos, but not their wild type or heterozygous littermates, are prone to renal dysgenesis in response to gestational high salt intake. Although impaired terminal differentiation and apoptosis are consistent findings in the Bdkrb2(-/-) mutant kidneys, the developmental pathways downstream of gene-environment interactions leading to the renal phenotype remain unknown. Here, we performed genome-wide transcriptional profiling on embryonic kidneys from salt-stressed Bdkrb2(+/+) and Bdkrb2(-/-) embryos. The results revealed significant alterations in key pathways regulating Wnt signaling, apoptosis, embryonic development, and cell-matrix interactions. In silico analysis revealed that nearly 12% of differentially regulated genes harbor one or more Pax2 DNA-binding sites in their promoter region. Further analysis showed that metanephric kidneys of salt-stressed Bdkrb2(-/-) have a significant downregulation of Pax2 gene expression. This was corroborated in Bdkrb2(-/-);Pax2(GFP+/tg) mice, demonstrating that Pax2 transcriptional activity is significantly repressed by gestational salt-Bdkrb2 interactions. We conclude that gestational gene (Bdkrb2) and environment (salt) interactions cooperate to impact gene expression programs in the developing kidney. Suppression of Pax2 likely contributes to the defects in epithelial survival, growth, and differentiation in salt-stressed BdkrB2(-/-) mice.
- Prevention of chronic disease in the 21st century: elimination of the leading preventable causes of premature death and disability in the USA. [REVIEW]
- Lancet 2014 Jul 1.
With non-communicable conditions accounting for nearly two-thirds of deaths worldwide, the emergence of chronic diseases as the predominant challenge to global health is undisputed. In the USA, chronic diseases are the main causes of poor health, disability, and death, and account for most of health-care expenditures. The chronic disease burden in the USA largely results from a short list of risk factors-including tobacco use, poor diet and physical inactivity (both strongly associated with obesity), excessive alcohol consumption, uncontrolled high blood pressure, and hyperlipidaemia-that can be effectively addressed for individuals and populations. Increases in the burden of chronic diseases are attributable to incidence and prevalence of leading chronic conditions and risk factors (which occur individually and in combination), and population demographics, including ageing and health disparities. To effectively and equitably address the chronic disease burden, public health and health-care systems need to deploy integrated approaches that bundle strategies and interventions, address many risk factors and conditions simultaneously, create population-wide changes, help the population subgroups most affected, and rely on implementation by many sectors, including public-private partnerships and involvement from all stakeholders. To help to meet the chronic disease burden, the US Centers for Disease Control and Prevention (CDC) uses four cross-cutting strategies: (1) epidemiology and surveillance to monitor trends and inform programmes; (2) environmental approaches that promote health and support healthy behaviours; (3) health system interventions to improve the effective use of clinical and other preventive services; and (4) community resources linked to clinical services that sustain improved management of chronic conditions. Establishment of community conditions to support healthy behaviours and promote effective management of chronic conditions will deliver healthier students to schools, healthier workers to employers and businesses, and a healthier population to the health-care system. Collectively, these four strategies will prevent the occurrence of chronic diseases, foster early detection and slow disease progression in people with chronic conditions, reduce complications, support an improved quality of life, and reduce demand on the health-care system. Of crucial importance, with strengthened collaboration between the public health and health-care sectors, the health-care system better uses prevention and early detection services, and population health is improved and sustained by solidifying collaborations between communities and health-care providers. This collaborative approach will improve health equity by building communities that promote health rather than disease, have more accessible and direct care, and focus the health-care system on improving population health.
- An evolutionary perspective of how infection drives human genome diversity: the case of malaria. [REVIEW]
- Curr Opin Immunol 2014 Jul 1.:39-47.
Infection with malaria parasites has imposed a strong selective pressure on the human genome, promoting the convergent evolution of a diverse range of genetic adaptations, many of which are harboured by the red blood cell, which hosts the pathogenic stage of the Plasmodium life cycle. Recent genome-wide and multi-centre association studies of severe malaria have consistently identified ATP2B4, encoding the major Ca(2+) pump of erythrocytes, as a novel resistance locus. Evidence is also accumulating that interaction occurs among resistance loci, the most recent example being negative epistasis among alpha-thalassemia and haptoglobin type 2. Finally, studies on the effect of haemoglobin S and C on parasite transmission to mosquitoes have suggested that protective variants could increase in frequency enhancing parasite fitness.
- [Genetics of blood pressure]. [English Abstract, Journal Article]
- Duodecim 2014; 130(11):1099-107.
Heritability estimates of blood pressure range from 30 to 60%. While monogenic hypertension/ ypotension syndromes are rare, they have provided important information on biological pathways participating in blood pressure regulation. The vast majority of elevated blood pressure cases are, however, "essential hypertension" resulting from multiple genetic and environmental factors. Our knowledge of the genetic background of blood pressure has advanced substantially over the past few years. Large genome-wide association studies have revealed tens of common single nucleotide polymorphisms that associate with blood pressure. Their effects are, however, small and explain only about 2% of the variation of blood pressure even when combined.
- [High blood pressure and obesity: Disparities among four French overseas territories.] [JOURNAL ARTICLE]
- Ann Cardiol Angeiol (Paris) 2014 Jun 5.
The epidemiological characteristics of hypertension and obesity in French overseas territories (FOTs) have never been compared.This cross-sectional survey included representative population-based samples of 602, 601, 620 and 605 men and women aged more than 15 years, respectively, from four FOTs of Guadeloupe, Martinique, French Guiana, and French Polynesia. Hypertension was defined as blood pressure (BP) at least 140/90mmHg or the current use of antihypertensive treatment.The prevalence of hypertension was 29.2% in Guadeloupe, 17.9% in French Guiana, 27.6% in Martinique and 24.5% in French Polynesia. Considering the Guadeloupe population as the reference group, prevalence of hypertension was significantly lower in French Guiana (P<0.001), even after controlling for age and sex (PU0.006). Awareness and treatment of hypertension were similar in French Guiana, Martinique and Guadeloupe (68.8-75.1% and 69.0-73.4%, respectively). Awareness was lower in French Polynesia (50.0%, adjusted P value U0.04), as was treatment of hypertension (32.4%, adjusted P value U0.001). Control of hypertension was also lower in French Polynesia (8.8%, adjusted P value U0.001) compared with the other territories (29.7-31.8%). French Polynesia had the highest prevalence of obesity (33.1%, adjusted P value<0.001) as compared with the other territories (17.9-22.8%). It had also the largest population attributable fraction of hypertension due to obesity (35.5%) compared with Guadeloupe (13.3%), Martinique (12.3%) and French Guiana (23.6%).Wide variations were observed in the prevalence and the management of hypertension between these FOTs, and an especially challenging low control of hypertension was found in French Polynesia. Obesity appears a key target to prevent hypertension, particularly in French Polynesia.
- Gene-Age Interactions in Blood Pressure Regulation: A Large-Scale Investigation with the CHARGE, Global BPgen, and ICBP Consortia. [JOURNAL ARTICLE]
- Am J Hum Genet 2014 Jun 18.
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.
- Variants Close to NTRK2 Gene Are Associated With Birth Weight in Female Twins. [JOURNAL ARTICLE]
- Twin Res Hum Genet 2014 Jun 20.:1-8.
Low weight at birth has previously been shown to be associated with a number of adult diseases such as type 2 diabetes, cardiovascular disease, high blood pressure, and obesity later in life. Genome-wide association studies (GWAS) have been published for singleton-born individuals, but the role of genetic variation in birth weight (BW) in twins has not yet been fully investigated. A GWAS was performed in 4,593 female study participants with BW data available from the TwinsUK cohort. A genome-wide significant signal was found in chromosome 9, close to the NTRK2 gene (OMIM: 600456). QIMR, an Australian twin cohort (n = 3,003), and UK-based singleton-birth individuals from the Hertfordshire cohort (n = 2,997) were used as replication for the top two single nucleotide polymorphism (SNPs) underpinning this signal, rs12340987 and rs7849941. The top SNP, rs12340987, was found to be in the same direction in the Australian twins and in the singleton-born females (fixed effects meta-analysis beta = -0.13, SE = 0.02, and p = 1.48 × 10-8) but not in the singleton-born males tested. These findings provide an important insight into the genetic component of BW in twins who are normally excluded due to their lower BW when compared with singleton births, as well as the difference in BW between twins. The NTRK2 gene identified in this study has previously been associated with obesity.
- Implementation and evaluation of the 5As framework of obesity management in primary care: design of the 5As Team (5AsT) randomized control trial. [JOURNAL ARTICLE]
- Implement Sci 2014 Jun 19; 9(1):78.
Obesity is a pressing public health concern, which frequently presents in primary care. With the explosive obesity epidemic, there is an urgent need to maximize effective management in primary care. The 5As of Obesity ManagementTM (5As) are a collection of knowledge tools developed by the Canadian Obesity Network. Low rates of obesity management visits in primary care suggest provider behaviour may be an important variable. The goal of the present study is to increase frequency and quality of obesity management in primary care using the 5As Team (5AsT) intervention to change provider behaviour.Methods/design: The 5AsT trial is a theoretically informed, pragmatic randomized controlled trial with mixed methods evaluation. Clinic-based multidisciplinary teams (RN/NP, mental health, dietitians) will be randomized to control or the 5AsT intervention group, to participate in biweekly learning collaborative sessions supported by internal and external practice facilitation. The learning collaborative content addresses provider-identified barriers to effective obesity management in primary care. Evidence-based shared decision making tools will be co-developed and iteratively tested by practitioners. Evaluation will be informed by the RE-AIM framework. The primary outcome measure, to which participants are blinded, is number of weight management visits/full-time equivalent (FTE) position. Patient-level outcomes will also be assessed, through a longitudinal cohort study of patients from randomized practices. Patient outcomes include clinical (e.g., body mass index [BMI], blood pressure), health-related quality of life (SF-12, EQ5D), and satisfaction with care. Qualitative data collected from providers and patients will be evaluated using thematic analysis to understand the context, implementation and effectiveness of the 5AsT program.The 5AsT trial will provide a wide range of insights into current practices, knowledge gaps and barriers that limit obesity management in primary practice. The use of existing resources, collaborative design, practice facilitation, and integrated feedback loops cultivate an applicable, adaptable and sustainable approach to increasing the quantity and quality of weight management visits in primary care.Trial registration: NCT01967797.
- Elevated blood pressure: Our family's fault? The genetics of essential hypertension. [Journal Article]
- World J Cardiol 2014 May 26; 6(5):327-37.
To provide an updated review on current genetic aspects possibly affecting essential hypertension (EH), and to further elucidate their role in EH.We searched for genetic and epigenetic factors in major studies associated with EH between Jan 2008-Oct 2013 using PubMed. We limited our search to reviews that discussed mostly human studies, and were accessible through the university online resource. We found 11 genome wide association studies (GWAS), as well as five methylation and three miRNA studies that fit our search criteria. A distinction was not made between genes with protective effects or negative effects, as this article is only meant to be a summary of genes associated with any aspect of EH.We found 130 genes from the studies that met our inclusion/exclusion criteria. Of note, genes with multiple study references include: STK39, CYP17A1, MTHFR-NPPA, MTHFR-NPPB, ATP2B1, CSK, ZNF652, UMOD, CACNB2, PLEKHA7, SH2B3, TBX3-TBX5, ULK4, CSK-ULK3, CYP1A2, NT5C2, CYP171A, PLCD3, SH2B3, ATXN2, CACNB2, PLEKHA7, SH2B3, TBX3-TBX5, ULK4, and HFE. The following genes overlapped between the genetic studies and epigenetic studies: WNK4 and BDKRB2. Several of the identified genes were found to have functions associated with EH. Many epigenetic factors were also correlated with EH. Of the epigenetic factors, there were no articles discussing siRNA and its effects on EH that met the search criteria, thus the topic was not included in this review. Among the miRNA targets found to be associated with EH, many of the genes involved were also identified in the GWAS studies.Genetic hypertension risk algorithms could be developed in the future but may be of limited benefit due to the multi-factorial nature of EH. With emerging technologies, like next-generation sequencing, more direct causal relationships between genetic and epigenetic factors affecting EH will likely be discovered creating a tremendous potential for personalized medicine using pharmacogenomics.
- 12q24 locus association with type 1 diabetes: SH2B3 or ATXN2? [REVIEW]
- World J Diabetes 2014 Jun 15; 5(3):316-327.
Genetic linkage analyses, genome-wide association studies of single nucleotide polymorphisms, copy number variation surveys, and mutation screenings found the human chromosomal 12q24 locus, with the genes SH2B3 and ATXN2 in its core, to be associated with an exceptionally wide spectrum of disease susceptibilities. Hematopoietic traits of red and white blood cells (like erythrocytosis and myeloproliferative disease), autoimmune disorders (like type 1 diabetes, coeliac disease, juvenile idiopathic arthritis, rheumatoid arthritis, thrombotic antiphospholipid syndrome, lupus erythematosus, multiple sclerosis, hypothyroidism and vitiligo), also vascular pathology (like kidney glomerular filtration rate deficits, serum urate levels, plasma beta-2-microglobulin levels, retinal microcirculation problems, diastolic and systolic blood pressure and hypertension, cardiovascular infarction), furthermore obesity, neurodegenerative conditions (like the polyglutamine-expansion disorder spinocerebellar ataxia type 2, Parkinson's disease, the motor-neuron disease amyotrophic lateral sclerosis, and progressive supranuclear palsy), and finally longevity were reported. Now it is important to clarify, in which ways the loss or gain of function of the locally encoded proteins SH2B3/LNK and ataxin-2, respectively, contribute to these polygenic health problems. SH2B3/LNK is known to repress the JAK2/ABL1 dependent proliferation of white blood cells. Its null mutations in human and mouse are triggers of autoimmune traits and leukemia (acute lymphoblastic leukemia or chronic myeloid leukemia-like), while missense mutations were found in erythrocytosis-1 patients. Ataxin-2 is known to act on RNA-processing and trophic receptor internalization. While its polyglutamine-expansion mediated gain-of-function causes neuronal atrophy in human and mouse, its deletion leads to obesity and insulin resistance in mice. Thus, it is conceivable that the polygenic pathogenesis of type 1 diabetes is enhanced by an SH2B3-dysregulation-mediated predisposition to autoimmune diseases that conspires with an ATXN2-deficiency-mediated predisposition to lipid and glucose metabolism pathology.