G-protein β3 subunit gene (GNB3) variant in causation of essential hypertension

Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein β3 subunit gene (GNB3) induces formation of a splice variant (Gβ3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group (χ2=22; P=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105±7, 109±16, and 128±28 mm Hg (mean±SD) for CC, CT, and 7T, respectively (P=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (P=0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein β3 subunit gene in the causation of essential hypertension.

Examination of the role of nitric oxide synthase and renal kallikrein as candidate genes for essential hypertension

Nitric oxide synthase and renal kallikrein are both involved in blood pressure regulation. Genes for these enzymes may, therefore, be considered candidates for hypertension pathogenesis. 2. In the present study, genotypes for nitric oxide synthase and renal kallikrein microsatellite markers were determined in a cross-sectional association analysis of hypertensive patients and normotensive control subjects. 3. Results from this study did not indicate an association of either of the candidate gene polymorphisms with essential hypertension. Hence, findings for this study do not support a role for these genes in human hypertension.

A locus on the long arm of chromosome 1 as a possible cause of essential hypertension

None of the genes responsible for essential hypertension has been identified. Recent work in genetically hypertensive rats has shown linkage of blood pressure with alleles of the renin gene. Since the renin gene is a member of a conserved synteny group that in humans spans chromosome 1q21.3-32.3 and includes the gene for antithrombin III (AT3), we used linkage studies to examine the relationship between alleles of AT3 and hypertension in a family having 10 affected members. From the lod score obtained at a recombination fraction of zero the odds for linkage of AT3 and hypertension in this family were calculated as 6:1 in favour of linkage. This result provides grounds for further examination of the possible role of the 1q23 locus in the aetiology of essential hypertension.

Frequency in hypertensives of alleles for a RFLP associated with the renin gene

The genetic basis of primary hypertension is not known. Renin is important in blood pressure and volume control and a HindIII restriction fragment length polymorphism (RFLP) is present within the human renin gene locus. To examine whether there is a relationship between this RFLP and primary hypertension, DNA and renin analyses were performed on leukocytes and plasma from hypertensive and normotensive individuals. In hypertensives the frequencies of alleles for the HindIII RFLP were found to be 0.55 and 0.45, compared with 0.60 and 0.40 in the total population of 231 subjects examined, a difference that was not statistically significant. There also appeared to be no significant difference in renin activity in plasma for hypertensive patients of each genotype, nor in their pre- or post-treatment blood pressures. We thus conclude that, within the limits of the present study, the suspected genetic abnormalities associated with primary hypertension in man do not appear to be related to a HindIII RFLP in the renin gene.

Scanning the genome for essential hypertension loci

1. Essential hypertension occurs in people with an underlying genetic predisposition who subject themselves to adverse environmental influences. The number of genes involved is unknown, as is the extent to which each contributes to final blood pressure and the severity of the disease. 2. In the past, studies of potential candidate genes have been performed by association (case-control) analysis of unrelated individuals or linkage (pedigree or sibpair) analysis of families. These studies have resulted in several positive findings but, as one may expect, also an enormous number of negative results. 3. In order to uncover the major genetic loci for essential hypertension, it is proposed that scanning the genome systematically in 100- 200 affected sibships should prove successful. 4. This involves genotyping sets of hypertensive sibships to determine their complement of several hundred microsatellite polymorphisms. Those that are highly informative, by having a high heterozygosity, are most suitable. Also, the markers need to be spaced sufficiently evenly across the genome so as to ensure adequate coverage. 5. Tests are performed to determine increased segregation of alleles of each marker with hypertension. The analytical tools involve specialized statistical programs that can detect such differences. Non- parametric multipoint analysis is an appropriate approach. 6. In this way, loci for essential hypertension are beginning to emerge.

Independent, marked associations of alleles of the insulin receptor and dipeptidyl carboxypeptidase-I genes with essential hypertension

1. There is evidence to suggest that essential hypertension is a polygenic disorder and that it arises from yet-to-be-identified predisposing variants of certain genes that influence blood pressure. The cloning of various hormone, enzyme, adrenoceptor and hormone receptor genes whose products are involved in blood pressure control and the identification of polymorphisms of these has permitted us to test their genetic association with hypertension. 2. Cross-sectional analyses of a number of candidate gene markers were performed in hypertensive and normotensive subjects who were selected on the basis of both parents being either hypertensive or normotensive, respectively, and the difference in total alleles on all chromosomes for each polymorphism between the hypertensive and normotensive groups was test by χ analysis with one degree of freedom. 3. A marked association was observed between hypertension and insertion alleles of polymorphisms of the insulin receptor gene (INSR) (P<0.0040) and the dipeptidyl carboxypeptidase-1 (angiotensin I-converting enzyme; kininase II) gene (DCP1) (P<0.0018). No association with hypertension was evident, however, for polymorphisms of the growth hormone, low-density lipoprotein receptor, renal kallikrein, α2- and β1-adrenoreceptor, atrial natriuretic factor and insulin genes. 4. All but one of the hypertensive subjects had at least one of the hypertension-associated alleles, and although subjects homozygous for both were three times more frequent in the hypertensive group, examination of the nine possible genotypes suggested that the INSR and DCP1 alleles are independent markers for hypertension. 5. The present results suggest that genetic variant(s) in close linkage disequilibrium with polymorphisms at INSR and DCP1 may be involved in part in the aetiology of essential hypertension.

Sibpair studies implicate chromosome 18 in essential hypertension

Interest in chromosome 18 in essential hypertension comes from comparative mapping of rat blood pressure quantitative trait loci (QTL), familial orthostatic hypotensive syndrome studies, and essential hypertension pedigree linkage analyses indicating that a locus or loci on human chromosome 18 may play a role in hypertension development. To further investigate involvement of chromosome 18 in human essential hypertension, the present study utilized a linkage scan approach to genotype twelve microsatellite markers spanning human chromosome 18 in 177 Australian Caucasian hypertensive (HT) sibling pairs. Linkage analysis showed significant excess allele sharing of the D18S61 marker when analyzed with SPLINK (P=0.00012), ANALYZE (Sibpair) (P=0.0081), and also with MAPMAKER SIBS (P=0.0001). Similarly, the D18S59 marker also showed evidence for excess allele sharing when analyzed with SPLINK (P=0.016), ANALYZE (Sibpair) (P=0.0095), and with MAPMAKER SIBS (P = 0.014). The adenylate cyclase activating polypeptide 1 gene (ADCYAP1) is involved in vasodilation and has been co-localized to the D18S59 marker. Results testing a microsatellite marker in the 3′ untranslated region of ADCYAP1 in age and gender matched HT and normotensive (NT) individuals showed possible association with hypertension (P = 0.038; Monte Carlo P = 0.02), but not with obesity. The present study shows a chromosome 18 role in essential hypertension and indicates that the genomic region near the ADCYAP1 gene or perhaps the gene itself may be implicated. Further investigation is required to conclusively determine the extent to which ADCYAP1 polymorphisms are involved in essential hypertension. © 2003 Wiley-Liss, Inc.

Association of a low density lipoprotein receptor microsatellite variant with obesity

OBJECTIVE To determine whether a microsatellite polymorphism located towards the 3' end of the low density lipoprotein receptor gene (LDLR) is associated with obesity. DESIGN A cross-sectional case-control study. SUBJECTS One hundred and seven obese individuals, defined as a body mass index (BMI) ≤ 26 kg/m2, and 163 lean individuals, defined as a BMI < 26 kg/m2. MEASUREMENTS BMI, blood pressure, serum lipids, alleles of LDLR microsatellite (106 bp, 108 bp and 112 bp). RESULTS There was a significant association between variants of the LDLR microsatellite and obesity, in the overall tested population, due to a contributing effect in females (χ2 = 12.3, P = 0.002), but not in males (χ2 = 0.3, P = 0.87). In females, individuals with the 106 bp allele were more likely to be lean, while individuals with the 112 bp and/or 108 bp alleles tended to be obese. CONCLUSIONS These results suggest that in females, LDLR may play a role in the development of obesity.

Association of a RFLP for the insulin receptor gene, but not insulin, with essential hypertension

Insulin has cardiovascular actions and patients with essential hypertension display insulin resistance. A cross-sectional study of the R1 RFLP of the insulin receptor gene (INSR) was carried out in 67 hypertensive (HT) and 75 normotensive (NT) subjects whose parents had a similar blood pressure status at age ≥50. The frequency of the minor (+) allele was 0.31 in HTs and 0.44 in NTs, and the difference between observed alleles in all subjects in each group was significant (χ2 = 4.8, P<0.05). Allele frequencies of a BglI RFLP of the insulin gene, however, did not differ between the HT and NT groups. The data thus provide evidence in favour of an association of HT with a polymorphism at the INSR locus (19p 13.3-13.2), so implicating this locus, and possibly a genetic variant of the insulin receptor itself, in HT.

Non-linkage of insulin receptor locus with essential hypertension in an affected pedigree

A recent cross-sectional study has demonstrated a significant association of the R1 RsaI restriction fragment length polymorphism of the insulin receptor gene (INSR) with human essential hypertension. In the present study, an alternative approach, involving linkage analysis, was carried out using 8 hypertensive families with 5 or more affected members. Five of the families were found to be informative and in one of these pedigrees a conclusion of non-linkage of INSR and hypertension could be made on the basis of an obligate recombinant in one generation which yielded a Lod score of - ∞ at a recombination fraction (θ) of zero. In another family, the largest studied, a positive Lod score was obtained at θ = 0, but this was below the level required for a conclusion of linkage. Lod score at θ = 0 for a marker at the insulin locus in this family was negative. The present study has thus demonstrated one pedigree in which hypertension is not linked to the insulin receptor locus.

Molecular genetic analyses of RFLPs for PCR-amplified growth hormone gene, renal kallikrein gene and atrial natriuretic factor gene in essential hypertension

The present study examined polymorphisms of genes that might be involved in the onset of essential hypertension (HT). These included the (i) growth hormone gene (GH1), whose locus has recently been linked to elevated blood pressure (BP) in the stroke-prone SHR, although recent sib-pair analysis of a polymorphism near the human chorionic somatomammotropin gene (a member of the GH cluster) was unable to show linkage with HT; (ii) renal kallikrein gene (KLK1); and (iii) atrial natriuretic factor gene (ANF), where a primary defect in production or activity of kallikrein or ANF could cause NaCl retention and vasoconstriction. Association analyses were conducted to compare restriction fragment length polymorphisms (RFLPs) of each gene in 85 HT and 95 normotensive (NT) Caucasian subjects whose parents had a similar BP status at age ≥50 years. The frequency of the minor allele of (i) a RsaI RFLP in the promoter of GH1, amplified from leukocyte DNA by the polymerase chain reaction, was 0.15 in the HT group and 0.14 in the NT group (χ1=0.34, P=0.55); (ii) a TaqI RFLP for KLK1 was 0.035 in the HT group and 0.015 in the NT group (χ2=1.5, P=0.21); and (iii) a XhoI RFLP for ANF was 0.50 in HTs and 0.46 in NTs (χ2=0.20, P=0.65). Studies of HT pedigrees found one family in which the ANF locus and HT were not linked, owing to an obligate recombinant. The present data thus provide no evidence for involvement of the growth hormone, renal kallikrein, nor ANF gene in the causation of essential hypertension.

Association and linkage analyses of restriction fragment length polymorphisms for the human renin and antithrombin III genes in essential hypertension

Essential hypertension is a highly hereditable disorder in which genetic influences predominate over environmental factors. The molecular genetic profiles which predispose to essential hypertension are not known. In rats with genetic hypertension, there is some recent evidence pointing to linkage of renin gene alleles with blood pressure. The genes for renin and antithrombin III belong to a conserved synteny group which, in humans, spans the q21.3-32.3 region of chromosome I and, in rats, is linkage group X on chromosome 13. The present study examined the association of particular human renin gene (REN) and antithrombin III gene (AT3) polymorphisms with essential hypertension by comparing the frequency of specific alleles for each of these genes in 50 hypertensive offspring of hypertensive parents and 91 normotensive offspring of normotensive parents. In addition, linkage relationships were examined in hypertensive pedigrees with multiple affected individuals. Alleles of a REN HindIII restriction fragment length polymorphism (RFLP) were detected using a genomic clone, λHR5, to probe Southern blots of HindIII-cut leucocyte DNA, and those for an AT3 Pstl RFLP were detected by phATIII 113 complementary DNA probe. The frequencies of each REN allele in the hypertensive group were 0.76 and 0.24 compared with 0.74 and 0.26 in the normotensive group. For AT3, hypertensive allele frequencies were 0.49 and 0.51 compared with normotensive values of 0.54 and 0.46. These differences were not significant by χ2 analysis (P > 0.2). Linkage analysis of a family (data from 16 family members, 10 of whom were hypertensive), informative for both markers, without an age-of-onset correction, and assuming dominant inheritance of hypertension, complete penetrance and a disease frequency of 20%, did not indicate linkage of REN with hypertension, but gave a positive, although not significant, logarithm of the odds for linkage score of 0.784 at a recombination fraction of 0 for AT3 linkage to hypertension. In conclusion, the present study could find no evidence for an association of a REN HindIII RFLP with essential hypertension or for a linkage of the locus defined by this RFLP in a family segregating for hypertension. In the case of an AT3 Pstl RFLP, although association analysis was negative, linkage analysis suggested possible involvement (odds of 6:1 in favour) of a gene located near the 1q23 locus with hypertension in one informative family.

Converse consumption : the converse blank canvas project

Research background For almost 80 years the Chuck Taylor (or Chuck T's) All Star basketball shoe has been an iconic item of fashion apparel. The Chuck T's were first designed in 1921 by Converse, an American shoe company and over the decades they became a popular item not purely for sports and athletic purposes but rather evolved into the shoe of choice for many subcultural groups as a fashion item. In some circles the Chuck Taylor is still seen as the "coolest" sneaker of all time - one which will never go out of fashion regardless of changing trends. With over 600 millions pairs sold all over the world since its release, the Converse shoe is representative of not only a fashion culture - but also of a consumption culture - that evolved as the driving force behind the massive growth of the Western economic system during the 20th Century. Artisan Gallery (Brisbane), in conjunction with the exhibition Reboot: Function, Fashion and the Sneaker, a history of the sneaker, selected 20 designers to customise and re-design the classic Converse Chuck Taylor All Stars shoe and in doing so highlighted the diversity of forms possible for creative outcomes. As Artisan Gallery Curator Kirsten Fitzpatrick states “We were expecting people to draw and paint on them. Instead, we had shoes... mounted as trophies.." referring to the presentation of "Converse Consumption". The exhibition ran from 21 June – 16 August 2012: Research question The Chuck T’s is one of many overwhelmingly commercially successful designs of the last century. Nowadays we are faced with the significant problems of overconsumption and the stress this causes on the natural ecosystem; and on people as a result. As an active member of the industrial design fraternity – a discipline that sits at the core of this problem - how can I use this opportunity to comment on the significant issue of consumption? An effective way to do this was to associate consumption of goods with consumption of sugar. There are significant similarities between our ceaseless desires to consume products and our fervent need to consume indulgent sweet foods. Artisan Statement Delicious, scrumptious, delectable... your pupils dilate, your blood pressure spikes, your liver goes into overdrive. Immediately, your brain cuts off the adenosine receptors, preventing drowsiness. Your body increases dopamine production, in-turn stimulating the pleasure receptors in your brain. Your body absorbs all the sweetness and turns it into fat – while all the nutrients that you actually require are starting to be destroyed, about to be expelled. And this is only after one bite! After some time though, your body comes crashing back to earth. You become irritable and begin to feel sluggish. Your eyelids seem heavy while your breathing pattern changes. Your body has consumed all the energy and destroyed all available nutrients. You literally begin to shut down. These are the physiological effects of sugar consumption. A perfect analogy for our modern day consumer driven world. Enjoy your dessert! Research contribution “Converse Consumption” contributes to the conversation regarding over-consumption by compelling people to reflect on their consumption behaviour through the reconceptualising of the deconstructed Chuck T’s in an attractive edible form. By doing so the viewer has to deal with the desire to consume the indulgent looking dessert with the contradictory fact that it is comprised of a pair of shoes. The fact that the shoes are Chuck T’s make the effect even more powerful due to their iconic status. These clashing motivations are what make “Converse Consumption” a bizarre yet memorable experience. Significance The exhibition was viewed by an excess of 1000 people and generated exceptional media coverage and public exposure/impact. As Artisan Gallery Curator Kirsten Fitzpatrick states “20 of Brisbane's best designers were given the opportunity to customise their own Converse Sneakers, with The Converse Blank Canvas Project.” And to be selected in this category demonstrates the calibre of importance for design prominence.

Synthesis and evaluation of resveratrol-based nitroxides as potential treatments for hypertension

The synthesis and evaluation of novel resveratrol-based nitroxides have been explored for the potential treatment of hypertension. New methodology for the direct aryl iodination of isoindoline and isoindoline nitroxide using periodic acid and potassium iodide in concentrated sulphuric acid was developed. Diiodinated tetramethyl and tetraethyl isoindolines and a tetramethyl isoindoline nitroxide were prepared in excellent yields (70 – 82%). A diiodinated tetraethyl isoindoline nitroxide was generated from the corresponding nitroxide in modest yield (37%) alongside iodinated nitrones. The mono-iodinated species were also generated in modest yields (34 – 48%). Incorporation of the nitroxide unit into the structure of resveratrol was achieved using palladium-catalysed Heck coupling. Use of the previously prepared iodo products 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloyl 18 and 5,6-diiodo-1,1,3,3-tetramethylisoindolin-2-yloyl 22 gave resveratrol nitroxides 12 and 13 in yields of 50% (optimized) and 1.6% respectively. Preliminary evaluation of the resveratrol analogue 12 as a treatment for hypertension was undertaken in the DOCA-salt rat model. A reduction in systolic blood pressure as well as alleviation of ventricular hypertrophy was observed. A larger study involving the DOCA salt rats is currently in progress.

The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer

Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective synthases differ considerably with respect to the pathways described. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of thromboxane synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. © 2010 Elsevier B.V. All rights reserved.