| 1. |
- Chen, Yuqing, et al.
(author)
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Naturally occurring human genetic variation in the 3'-untranslated region of the secretory protein chromogranin A is associated with autonomic blood pressure regulation and hypertension in a sex-dependent fashion
- 2008
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 52:18, s. 1468-81
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Journal article (peer-reviewed)abstract
- OBJECTIVES: We aimed to determine whether the common variation at the chromogranin A (CHGA) locus increases susceptibility to hypertension. BACKGROUND: CHGA regulates catecholamine storage and release. Previously we systematically identified genetic variants across CHGA. METHODS: We carried out dense genotyping across the CHGA locus in >1,000 individuals with the most extreme blood pressures (BPs) in the population, as well as twin pairs with autonomic phenotypes. We also characterized the function of a trait-associated 3'-untranslated region (3'-UTR) variant with transfected CHGA 3'-UTR/luciferase reporter plasmids. RESULTS: CHGA was overexpressed in patients with hypertension, especially hypertensive men, and CHGA predicted catecholamines. In individuals with extreme BPs, CHGA genetic variants predicted BP, especially in men, with a peak association occurring in the 3'-UTR at C+87T, accounting for up to approximately 12/ approximately 9 mm Hg. The C+87T genotype predicted CHGA secretion in vivo, with the +87T allele (associated with lower BP) also diminishing plasma CHGA by approximately 10%. The C+87T 3'-UTR variant also predicted the BP response to environmental (cold) stress; the same allele (+87T) that diminished basal BP in the population also decreased the systolic BP response to stress by approximately 12 mm Hg, and the response was smaller in women (by approximately 6 mm Hg). In a chromaffin cell-transfected CHGA 3'-UTR/luciferase reporter plasmid, the +87T allele associated with lower BP also decreased reporter expression by approximately 30%. In cultured chromaffin cells, reducing endogenous CHGA expression by small interfering ribonucleic acid caused approximately two-thirds depletion of catecholamine storage vesicles. CONCLUSIONS: Common variant C+87T in the CHGA 3'-UTR is a functional polymorphism causally associated with hypertension especially in men of the population, and we propose steps ("intermediate phenotypes") whereby in a sex-dependent fashion this genetic variant influences the ultimate disease trait. These observations suggest new molecular strategies to probe the pathophysiology, risk, and rational treatment of hypertension.
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| 2. |
- Connor, K. M., et al.
(author)
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Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis
- 2007
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In: Nat Med. - 1078-8956.
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Journal article (peer-reviewed)abstract
- Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of omega-3- and omega-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy. We show that increasing omega-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive omega-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of omega-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-alpha. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of omega-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in omega-3-PUFA, and premature infants lack the important transfer from the mother to the infant of omega-3-PUFA that normally occurs in the third trimester of pregnancy. Supplementing omega-3-PUFA intake may be of benefit in preventing retinopathy.
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| 3. |
- Rao, Fangwen, et al.
(author)
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Catecholamine release-inhibitory peptide catestatin (chromogranin A352-372) : Naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension
- 2007
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In: Circulation. - 0009-7322 .- 1524-4539. ; 115:17, s. 2271-2281
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Journal article (peer-reviewed)abstract
- BACKGROUND - Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure. METHODS AND RESULTS - Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by ≈47%) and downward deflections (by ≈44%), increased cardiac parasympathetic index (by ≈2.4-fold), and decreased cardiac sympathetic index (by ≈26%). Renal norepinephrine excretion was diminished by ≈26% and epinephrine excretion by ≈34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to ≈70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by ≈5 to 6 mm Hg, and the polymorphism accounted for ≈1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. CONCLUSIONS - The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.
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| 4. |
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| 5. |
- Zhang, Kuixing, et al.
(author)
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Autonomic function in hypertension; role of genetic variation at the catecholamine storage vesicle protein chromogranin B
- 2009
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In: Circulation: Cardiovascular Genetics. - 1942-3268. ; 2:1, s. 46-56
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Journal article (peer-reviewed)abstract
- Background: Hypertension is a complex trait, with deranged autonomic control of circulation. Chromogranin B (CHGB) is the most abundant core protein in human catecholamine secretory vesicles, playing an important role in their biogenesis. Does common interindividual variation at the CHGB locus contribute to phenotypic variation in CHGB and catecholamine secretion, autonomic stability of circulation, or blood pressure (BP) in the population? Methods and Results: To probe interindividual variability in CHGB, we systematically studied polymorphism across the locus by resequencing CHGB (≈6 kbp footprint spanning the promoter, 5 exons, exon/intron borders, untranslated regions) in 160 subjects (2n=320 chromosomes) of diverse biogeographic ancestries. We identified 53 single-nucleotide polymorphisms, of which 22 were common. We then studied 1182 subjects drawn from the most extreme BP values in the population (highest and lowest 5th percentiles), typing 4 common polymorphisms spanning the ≈14 kbp locus. Sliding-window haplotype analysis indicated BP associations peaking in the 5'/promoter region, most prominent in men, and a peak effect in the proximal promoter at variant A-261T (A>T), accounting for ≈8/≈6 mm Hg BP in males. The promoter allele (A-261) that was a predictor of higher diastolic BP and systolic BP was also associated with lower circulating/plasma CHGB concentration (CHGB439to451 epitope) in twin pairs. In twins, the same CHGB variants that were predictors of lower basal CHGB secretion were also associated with exaggerated catecholamine secretion and BP response to environmental (cold) stress; likewise, women displayed increased plasma CHGB439to451 but decreased catecholamine secretion as well as BP response to environmental stress. The effect of A-261T on CHGB expression was confirmed in chromaffin cells by site-directed mutagenesis on transfected CHGB promoter/luciferase reporter activity, and the allelic effects of A-261T on gene expression were directionally coordinate in cella and in vivo. To confirm these clinical associations experimentally, we undertook targeted homozygous (-/-) ablation of the mouse CHGB gene; knockout mice displayed substantially increased BP, by ≈20/≈18 mm Hg, confirming the mechanistic basis of our findings in humans. Conclusion-Common genetic variation at the CHGB locus, especially in the proximal promoter, influences CHGB expression and later catecholamine secretion and the early heritable responses to environmental stress, eventuating in changes in resting/basal BP in the population. Both the early (gene expression) and late (population BP) consequences of CHGB variation are sex dependent. These results point to new molecular strategies for probing autonomic control of circulation and, ultimately, the susceptibility to and pathogenesis of cardiovascular disease states such as hypertension.
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| 6. |
- Luo, J.L, et al.
(author)
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Impact of diagenesis on reservoir-quality evolution in fluvial and lacustrine-deltaic sandstones: evidence from Jurassic and Triassic sandstones from the Ordos Basin, China
- 2009
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In: Journal of Petroleum Geology. - : Wiley. - 0141-6421 .- 1747-5457. ; 32:1, s. 79-102
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Journal article (peer-reviewed)abstract
- The reservoir quality of Jurassic and Triassic fluvial and lacustrine-deltaic sandstones in the intracratonic Ordos Basin is strongly influenced by depositional facies and various types of diagenetic modifications. The fluvial sandstones have higher average He-porosity and permeability (14.8% and 12.7 mD, respectively) than the deltaic sandstones (9.8% and 5.8 mD, respectively). In addition to extensive mechanical compaction, eodiagenesis (220-97 Ma; depth < 2000 m; T < 70 degrees C) has resulted in dissolution and kaolinitization of detrital silicates in the Jurassic fluvial sandstones, and in smectite infiltration and minor cementation by calcite and siderite in the Triassic fluvial and deltaic sandstones. Pervasive eogenetic carbonate cementation (> 20 vol.%) occurred in Triassic deltaic siltstones and very fine-grained sandstones which are closely associated with organic-rich mudstones. Mesodiagenesis (97-65 Ma), which occurred during rapid subsidence to depths of 3700-4400 m, resulted in the albitization of plagioclase, checmical compaction, the conversion of kaolinite into dickite, and cementation by quartz overgrowths, chlorite, illite, ankerite (delta C-13(VPDB) = -2.4 parts per thousand to +2.6 parts per thousand; delta O-18(VPDB) = -21.5 parts per thousand to -10 parts per thousand) and calcite (delta C-13(VPDB) = -4.7 parts per thousand to +3.7 parts per thousand; delta O-18(VPDB) = -21.8 parts per thousand to -13.4 parts per thousand). Oil emplacement (95 Ma) retarded cementation by mesogenetic quartz and carbonate but had little influence on dickite, illite and chlorite formation. Retardation of quartz cementation was also due to the presence of chlorite fringes around detrital quartz grains. Dickitization of eogenetic kaolinite together with the short residence time at maximum burial temperatures (105-124 degrees C) has retarded the albitization of K-feldspars and illite formation and hence prevented severe permeability destruction. Telodiagenesis, which occurred after uplift (Eocene to end-Neogene), caused slight dissolution and kaolinitization of feldspars. This study demonstrates that despite complex patterns of diagenetic modifications in the Triassic and Jurassic successions, depositional porosity and permeability are better preserved in fluvial meandering channel sandstones than in deltaic sandstones. These results should be important for modelling of reservoir-quality distribution and exploration risk evaluation in the basin.
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| 7. |
- Mansurbeg, Howri, et al.
(author)
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Diagenesis and reservoir quality evolution of paleocene deep-water, marine sandstones, the Shetland-Faroes Basin, British Continental Shelf
- 2008
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In: Marine and Petroleum Geology. - : Elsevier BV. - 0264-8172 .- 1873-4073. ; 25:6, s. 514-543
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Journal article (peer-reviewed)abstract
- The Palaeocene, deep-water marine sandstones recovered from six wells in the Shetland-Faroes Basin represent lowstand, transgressive and highstand systems tract turbiditic sediments. Mineralogic, petrographic, and geochemical analyses of these siliciclastics are used to decipher and discuss the diagenetic alterations and subsequent reservoir quality evolution. The Middle-Upper Palaeocene sandstones (subarkoses to arkoses) from the Shetland-Faroes Basin, British continental shelf are submarine turbiditic deposits that are cemented predominantly by carbonates, quartz and clay minerals. Carbonate cements (intergranular and grain replacive calcite, siderite, ferroan dolomite and ankerite) are of eogenetic and mesogenetic origins. The eogenetic alterations have been mediated by marine, meteoric and mixed marine/meteoric porewaters and resulted mainly in the precipitation of calcite (δ18OV−PDB=−10.9‰ and −3.8‰), trace amounts of non-ferroan dolomite, siderite (δ18OV−PDB=−14.4‰ to −0.6‰), as well as smectite and kaolinite in the lowstand systems tract (LST) and highstand systems tract (HST) turbiditic sandstone below the sequence boundary. Minor eogenetic siderite has precipitated between expanded and kaolinitized micas, primarily biotite. The mesogenetic alterations are interpreted to have been mediated by evolved marine porewaters and resulted in the precipitation of calcite (δ18OV−PDB=−12.9‰ to −7.8‰) and Fe-dolomite/ankerite (δ18OV−PDB=−12.1‰ to −6.3‰) at temperatures of 50–140 and 60–140 °C, respectively. Quartz overgrowths and outgrowth, which post- and pre-date the mesogenetic carbonate cements is more common in the LST and TST of distal turbiditic sandstone. Discrete quartz cement, which is closely associated with illite and chlorite, is the final diagenetic phase. The clay minerals include intergranular and grain replacive eogenetic kaolinite, smectite and mesogenetic illite and chlorite. Kaolinite has been subjected to mesogenetic replacement by dickite. The K-feldspar and plagioclase grains have been albitized. Dissolution of calcite cement and of framework grain (feldspar, volcanic fragments and mud intraclasts) has resulted in a considerable enhancement of reservoir quality.
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| 8. |
- Salem, Rany M., et al.
(author)
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Chromogranin a polymorphisms are associated with hypertensive renal disease
- 2008
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In: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 19:3, s. 600-614
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Journal article (peer-reviewed)abstract
- Chromogranin A is released together with epinephrine and norepinephrine from catecholaminergic cells. Specific endopeptidases cleave chromogranin A into biologically active peptide fragments, including catestatin, which inhibits catecholamine release. Previous studies have suggested that a deficit in this sympathetic “braking” system might be an early event in the pathogenesis of human hypertension. Whether chromogranin A (CHGA) polymorphisms predict end-organ complications of hypertension, such as end-stage renal disease, is unknown. Among blacks, we studied common genetic variants spanning the CHGA locus in 2 independent case-control studies of hypertensive ESRD. Two haplotypes were significantly more frequent among subjects with hypertensive ESRD: 1) in the promoter (5′) region, G-462A→T-415C→C-89A, haplotype ATC (adjusted odds ratio = 2.65; P = 0.037), and 2) at the 3′-end, C11825T (3′-UTR, C+87T)→G12602C, haplotype TC (adjusted odds ratio = 2.73, P = 0.0196). Circulating levels of catestatin were lower among those with hypertensive ESRD than controls, an unexpected finding given that peptide levels are usually elevated in ESRD because of reduced renal elimination. We found that the 3′-UTR + 87T variant decreased reporter gene expression, providing a possible mechanistic explanation for diminished catestatin. In summary, common variants in chromogranin A associate with the risk of hypertensive ESRD in blacks.
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