Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low birth weight is associated with an increased risk in adult life of type 2 diabetes, hypertension and cardiovascular disease (CVD). The fetal insulin hypothesis postulates that genes involving insulin resistance could effect birth weight and disease in later life (Hattersley, 1999). Besides insulin, there is extensive evidence that insulin-like growth factor-I and -II (IGF-I, IGF-II) play an important role in fetal growth. We hypothesized that minor genetic variation in the IGF-I gene could influence pre- and postnatal growth. Three microsatellite markers located in the IGF-I gene in 124 short children (height < -1.88 SDS) who were born small for gestational age (SGA) and their parents were studied. SGA was defined as both a birth weight and birth length below -1.88 SDS for gestational age. Two polymorphic markers showed transmission disequilibrium. Allele 191 of the IGF1.PCR1 marker was transmitted more frequently from parent to child (chi(2) = 4.8 and p = 0.02) and allele 198 of the 737/738 marker was transmitted less frequently from parent to child (chi(2)= 4.5 and p = 0.03). Children carrying the 191-allele had significantly lower IGF-1 levels than children not carrying this allele (-1.1 SDS vs. -0.05 SDS; p = 0.03). Also, head circumference SDS remained smaller in children with allele 191 compared to children without allele 191 (-2.1 SDS vs. -0.9 SDS; p = 0.003). Our results show that genetically determined low IGF-I levels may lead to a reduction in birth weight, length and head circumference and to persistent short stature and small head circumference in later life (proportionate small). Since low IGF-I levels are associated with type 2 diabetes and CVD, we propose that the IGF-I gene may provide a link between low birth weight and such diseases in later life.
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PMID:Polymorphism in the IGF-I gene: clinical relevance for short children born small for gestational age (SGA). 1205 Feb 40

Hypertrichosis, characterized by increased hair growth located in non-androgen-dependent areas, does not justify the monitoring of hormone levels, conversely to hirsutism, with increased hair growth in androgen-dependent areas of the female genitals. Adult hypertrichosis is iatrogenic (minoxidil, ciclosporine, diazoxide or glucocorticosteroids), of metabolic origin (porphyria), nutritional (anorexia) or paraneoplastic (hypertrichosis lanuoginosa). Metabolic or general assessment can help clinical diagnosis. In non-iatrogenic hirsutism the following must be eliminated: 1) a virilizing tumor (ovarian, adrenal) when confronted with rapid progression or recent hirsutism, plasma testosterone (T)>1.5ng/ml and/or (adrenal tumor) DHEA-sulfate (DHEAS)>700 microgram/dl and associated with hypertension; 2) when confronted with characteristic signs of hirsutism, Cushing's syndrome (post-dexamethasone cortisol), hyperprolactinemia (pooled PRL), or acromegalia (IGF1). Measurement of 17-OH-progesterone at 8 am on the 4th day of the cycle detects the late manifestation homozygous forms of a 21-hydroxylase (21OHD) block. The more frequent forms are: 1) ovarian polymicrocystic or hirsutism-anovulation syndromes without other causes (LH/FSH, T, hyperinsulinemia, sonography); 2) functional adrenal hyperandrogenia (increased DHEAS without organic cause); 3) idiopathic hirsutism. Treatment can be local (discoloration, depilation, diathermo-coagulation, laser). Treatment of hirsutism of organic origin is etiologic. The inhibitory effects of glucocorticosteroids are mediated by 21OHD. The most effective treatments are anti-androgenic: cyproterone acetate, progesterone-like and anti-gonadotropic (contraceptive) agents; and the only product in France officially indicated in hirsutism , spironolactone (anti-mineralocorticosteroid); and flutamide, pure anti-androgen (probably hepatoxic). Finasteride (type II 5 alpha-reductase inhibitor) appears less effective. Estrogen-progestagen-like agents can be associated with anti-androgens. We should also mention the GnRH-agonists, and finally, dietetics and metformine (in cases of insulin-resistance).
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PMID:[Hirsutism and hypertrichosis in adults: investigations and treatment]. 1222 63

Recent evidence indicates that mutations in the gene encoding the WNK1 [with no K (lysine) protein kinase-1] results in an inherited hypertension syndrome called pseudohypoaldosteronism type II. The mechanisms by which WNK1 is regulated or the substrates it phosphorylates are currently unknown. We noticed that Thr-60 of WNK1, which lies N-terminal to the catalytic domain, is located within a PKB (protein kinase B) phosphorylation consensus sequence. We found that PKB phosphorylated WNK1 efficiently compared with known substrates, and both peptide map and mutational analysis revealed that the major PKB site of phosphorylation was Thr-60. Employing a phosphospecific Thr-60 WNK1 antibody, we demonstrated that IGF1 (insulin-like growth factor) stimulation of HEK-293 cells induced phosphorylation of endogenously expressed WNK1 at Thr-60. Consistent with PKB mediating this phosphorylation, inhibitors of PI 3-kinase (phosphoinositide 3-kinase; wortmannin and LY294002) but not inhibitors of mammalian target of rapamycin (rapamycin) or MEK1 (mitogen-activated protein kinase kinase-1) activation (PD184352), inhibited IGF1-induced phosphorylation of endogenous WNK1 at Thr-60. Moreover, IGF1-induced phosphorylation of endogenous WNK1 did not occur in PDK1-/- ES (embryonic stem) cells, in which PKB is not activated. In contrast, IGF1 still induced normal phosphorylation of WNK1 in PDK1(L155E/L155E) knock-in ES cells in which PKB, but not S6K (p70 ribosomal S6 kinase) or SGK1 (serum- and glucocorticoid-induced protein kinase 1), is activated. Our study provides strong pharmacological and genetic evidence that PKB mediates the phosphorylation of WNK1 at Thr-60 in vivo. We also performed experiments which suggest that the phosphorylation of WNK1 by PKB is not regulating its kinase activity or cellular localization directly. These results provide the first connection between the PI 3-kinase/PKB pathway and WNK1, suggesting a mechanism by which this pathway may influence blood pressure.
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PMID:WNK1, the kinase mutated in an inherited high-blood-pressure syndrome, is a novel PKB (protein kinase B)/Akt substrate. 1461 43

Renal failure is a frequent and costly complication of many chronic diseases, including diabetes and hypertension. One common feature of renal failure is glomerulosclerosis, the pathobiology of which is unclear. To help elucidate this, we generated a mouse strain carrying the missense mutation Wt1 R394W, which predisposes humans to glomerulosclerosis and early-onset renal failure (Denys-Drash syndrome [DDS]). Kidney development was normal in Wt1(+/R394W) heterozygotes. However, by 4 months of age 100% of male heterozygotes displayed proteinuria and glomerulosclerosis characteristic of DDS patients. This phenotype was observed in an MF1 background but not in a mixed B6/129 background, suggestive of the action of a strain-specific modifying gene(s). WT1 encodes a nuclear transcription factor, and the R394W mutation is known to impair this function. Therefore, to investigate the mechanism of Wt1 R394W-induced renal failure, the expression of genes whose deletion leads to glomerulosclerosis (NPHS1, NPHS2, and CD2AP) was quantitated. In mutant kidneys, NPHS1 and NPHS2 were only moderately downregulated (25 to 30%) at birth but not at 2 or 4 months. Expression of CD2AP was not changed at birth but was significantly upregulated at 2 and 4 months. Podocalyxin was downregulated by 20% in newborn kidneys but not in kidneys at later ages. Two other genes implicated in glomerulosclerosis, TGFB1 and IGF1, were upregulated at 2 months and at 2 and 4 months, respectively. It is not clear whether the significant alterations in gene expression are a cause or a consequence of the disease process. However, the data do suggest that Wt1 R394W-induced glomerulosclerosis may be independent of downregulation of the genes for NPHS1, NPHS2, CD2AP, and podocalyxin and may involve other genes yet to be implicated in renal failure. The Wt1(R394W) mouse recapitulates the pathology and disease progression observed in patients carrying the same mutation, and the mutation is completely penetrant in male animals. Thus, it will be a powerful and biologically relevant model for investigating the pathobiology of the earliest events in glomerulosclerosis.
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PMID:The Wt1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys-Drash syndrome. 1550 92

This study was carried out to build statistical models for defining FGR (Fetal Growth Restriction) in weight and/or length after taking growth potential of an infant into account. From a cohort of pregnant women having given birth to 47,733 infants in 141 French maternity units, two statistical models gave individualized limits of birth weight and birth length (based on the 5th centile) below which, after adjustment for its individual growth potential, a newborn must be considered as FGR in weight and/or in length. A sample of 906 infants had measures taken of cord blood growth factors (IGF1, IGFBP3). The FGR(W) definition (weight<5th centile for growth potential) permitted the identification of infants who presented rates of maternal hypertension (13.6%) and of Apgar score at 5 min<6 (2.9%) higher than in the classical group SGA(W) (weight<5th centile for sex and gestational age) (9.6% and 2.2% respectively). By combining FGR(W) and SGA(W), a subgroup of infants, not currently recognized as SGA, presented very high rates of maternal hypertension (19.9%) and of low Apgar score (3.9%). Conversely a subgroup of infants, currently recognized as SGA(W), had rates as low as in the normal infants group, and had to be considered as "constitutionally small" (that is to say 24% of the SGA(W)). Combining FGR(W) and FGR(L) (length<5th centile of growth potential), 7.6% of infants appeared growth-restricted, and 1.8% appeared constitutionally small in weight and/or in length. The FGR(W)-FGR(L) infants showed the lowest mean values of IGF1 (126.2+/-3.2) and IGFBP3 (0.86+/-0.03). These new definitions of FGR(W) and FGR(L) could help to better identify infants at birth requiring neonatal care, and monitoring of growth catch-up and neurodevelopmental outcome.
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PMID:Identification of newborns with Fetal Growth Restriction (FGR) in weight and/or length based on constitutional growth potential. 1683 59

Design Data on lipids, body composition, and blood pressure (BP) from all published KIMS papers are summarized and compared with a literature review. Results KIMS data confirm and extend previous research showing that adults with GH deficiency (GHD) have an adverse cardiovascular risk profile. GHD patients have high levels of dyslipidemia, elevated body mass index, unfavorable waist-to-hip ratio and body composition, and a high risk of hypertension. These abnormalities are likely to explain the increased cardiovascular mortality observed in patients with hypopituitarism. When given GH replacement therapy, an improvement is seen in KIMS as well as earlier studies for lipid profile, body composition, and BP. The added value of the different KIMS papers over previous research is that KIMS involves a much larger number of patients, that lipid concentrations and IGF1 are measured in a single central laboratory, and that the effects of GH replacement therapy can be followed longer than the duration of earlier trials. By the large number of patients, KIMS gives insight into the effects of GH in different patients' subgroups such as elderly patients, patients with idiopathic GHD, patients with craniopharyngioma, patients after irradiation, and so on. In addition, KIMS has made it possible to calculate more exactly the influence of baseline parameters on these cardiovascular risk parameters and their response to GH. Conclusions Taken together, data from KIMS confirm earlier knowledge about the important benefits of GH replacement therapy, but also on the use of GH in specific subgroups such as isolated GHD, patients above 65 years, and patients after irradiation. No subgroup yet has been identified as not responding well to GH.
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PMID:Cardiovascular risk factors in hypopituitary GH-deficient adults. 1968 57

Adaptive growth responses of the embryo and fetus to nutritional restraint are important in ensuring early survival, but they are implicated in the programming of hypertension. It has been demonstrated that kidney growth and nephrogenesis are each regulated by intrarenal factors, including the insulin-like growth factors, glucocorticoids, and the renin-angiotensin system. Therefore, we have investigated the impact of periconceptional undernutrition (PCUN; from approximately 6 wk before to 7 days after conception) in singleton (control, n = 18; PCUN, n = 16) and twin pregnancies (control, n = 6; PCUN, n = 5) on the renal mRNA expression of 11beta- hydroxysteroid dehydrogensase type 1 and type 2 (11beta-HSD-1 and -2), the glucocorticoid (GR), and mineralocorticoid receptors, angiotensinogen, angiotensin receptor type 1 (AT1R) and 2 (AT2R), IGF-1 and IGF-2, and IGF1R and IGF2R at approximately 55 days gestation. There was no effect of PCUN or fetal number on fetal weight on relative kidney weight at approximately day 55 of gestation. There was an inverse relationship between the relative weight of the fetal kidney at approximately day 55 and maternal weight loss during the periconceptional period in fetuses exposed to PCUN. Exposure to PCUN resulted in a higher expression of IGF1 in the fetal kidney in singleton and twin pregnancies. Being a twin resulted in higher intrarenal expression of IGF-1 and IGF-2, GR, angiotensinogen, AT1R, and AT2R mRNA at 55 days gestation. Renal 11beta-HSD-2 mRNA expression was higher in PCUN singletons, but not PCUN twins, compared with controls. Thus, there may be an adaptive response in the kidney to the early environment of a twin pregnancy, which precedes the fetal growth restriction that occurs later in pregnancy. The kidney of the twin fetus exposed to periconceptional undernutrition may also be less protected from the consequences of glucocorticoid exposure.
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PMID:Periconceptional undernutrition and being a twin each alter kidney development in the sheep fetus during early gestation. 2005 64

Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to Taiwanese populations, because they were not validated by the two replication studies. Identification of these genes enriches the collection of hypertension susceptibility genes, thereby shedding light on the etiology of hypertension in Han Chinese populations.
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PMID:Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes in Han Chinese with a genome-wide gene-based association study. 2247 46

Cardiac apoptosis was found in hearts from hypertensive animals, therefore in this study we aimed to evaluate the anti-apoptotic and pro-survival effects of protocatechuic acid (PCA) on hypertensive hearts. At first we found that, sedentary group (SHR)-PCA group's decreased TUNEL-positive apoptotic cells than SHR group alone. Protein levels of Fas ligand, Fas death receptor, Fas-associated death domain (FADD), Bid, t-Bid, Bax, cytochrome c, activated caspase-8, activated caspase 9 and activated caspase-3 were decreased in SHR-PCA group compared with SHR group. Moreover, SHR-PCA groups increased pro-survival pathway proteins like IGF1, pIGF1R, pPI3K, p-Akt, Bcl-xL, and Bcl-2 than SHR and sedentary normotensive group (WKY). All these finding suggest us that, Protocatechuic acid prevented hypertension-enhanced cardiac Fas-dependent and mitochondria-dependent apoptotic pathways and enhanced cardiac pro-survival pathway in rat models.
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PMID:Anti-apoptotic and pro-survival effect of protocatechuic acid on hypertensive hearts. 2435 28

Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation.
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PMID:Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans. 2487 78


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