A common polymorphism in the oxygen-dependent degradation (ODD) domain of hypoxia inducible factor-1alpha (HIF-1alpha) does not impair Pro-564 hydroxylation

The hypoxia-inducible factor (HIF) transcription complex, which is activated by low oxygen tension, controls a diverse range of cellular processes including angiogenesis and erythropoiesis. Under normoxic conditions, the alpha subunit of HIF is rapidly degraded in a manner dependent on hydroxylation of two conserved proline residues at positions 402 and 564 in HIF-1alpha in the oxygen-dependent degradation (ODD) domain. This allows subsequent recognition by the von Hippel-Lindau (VHL) tumor suppressor protein, which targets HIF for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, prolyl hydroxylation of HIF is inhibited, allowing it to escape VHL-mediated degradation. The transcriptional regulation of the erythropoietin gene by HIF raises the possibility that HIF may play a role in disorders of erythropoiesis, such as idiopathic erythrocytosis (IE).

Relationship between G894T polymorphism (Glu 298 Asp variant) in endothelial nitric oxide synthase and nitric oxide mediated endothelial function in human atherosclerosis.

Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), plays important roles in normal vascular homeostasis, and reduced endothelial NO bioactivity is an important feature of vascular disease states. The Glu298Asp (G894T) polymorphic variant of eNOS has been associated with vascular disease, but functional data are lacking. Accordingly, we examined the relationships between NO-mediated endothelial function, the presence of the eNOS Glu298Asp variant, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations to different agonists were determined in human saphenous veins obtained from patients with coronary artery disease and identified risk factors (n = 104). Patients were genotyped for the eNOS G894T polymorphism. Nitric oxide-mediated endothelial vasorelaxations were highly variable between patients. Reduced vasorelaxations were associated with increased number of clinical risk factors for atherosclerosis (r = - 0.54, P

Effect of a COL1A1 Sp1 Binding Site Polymorphism on Arterial Pulse Wave Velocity: An Index of Compliance.

Reduced arterial compliance precedes changes in blood pressure, which may be mediated through alterations in vessel wall matrix composition. We investigated the effect of the collagen type I-1 gene (COL1A1) +2046G>T polymorphism on arterial compliance in healthy individuals. We recruited 489 subjects (251 men and 238 women; mean age, 22.6±1.6 years). COL1A1 genotypes were determined using polymerase chain reaction and digestion by restriction enzyme Bal1. Arterial pulse wave velocities were measured in 3 segments, aortoiliac (PWVA), aortoradial (PWVB), and aorto-dorsalis-pedis (PWVF), as an index of compliance using a noninvasive optical method. Data were available for 455 subjects. The sample was in Hardy-Weinberg equilibrium with genotype distributions and allele frequencies that were not significantly different from those reported previously. The T allele frequency was 0.22 (95% confidence interval, 0.19 to 0.24). Two hundred eighty-three (62.2%) subjects were genotype GG, 148 (35.5%) subjects were genotype GT, and 24 (5.3%) subjects were genotype TT. A comparison of GG homozygotes with GT and TT individuals demonstrated a statistically significant association with arterial compliance: PWVF 4.92±0.03 versus 5.06±0.05 m/s (ANOVA, P=0.009), PWVB 4.20±0.03 versus 4.32±0.04 m/s (ANOVA, P=0.036), and PWVA 3.07±0.03 versus 3.15±0.03 m/s (ANOVA, P=0.045). The effects of genotype were independent of age, gender, smoking, mean arterial pressure, body mass index, family history of hypertension, and activity scores. We report an association between the COL1A1 gene polymorphism and arterial compliance. Alterations in arterial collagen type 1A deposition may play a role in the regulation of arterial compliance

Association of Functional Heme Oxygenase-1 Gene Promoter Polymorphism with Renal Transplantation Outcomes

Heme oxygenase-1 (HO-1) is a cytoprotective molecule and increased expression in experimental transplant models correlates with reduced graft injury. A functional dinucleotide repeat (GT)n polymorphism, within the HO-1 promoter, regulates gene expression; a short number of repeats (S-allele

Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism

A side-effect of treatment with antipsychotic drugs for schizophrenia is increased body fat, which leads to further morbidity and poor adherence to treatment. The 5-hydroxytryptamine 2C receptor (5-HT2C) has been associated with this effect; we aimed to establish whether a genetic polymorphism of the promoter region of this receptor affects weight gain after drug treatment in first-episode patients with schizophrenia. We noted significantly less weight gain in patients with the -759T variant allele (p=0.0003) than in those without this allele, who were more likely to have substantial (>7%) weight gain (p=0.002). We have identified a genetic factor that is associated with antipsychotic drug-induced weight gain.