Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Haptoglobin is a hemoglobin-binding protein expressed by a genetic polymorphism as three major phenotypes: 1-1, 2-1, and 2-2. Most attention has been paid to determining haptoglobin phenotype as a genetic fingerprint used in forensic medicine. More recently, several functional differences between haptoglobin phenotypes have been demonstrated that appear to have important biological and clinical consequences. Haptoglobin polymorphism is associated with the prevalence and clinical evolution of many inflammatory diseases, including infections, atherosclerosis, and autoimmune disorders. These effects are explained by a phenotype-dependent modulation of oxidative stress and prostaglandin synthesis. Recent evidence is growing that haptoglobin is involved in the immune response as well. The strong genetic pressure favoring the 2-2 phenotype suggests an important role of haptoglobin in human pathology.
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PMID:Biological and clinical significance of haptoglobin polymorphism in humans. 934 38

Haptoglobin (Hp) 2-2 type has been associated with accumulation of atherosclerotic lesions in essential hypertension. The aim of this study was to investigate the relationship between Hp type and the extension of coronary lesions in 765 male patients who underwent coronary artery bypass grafting (CABG). In this group, relative Hp1 (0.418) and Hp2 (0.582) allele frequencies were comparable with those of the reference population. Candidate CABG patients with a Hp 2-2 type were overrepresented in the younger (< 45 years) age group (P < 0.05). Hp 2-2 patients needed more bypass grafts than Hp 1-1 patients (relative risk 1.92 95% C.I. 1.24-2.96). The Hp 2-2 type was overrepresented among victims of a previous acute myocardial infarction (P < 0.05) and among patients with a lower (< 45 years) age at infarction (P < 0.05). In patients who already underwent a previous CABG graft survival time was shortest in Hp 2-2 type (P < 0.05). Patients with a Hp 2-2 type more likely develop atherosclerotic lesions despite comparable serum lipid concentrations.
Atherosclerosis 1997 Jul 25
PMID:Haptoglobin polymorphism, a genetic risk factor in coronary artery bypass surgery. 924 67

Haptoglobin is a hemoglobin-binding antioxidant showing a genetic polymorphism with three types: Hp 1-1, Hp 2-1, and Hp 2-2. The Hp 2-2 type has been associated with an increased risk of atherosclerosis. We investigated vitamin C metabolism in vivo and in vitro according to haptoglobin type in a study group of 135 healthy volunteers. Serum vitamin C concentrations were associated with haptoglobin type, showing lowest values in serum from Hp 2-2 subjects (P < 0.01). Renal threshold for L-ascorbic acid was within the normal range and metabolization to oxalate was not different among haptoglobin-type groups. Serum concentrations of other endogenous antioxidants (uric acid, bilirubin, albumin, ceruloplasmin, and total antioxidative status) were not different among haptoglobin-type groups. In vitro experiments showed a lower stability of L-ascorbic acid in blood from subjects with the Hp 2-2 type (P < 0.01). L-Ascorbic acid depletion in vitro was inversely related to haptoglobin concentration (r = -0.738). The results of this study indicate a higher rate of L-ascorbic acid oxidation in Hp 2-2 carriers because they have less protection against hemoglobin-iron driven peroxidation.
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PMID:Effect of haptoglobin on the metabolism of vitamin C. 928 Jan 80

Haptoglobin (Hp) 2-2 phenotype is a genetic risk factor in coronary atherosclerosis. In this study, haptoglobin phenotypes were determined in 141 patients with peripheral arterial occlusive disease (PAOD) and compared to a reference population (n = 1000). The relative Hp1 allele frequency was decreased among PAOD patients (0.294 vs. 0.403 for the reference population, P < 0.01) due to an overrepresentation of the Hp 2-2 phenotype (50%, odds ratio 1.82 (95% C.I. 1.28-2.60), P < 0.001). This finding was even more pronounced in non-diabetic and in non-smoking PAOD patients (Hp1 allele frequencies: 0.265 and 0.228, respectively). Serum lipids, inflammatory parameters, and blood pressure levels were comparable among the Hp phenotypes, but serum levels of the antioxidant vitamin C were lower in Hp 2-2 patients than in patients with another phenotype (P < 0.05). In PAOD patients with severe atherosclerotic lesions, maximal walking distance of patients carrying a Hp 2-2 phenotype (225-525 m) exceeded that of other Hp phenotypes (50-242 m) (interquartile ranges) (P < 0.05). The findings demonstrate that, despite an increased risk for developing PAOD, the Hp 2-2 phenotype is associated with a longer maximal walking distance which might be attributed to the earlier reported in vitro angiogenic properties of the Hp 2-2 molecule.
Atherosclerosis 1999 Aug
PMID:Haptoglobin polymorphism and peripheral arterial occlusive disease. 1048 55

Cross-cultural epidemiological studies of incident cardiovascular disease in the diabetic patient have demonstrated marked differences in susceptibility that may be due to a genetic factor. The coronary artery collateral circulation is the chief determinant of the size of a myocardial infarction and is highly variable between patients. We recently demonstrated that a functional allelic polymorphism in the haptoglobin gene is correlated with a number of diabetic vascular complications. We thus set out to test the hypothesis that haptoglobin phenotype is associated with collateral formation in the setting of diabetes. We correlated the Hp phenotype (1-1, 2-1 or 2-2) as determined by polyacrylamide electrophoresis with the presence or absence of coronary collaterals by angiography in 82 consecutive diabetic patients and 138 consecutive non-diabetic patients undergoing catheterization. We found that diabetic patients with the Hp phenotype 2-1 were more likely to have collaterals than diabetic patients with the Hp phenotype 2-2 (P=0.007). There was no correlation between Hp phenotypes and the presence of collaterals in non-diabetic patients. Hp phenotype thus appears to be associated with the development of the coronary collateral circulation in diabetic patients with coronary artery disease. Haptoglobin 2-2 may predispose to less compensation for coronary artery stenosis in diabetic patients, and thereby portend a worse prognosis.
Atherosclerosis 2002 Apr
PMID:Haptoglobin phenotype and coronary artery collaterals in diabetic patients. 1188 29

The haptoglobin genotype has been demonstrated to be an independent risk factor for CVD in multiple epidemiological studies. The primary function of haptoglobin is to mitigate the deleterious effects of extracorpuscular hemoglobin. We sought to determine if the protein products of the two haptoglobin alleles differed in their ability to modulate the cytokine profile produced by macrophages in response to hemoglobin. Peripheral blood mononuclear cells were isolated from normal human volunteers and cultured in the presence of complexes formed by the protein products of the two different haptoglobin alleles with hemoglobin. The release of specific cytokines in the conditioned media of these cells was assessed by ELISA. We found that the haptoglobin 1 allele protein product-hemoglobin complex stimulated the secretion of significantly more Il-6 and Il-10 than the haptoglobin 2 allele protein product-hemoglobin complex. We demonstrate that the release of these cytokines is dependent on the liganding of the haptoglobin-hemoglobin complex to the CD163 receptor and the activity of casein kinase II. Haptoglobin genotype modulates the balance of inflammatory (Th1) and anti-inflammatory (Th2) cytokines produced by macrophages exposed to free hemoglobin. This may have implications in understanding inter-individual differences in the inflammatory response to hemorrhage.
Atherosclerosis 2007 Mar
PMID:Haptoglobin genotype modulates the balance of Th1/Th2 cytokines produced by macrophages exposed to free hemoglobin. 1682 Jan 50

Hemoglobin (Hb) released during hemolysis is a potent oxidant. Extracorpuscular Hb may enter the vessel wall and mediate low-density lipoprotein oxidation, thereby promoting the development and progression of atherosclerosis. Haptoglobin (Hp) is an antioxidant protein as a result of its ability to bind Hb and block Hb-induced oxidative damage. Hp also facilitates the removal of Hb from the extravascular compartment via the CD163 macrophage scavenger receptor. In man, there are two common alleles for Hp denoted 1 and 2, and correspondingly, three different possible genotypes: Hp1-1, Hp2-1, and Hp2-2. We have recently demonstrated in several longitudinal studies that Hp genotype is an independent risk factor for diabetic vascular complications. Specifically, we have shown that diabetic individuals with Hp2-2 are more likely to develop nephropathy, retinopathy, and cardiovascular disease as compared with those with Hp2-1 or Hp1-1. Mechanistically, we have found significant Hp type differences in the antioxidant and CD163-mediated scavenging and activation functions of the different Hp protein types. Furthermore, we have demonstrated that these functions are modified in the diabetic state. In this review, we focus on the clinical studies associating the Hp polymorphism and diabetic vascular complications, and the molecular basis behind this interaction.
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PMID:In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease. 1731 95

Haptoglobin (Hp) is an antioxidant protein and the major susceptibility gene for atherosclerosis in diabetic patients. The effect of Hp phenotype on arterial compliance and metabolic and inflammatory parameters was investigated. Patients were divided into 3 groups according to Hp phenotype of Hp 2-2, Hp 2-1, and Hp 1-1. Arterial elasticity of large and small arteries was evaluated using the pulse-wave contour analysis method. The large-artery elasticity index (LAEI) was lower in patients with Hp 2-2 compared with Hp 1-1 (8.4 +/- 2.3 vs 12.6 +/- 4.1 ml/mm Hg x 100; p <0.0001). The difference in LAEIs between the Hp 2-1 and Hp 1-1 groups was also significant (9.9 +/- 2.6 vs 12.6 +/- 4.1 ml/mm Hg x 100; p = 0.025). The Hp 2-2 and Hp 2-1 groups did not differ from one another. The small-artery elasticity index (SAEI) was significantly lower in patients with Hp 2-2 compared with Hp 1-1 (2.8 +/- 1.0 vs 4.4 +/- 1.9 ml/mm Hg x 100; p = 0.004). Differences in SAEIs between patients with Hp 2-1 and Hp 1-1, as well as those with Hp 2-1 and Hp 2-2, were not detected. Systemic vascular resistance differed significantly across groups, driven by the difference between patients with Hp 2-2 and Hp 1-1. In conclusion, LAEI and SAEI were significantly lower and systemic vascular resistance was higher in homozygotes for the 2 allele (Hp 2-2) compared with patients with Hp 2-1 or Hp 1-1 phenotypes. Differences in arterial elasticity were detected despite the lack of by-phenotype differences in glycemic control, blood pressure, or presence of cardiovascular risk factors.
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PMID:Relation of haptoglobin phenotype to early vascular changes in patients with diabetes mellitus. 1808 23

This study investigated the effect of mechanical infection control for periodontitis and periodontal surgery on the prevalence of well-established risk factors for atherosclerosis, and plasma levels of cytokines, antibodies against heat shock proteins and markers of systemic inflammation. Sixty-eight patients between 39 and 73 years of age with severe periodontitis who had been referred to four specialist periodontology clinics in Sweden were investigated. A fasting venous blood sample was taken at baseline and additional samples were collected after 3 and 12 months. A total of 54 patients underwent periodontal treatment. The periodontal treatment was successful, as pathogenic gingival pockets decreased significantly. Plasma glucose, lipids and markers of systemic inflammation were not significantly altered after 3 months. One year after the initial treatment, HDL-C concentrations were significantly increased (Delta0.08mmol/L) whereas LDL-C concentrations decreased (Delta0.23mmol/L). Haptoglobin concentrations were also lower. Interleukin-18 and interferon-gamma levels were also lower after 12 months (60ng/L (-23%) and 11ng/L (-97%) respectively). Treatment had no effect on plasma levels of IgA, IgG1, IgG2 antibodies against heat shock proteins. In conclusion, this study indicates that standard treatment for periodontal disease induces systemic changes in several biochemical markers that reflect the risk for atherosclerosis.
Atherosclerosis 2009 Oct
PMID:Periodontal treatment influences risk markers for atherosclerosis in patients with severe periodontitis. 1941 Oct 77

Haptoglobin (Hpt) binds apolipoprotein A-I (ApoA-I), and impairs its stimulation of lecithin:cholesterol acyltransferase (LCAT). LCAT plays a major role in reverse cholesterol transport (RCT). Apolipoprotein E (ApoE), like ApoA-I, promotes different steps of RCT, including LCAT stimulation. ApoE contains amino acid sequences that are homologous with the ApoA-I region bound by Hpt and are involved in the interaction with LCAT. Therefore, Hpt was expected to also bind ApoE, and inhibit the ApoE stimulatory effect on LCAT. Western blotting and ELISA experiments demonstrated that the Hpt beta-subunit binds ApoE. The affinity of Hpt for ApoE was higher than that for ApoA-I. High ratios of Hpt with either apolipoprotein, such as those associated with the acute phase of inflammation, inhibited, in vitro, the stimulatory effect of ApoE on the cholesterol esterification activity of LCAT. Hpt also impaired human hepatoblastoma-derived cell uptake of [(3)H]cholesterol from proteoliposomes containing ApoE or ApoA-I. We suggest that the interaction between Hpt and ApoE represents a mechanism by which inflammation affects atherosclerosis progression. Hpt might influence ApoE function in processes other than RCT.
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PMID:Haptoglobin binds the antiatherogenic protein apolipoprotein E - impairment of apolipoprotein E stimulation of both lecithin:cholesterol acyltransferase activity and cholesterol uptake by hepatocytes. 1975 44


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