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)

Familial defective apolipoprotein B-100 (FDB) is a dominantly inherited disorder associated with hypercholesterolemia, in which substitution of the amino acid glutamine for arginine at position 3500 in the apoprotein B molecule results in LDL particles which bind poorly to the LDL receptor. To date, patients with FDB have been heterozygous for this disorder and their plasma contains both normal and defective-binding LDL particles, with a predominance of the latter. In the present report, we have compared the hypocholesterolemic effects of bile acid sequestrant therapy (cholestyramine or colestipol) in eight patients with FDB, to the response seen in sixteen patients with heterozygous familial hypercholesterolemia (FH), treated with the same drugs. Concentrations of LDL cholesterol fell by 32.0% in the patients with FDB and by 21.6% in the patients with FH. The results indicate that the hypercholesterolemia of both FDB and FH responds to treatment with bile acid sequestrants.
Atherosclerosis 1993 Jan 25
PMID:Hypocholesterolemic effects of cholestyramine and colestipol in patients with familial defective apolipoprotein B-100. 845 60

Coronary artery disease (CAD) is a complex trait caused by a number of genetic and environmental factors. Recently, paraoxonase/arylesterase (PONA) enzyme has been implicated in the pathogenesis of atherosclerosis. There is a 10-40-fold variability in the activity of this enzyme among individuals. This variability is due to the presence of an A/G polymorphism in the coding region of the gene (HUMPONA). The A and G alleles code for glutamine (A genotype) and arginine (B genotype), respectively. Individuals with A genotype have a lower enzymatic activity than those with B genotype. We determined the HUMPONA genotypes and alleles in 223 patients with angiographically documented CAD and in 247 individuals in the general population. The distribution of genotypes were in Hardy-Weinberg equilibrium in patients and in controls. Genotypes A and B were present in 120 (49%) and 28 (11%) individuals in controls and in 68 (30%) and 40 (18%) patients with CAD, respectively (chi squared= 16.5, P= 0.0003). The frequency of the A allele was 0.69 in controls and 0.56 in patients (OR= 1.7, P= 0.0001). There were no differences in the distribution of HUMPONA genotypes in the subgroups of patients with restenosis, myocardial infarction, or any of the conventional risk factors for CAD as compared with corresponding subgroups. In summary, variants of the HUMPONA gene are involved in predisposition to coronary atherosclerosis.
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PMID:A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease. 867 73

We identified two apolipoprotein (apo) A-I variants, using isoelectric focusing gel electrophoresis: apo A-I Karatsu, which had a relative charge of +1 compared to normal apo A-I4, and apo A-I Kurume, which had a relative charge of -1. Direct sequence analysis of the PCR-amplified DNA from the proband of apo A-I Karatsu revealed a single substitution of tyrosine (TAC) for histidine (CAC) at position 100. Sequence analysis of apo A-I Kurume revealed a single substitution of histidine (CAT) for glutamine (CAG) at position 162. Probands of these two mutants and limited family study showed no accelerated atherosclerosis.
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PMID:Identification of two apolipoprotein variants, A-I Karatsu (Tyr 100-->His) and A-I Kurume (His 162-->Gln). 874 Sep 17

It has long been known that there is an extremely high degree of variability in both human and nonhuman primates in terms of low density lipoprotein cholesterol (LDL-C) lowering in response to restriction of dietary saturated fat and cholesterol. In this regard we have reviewed the current knowledge regarding the gene-diet interaction in relation to plasma lipid response to dietary intervention. Several candidate gene loci have been examined in humans: apolipoprotein (apo) A-I, apo A-IV, apo B, apo C-III and apo E, as well as lipoprotein lipase (LPL). Several mutations at these loci have been found to be associated with responsiveness. We and others have documented that subjects carrying the apo E4 allele are more responsive with regard to LDL-C lowering in response to dietary fat and cholesterol restriction than subjects carrying the apo E3 or apo E2 alleles, whereas some studies report no association of apo E phenotypes with lipid response to some dietary interventions. Our own meta-analysis indicates that apo E genotype effects are modulated via alterations of amount and type of dietary fat. We have also documented that subjects carrying the common glutamine for histidine mutation at amino acid 360 of apo A-IV are significantly less responsive in terms of LDL-C lowering than subjects with the normal apo A-IV genotype is modulated via changes in dietary cholesterol. In addition, we have documented that the common G/A mutation within the promoter region of the apo A-I gene is associated with greater responsiveness of LDL-C to dietary fat alterations. The XbaI and insertion/deletion polymorphisms at the apo B gene locus and the HindIII restriction fragment length polymorphism (RFLP) at the LPL locus have also been associated with diet responsiveness. Therefore, in humans these gene loci account for a significant portion of the variability in plasma lipid response to dietary alterations.
Atherosclerosis 1995 Dec
PMID:Gene-diet interaction in determining plasma lipid response to dietary intervention. 882 61

Familial ligand-defective apolipoprotein (apo) B-100 (FDB) is an autosomal codominant disorder which may give rise to hypercholesterolaemia. It is caused by the substitution of glutamine for arginine at codon 3500 of the apo B gene (apo B R3500Q), resulting in decreased binding of low density lipoprotein (LDL) to the LDL receptor. In order to search for other mutations in this region of the apo B gene, we have screened genomic DNA, obtained from 412 hypercholesterolaemic individuals, using heteroduplex analysis. Additional heteroduplex bands were observed following analysis of DNA from 11 individuals, nine of whom were heterozygous for apo B R3500Q. The two remaining individuals, both of Celtic origin, were shown by DNA sequencing to be heterozygous for a C-->T transition at nucleotide 10800 of the apo B gene, resulting in the substitution of cysteine for arginine at codon 3531 (apo B R3531C). Both had a strong family history of atherosclerosis and family studies revealed a further four individuals heterozygous for the mutation, three of whom were hypercholesterolaemic. Individuals heterozygous for apo B R3531C and R3500Q had mean +/- S.E.M. cholesterol concentrations of 7.82 +/- 0.68 and 8.53 +/- 0.31 mmol/l, respectively. These values were significantly higher than the value of 5.51 +/- 0.23 mmol/l observed in their unaffected relatives. These findings suggest that apo B R3531C is both less common in the UK and gives rise to a less severe form of hypercholesterolaemia than the classical 3500 mutation. In one of the families, the R3531C mutation occurred on a haplotype, compatible with that previously assigned to the mutation in a North American family also of Celtic origin. This is consistent with the mutation having been inherited from a common distant ancestor in individuals of Celtic origin.
Atherosclerosis 1997 Mar 21
PMID:Familial ligand-defective apolipoprotein B-100: detection, biochemical features and haplotype analysis of the R3531C mutation in the UK. 910 60

Cholesteryl ester transfer protein (CETP), as a candidate gene for dyslipoproteinemia and coronary heart disease, was studied in 105 men with low plasma concentrations of high density lipoprotein cholesterol (HDL-C) and established coronary heart disease as well as in 515 randomly selected men and women. A one-nucleotide substitution (G to A) in exon 15, which changes arginine (451) to glutamine in CETP protein, was detected by PCR-SSCP and direct sequencing and screened in the population sample by a simple PCR-based restriction assay. In the random population sample the allele frequency of the R451Q mutation was 1.9%. Men heterozygous for the R451Q mutation (n = 7) had 27% higher CETP activity than age-, body mass index-, smoking- and alcohol consumption-matched controls with normal genotype (n = 21; P = 0.003). Women heterozygous for the R451Q mutation (n = 7) had 16% lower total cholesterol compared to matched controls (n = 21; P = 0.07), but no such difference was detected in men. In the random population sample the correlation between plasma total cholesterol level and CETP activity was 0.19 (P = 0.044), both in men and women. When women with total cholesterol over 5.2 mmol/l were excluded from analysis, heterozygotes (n = 4) had plasma CETP activity of 113 nmol/h/ml plasma, whereas those of normal genotype (n = 12) had 103 nmol/h/ml plasma, but this difference was not statistically significant. Women heterozygous for the R451Q mutation and consuming less than 10 g alcohol a week had 23% lower HDL-C compared to women with the normal genotype (P = 0.032). In conclusion, we describe a mutation in the CETP gene associated with high plasma CETP activity in men and with low total cholesterol in women. Further studies are needed to evaluate the effect of mutation on the risk of coronary heart disease.
Atherosclerosis 1998 Feb
PMID:R451Q mutation in the cholesteryl ester transfer protein (CETP) gene is associated with high plasma CETP activity. 954 93

Central retinal vein occlusion (CRVO) is a complex trait caused by a number of local and systemic factors. Among the latter, atherosclerosis has been attributed a major pathogenic role. Recently, the paraoxonase/arylesterase (PONA) enzyme has been implicated in the pathogenesis of atherosclerosis. There is a 10- to 40-fold variability in the activity of this enzyme among individuals. This variability is due to the presence of an A/G polymorphism in the coding region of the gene. The A and G alleles code for glutamine (A genotype) and arginine (B genotype), respectively. We determined the PONA genotypes and alleles in 42 patients with CRVO and in 45 control subjects of the Japanese population. The distribution of AA, AB and BB genotypes were 9.6, 45.2 and 45.2%, respectively, in the patients and 26.7, 53.3 and 20.0% in the control subjects, respectively (p < 0.05). The A allele frequency was 0.32 in patients and 0.53 in controls (p < 0.01). In conclusion, molecular variants of the PONA gene are involved in the predisposition to CRVO. Further studies are needed to characterize the molecular mechanism by which the PONA enzyme is involved in atherosclerosis.
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PMID:Molecular variant of the human paraoxonase/arylesterase gene is associated with central retinal vein occlusion in the Japanese population. 967 15

Human serum paraoxonase (PON1) is located on high density lipoprotein and has been implicated in the detoxification of organophosphates and possibly in the prevention of low density lipoprotein lipid peroxidation. PON1 has two genetic polymorphisms both due to amino acid substitution, one involving glutamine (A genotype) and arginine (B genotype) at position 192 and the other leucine (L genotype) and methionine (M genotype) at position 55. We investigated the effect of these polymorphisms on serum PON1 activity and concentration in 252 non-insulin dependent diabetes mellitus (NIDDM) individuals and 282 non-diabetic controls. Serum PON1 activity in the controls (214.6 nmol/min per ml (26.3-620.8)) was significantly higher than in NIDDM (158.7 nmol/min per ml (3.6-550.5) (P < 0.001) as was serum PON1 concentration (89.1 microg/ml (16.8-527.4)) compared to 76.7 microg/ml (3.6-443.8) (P < 0.01). In the control population MM homozygotes had significantly lower serum PON1 activity regardless of the 192 polymorphism whereas in NIDDM both LM and MM genotypes had lower serum PON1 activity than LL homozygotes only when the 192 AA genotype was present. Serum PON1 concentration was lower in NIDDM with AA/LM, AA/LL, AB/LL and AB/MM genotypes than in controls. Differences in PON1 activity were the major cause of differences in specific activity between genotypes. Neither the PON1 55 or 192 polymorphisms consistently influenced the serum lipid or lipoprotein concentrations in either population. Low serum PON1 activity in NIDDM may be related to an increased tendency to lipid peroxidation and may also increase susceptibility to toxicity from organophosphate exposure. Our findings thus raise the possibility that PON1 may be of importance in both the genetic and acquired predisposition to premature atherosclerosis and neuropathy in diabetes.
Atherosclerosis 1998 Aug
PMID:Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus. 971 41

Paraoxonase is an HDL-associated enzyme implicated in the pathogenesis of atherosclerosis by protecting lipoproteins against peroxidation. Its biallelic gene polymorphism at codon 192 (glutamine/arginine) has been associated with coronary artery disease (CAD). To further evaluate the role of this paraoxonase gene polymorphism for CAD in type 2 diabetes, we determined the paraoxonase genotype in 288 type 2 diabetic patients (170 with and 118 without angiographically documented CAD). The paraoxonase 192 Gln/Arg genotype was assessed using polymerase chain reaction followed by AlwI digestion. The frequency of the Gln allele was 0.656 in the CAD patients and 0.746 in the controls (chi2 = 5.36, P = 0.02). Compared with the Gln/Gln genotypes, the age-adjusted odds ratio for CAD was 1.78 (95% CI 1.08-2.96, P = 0.02) in subjects carrying at least one Arg allele. In the multivariate analysis, this association was even stronger after correction for the possible confounders age, sex, smoking history, and hypertension. Among current and former smokers, the odds ratio (OR) for having CAD among patients with at least one Arg allele was 3.58 (1.45-9.53, P < 0.01). The paraoxonase Arg allele was not associated with the history of myocardial infarction (OR 1.20 [0.73-1.99, NS]), but was with the extent of CAD (OR for three-vessel disease 1.92 [1.15-3.27, P = 0.01]). Our data indicate that the 192 Arg allele of the human paraoxonase gene is a risk factor for CAD but not myocardial infarction in type 2 diabetic patients, a risk factor further modified by cigarette smoking. This risk could possibly be explained by a reduced ability of the paraoxonase Arg isoform to protect lipoproteins against peroxidation.
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PMID:Paraoxonase 192 Gln/Arg gene polymorphism, coronary artery disease, and myocardial infarction in type 2 diabetes. 1007 66

Human serum paraoxonase (PON) is a high density lipoprotein (HDL) associated enzyme capable of hydrolyzing lipid peroxides in vitro. PON has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two frequent mutations at the paraoxonase gene locus (PON1) are the leucine (L allele)-->methionine (M allele) and the glutamine (Q allele)-->arginine (R allele) substitutions at residues 55 and 192, respectively. We have examined the influence of these two polymorphisms on carotid atherosclerosis in familial hypercholesterolemia (FH) patients. The allele frequencies of these two polymorphisms were determined by PCR and restriction fragment analysis, for both the FH population and healthy controls. High resolution B-mode ultrasound was used to assess intima-media wall thickness (IMT) of the carotid artery. No differences were found in allele frequencies between the FH and the control population. In FH patients, the LL, LM and MM genotypes at position 55 occurred in 86 (46.0%), 78 (41.7%) and 23 (12.3%) subjects, respectively, whereas the QQ, QR and RR genotypes at position 192 were found in 90 (48.1%), 79 (42.2%) and 18 (9.6%) individuals. When both polymorphisms were considered separately, no different carotid IMTs were found between the genotype groups. However, our data did show a significant association between the various genotypes of the combined polymorphisms at position 55 and 192 of PON1 and the carotid artery IMT in FH subjects. Subjects with the homozygous wildtype LL/QQ for paraoxonase had the highest mean carotid IMTs when compared to other genotypes, combined. Multiple regression analysis demonstrated age (beta=0.34, P<0.0001), total plasma cholesterol (beta=0.17, P=0. 0109) and the LL/QQ genotype of the PON1 gene (beta=0.22, P=0.0018) to be significant risk factors for carotid atherosclerosis in subjects with FH. The LL/QQ genotype could explain 5.3% of total variance of carotid IMT. In conclusion, this is the first study to report an independent association between the combined PON1 polymorphism genotypes and carotid wall thickness. The homozygous wildtype LL/QQ for PON1 may represent an additional risk factor for carotid atherosclerosis in subjects with FH.
Atherosclerosis 2000 Apr
PMID:Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia. 1072 87


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