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A Spanish Merino sheep population is characterized, for the first time, according to its frequencies for a total of nine polymorphic loci: three blood group factor systems, A, B and C, and the following red cell or serum polymorphisms: haemoglobin (Hb), carbonic anhydrase (CA), 'X protein', transferrin (Tf), arylesterase (EsA) and albumin (Al). Another locus, amylase (Am), did not show polymorphism.
In the musk shrew (Suncus murinus), the electrophoretic bands in the post-albumin region were identified as vitamin D binding protein (Gc) by the [3H] vitamin D3 binding method. Three Gc phenotypes were distinguished from each other: a single faster band (Gc-A), a single slower band (Gc-B) and the double bands (Gc-AB). Results of mating experiments indicated that the Gc-A and Gc-B are controlled by two codominant alleles, Gca and Gcb at an autosomal locus (Gc), respectively. It was noticed that, in the Gc-AB phenotypes, the Gc-B band was constantly more intense than the Gc-A band in the protein staining. The same tendency was also observed between the homozygous Gc-A and Gc-B bands, and further, radioactivity of the Gc-B bound with [3H] vitamin D3 was about twofold higher than that of the Gc-A. These results suggest that the Gcb yields its protein product twofold more than the Gca. No cross-reaction between the shrew proteins and a rabbit anti-human Gc protein was observed.
The oxidation of mephenytoin was polymorphic in 358 healthy Danish volunteers. The ratio between the chromatographic peak areas of (S)- and (R)-mephenytoin (S/R) in 12 h urine was less than or equal to 0.48 in 349 extensive metabolizers (EM) and greater than or equal to 1 in 9 (2.5%) poor metabolizers (PM). Concomitant intake of mephenytoin and sparteine and subsequent assay by gas chromatography had no influence on the test results (mephenytoin S/R ratio or sparteine metabolic ratio). Among ten parents and seven siblings to six unrelated PM of mephenytoin only one (1/17 = 5.9%) was a PM. The pedigrees were compatible with an autosomal recessive mode of inheritance.
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A mephenytoin test was carried out in 106 unrelated healthy Turkish volunteers. Racemic mephenytoin was coadministered with either debrisoquine or sparteine. The S/R mephenytoin ratio ranged from < 0.1 to 0.73 in 105 subjects, accordingly phenotyped as extensive metabolisers. One subject had an S/R mephenytoin ratio of 1.02, showing that he was a poor metaboliser of mephenytoin (0.94%, confidence interval 0.25% and 13.65%). In 48 subjects, the metabolic ratios of debrisoquine and sparteine were correlated significantly (rs = 0.61, P < 0.001).
AIMS: Polymorphisms of the NOSIII gene and of the CYBA gene have been associated with a number of pathological conditions such as arterial hypertension, coronary artery disease, and myocardial infarction. Because endothelium-dependent vasodilation is impaired in these disorders, we hypothesized that polymorphisms of NOSIII or CYBA might modulate endothelial function of venous capacitance vessels already before cardiovascular disease becomes overt. METHODS: Endothelium-dependent and -independent venodilation was assessed by measuring local vascular responses to bradykinin and sodium nitroprusside in the dorsal hand vein after preconstriction with phenylephrine in 72 healthy male Caucasians after careful exclusion of cardiovascular risk factors. Genotyping was performed for polymorphisms of the NOSIII gene (T-786C, G894T, (CA)(n)) and the CYBA gene (C242T). RESULTS: Genotype distribution for each polymorphism followed the Hardy-Weinberg equilibrium. In all studied single nucleotide polymorphisms no significant difference between the respective genotypes and the venodilator response to either sodium nitroprusside or bradykinin was observed, and the number of CA repeat copies was not related to the venodilator response to bradykinin. Mean venodilation induced by bradykinin 50 ng min(-1) (+/-SEM) for homozygote carriers of the single nucleotide polymorphisms was 48.9 +/- 8.5% venodilation (G894T; wild type: 49.8 +/- 6.9), 50.3 +/- 11.0% venodilation (T-786C; wild type: 42.6 +/- 5.2), and 30.4 +/- 9.1% venodilation (C242T; wild type: 49.2 +/- 6.0), respectively. CONCLUSIONS: This study suggests that the studied polymorphisms of NOSIII and CYBA do not significantly modulate endothelium-dependent venodilation in individuals without vascular risk factors.
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BACKGROUND AND OBJECTIVE: CYP2D6 polymorphisms are well described in normal populations but there are few data on its clinical significance. We therefore investigated the influence of CYP2D6 polymorphism on steady-state plasma concentrations and apparent oral clearance of metoprolol in patients with cardiovascular diseases. METHODS: Ninety-one patients on metoprolol were recruited. Plasma concentrations of metoprolol and alpha-hydroxy metoprolol were measured at 4-h post-dose. CYP2D6 genotyping (*1, *3, *4, *5, *9, *8, *10, *17 and duplication) were performed on the DNA extracted. Ratio of plasma concentrations of metoprolol and alpha-hydroxy metoprolol and the apparent oral clearance of metoprolol were calculated. The influences of CYP2D6 genotypes were investigated. RESULTS: A 100-fold variation was noted for both plasma concentrations of metoprolol and alpha-hydroxy metoprolol. There was a weak correlation between the total daily doses and plasma concentrations of both. Plasma concentrations were found to be higher in patients with genotypes that predicted lower enzyme activity. One patient homozygous for CYP2D6*4 had the highest metoprolol concentration per unit dose. With an antimode of 10. Two patients were identified as poor metabolizers (PMs) (2.1%; 95% CI: 2.9). The PMs who had a plasma metabolic ratio (pMR) of 37.8 was homozygous CYP2D6*4 whereas the other with pMR 14.5 was genotyped CYP2D6 *4/*10. There was a 36-fold difference between the highest and lowest clearance values. Large overlaps in the clearance values were noted between most of the genotypes. CONCLUSIONS: Our data suggest that pharmacogenetic measures could be used to design a more individualized metoprolol dosage regimen for patients.
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The XbaI, EcoRI and the signal peptide insertion/deletion (I/D) polymorphic sites of APOB gene, the CfoI polymorphic site of apolipoprotein E gene (APOE), and the insertion/deletion polymorphism of angiotensin I-converting enzyme (ACE) gene were studied using polymerase chain reaction (PCR) in 55 postmenopausal women with coronary artery disease (CAD) and in 119 control women of equivalent age. Patients and controls were recruited from the population of Rome, considered representative of Central and Southern Italy. There were no significant differences in allele frequencies between the two groups, though APOB X-, R- and I, APOE*3, and ACE D alleles were slightly more frequent in the cases than in the controls. The patients did not differ from the controls for plasma total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, and apoAI values, while they presented significantly higher levels of triglycerides and apoB, and lower apoE levels. TC, apoE, and apoB quantitative values, adjusted for age, varied significantly among APOB XbaI and APOE genotypes. APOB X-X- genotype was associated in patients with a significantly lower mean TC concentration than the other two genotypes pooled together. APOE 3-2 genotype in the controls had significantly lower TC levels with respect to the other two pooled genotypic classes and higher apoE levels compared to 3-3 and 4-3 genotypes. In the patients, 3-2 genotype had significantly lower apoB levels than the pooled 3-3 and 4-3 class. We conclude that in the Italian women the DNA polymorphisms studied in this work do not seem to be important risk factors for CAD occurrence; that apoE quantitation could be another useful parameter to identify subjects at risk of CAD; and that APOB X- and APOE*2 are the alleles that most influence the interindividual plasma lipid variation among CAD female patients.
Plasma samples from 129 dogs have been typed using an immunofixation technique to define the polymorphism of canine C4. The mode of inheritance was inferred by study of four large pedigrees. In contrast to the situation in man, canine C4 may be encoded by a single locus. At least five different co-dominant structural alleles have been detected. A deficiency allele has not been found as yet. Because there are associations between C4 allotypes and spontaneous autoimmune disease in man, the well defined polymorphism of canine C4 may provide an excellent model for understanding of the pathogenetic mechanisms of autoimmune disease.
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A modified electrophoretic system for the determination of C4 polymorphism has been found with which the new allotype F1 could be detected. The system has been applied to the population distribution of C4 in 266 unrelated Germans, further to association and linkage studies. Gene frequency was 0.3985 for C4F, 0.5526 for C4S and 0.0489 for the rare C4 genes. In the population sample, significant association between Bf and C4 but no indication for close association between C4 and GLO I has been found. In the families HLA, Bf and C4 segregated together.
1. We examined common polymorphisms in the genes encoding the LDL receptor, lipoprotein lipase, apoAI, apoB, apoAIV and cholesteryl ester transfer protein and related them to changes in LDL and HDL cholesterol after high fat/high cholesterol diets. 2. The only significant association was seen with the apoIV polymorphism, which leads to a structural change in the protein. The response to fat and cholesterol in subjects with at least one apoAIV 2 allele was only 30% of that seen in subjects with the common apoIV 1 allele (P < 0.01), accounting for 6-7% of the variance in response. This confirms the results of two previous studies in which dietary cholesterol intake was changed. 3. No association were seen with polymorphisms of the other five genes examined.
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HDL cholesterol and apolipoprotein A-I are associated with the development of coronary artery disease (CAD). The presence of a PstI site polymorphism adjacent to the gene encoding apo A-I (known as P2) has also been shown to be associated with CAD but this relationship is controversial. A case control study was conducted in an Australian population to re-examine whether the rare P2 allele is associated with CAD. Data were derived from 159 cases of angiographically confirmed CAD and 99 healthy controls. The proportion of CAD cases carrying the P2 allele did not differ significantly from controls (11% versus 9%). In a multiple logistic regression model controlling for the effects of age, country of birth, hypertension and hypotensive drugs, body mass index and lipid variables, the P2 allele failed to predict significantly the presence of CAD (odds ratio 1.83; 95% confidence interval 0.65-5.19).
AIMS: We examined whether the common polymorphisms of the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene are associated with Type 2 diabetes or obesity in the Korean population. METHODS: We genotyped two common PPARgamma polymorphisms (Pro12Ala and 161C > T) and examined their association with the clinical phenotypes found in 684 patients with Type 2 diabetes mellitus and 291 non-diabetic control subjects. RESULTS: The 12Ala allele was less frequent in the Type 2 diabetic patients than in the non-diabetic control subjects (0.036 vs. 0.053, P = 0.024). The allele frequencies of the 161C > T polymorphism did not differ between the control and Type 2 diabetic group (0.158 vs. 0.173). In the non-diabetic controls, those with the T allele had lower BMI and fasting serum triglyceride (TG) concentrations than those with the C/C homozygote (22.7 +/- 2.9 vs. 23.8 +/- 3.2 kg/m2, P = 0.002; 1.45 +/- 0.81 vs. 1.65 +/- 0.83 mmol/l, P = 0.03, respectively). The 12Ala-161T haplotype was associated with a decreased risk for Type 2 diabetes (OR = 0.47, P = 0.009), whereas the 12Pro-161T haplotype was associated with lower BMI and lower fasting serum TG (22.5 +/- 2.8 vs. 23.7 +/- 3.2 kg/m2, P = 0.004; 1.41 +/- 0.87 vs. 1.64 +/- 0.79 mmol/l, P = 0.02, respectively). CONCLUSIONS: The PPARgamma 12Ala allele was associated with a reduced risk of Type 2 diabetes, whereas the PPARgamma 161T allele was associated with lower BMI and fasting serum TG concentrations in the Korean subjects. The subjects with 12Ala-161T haplotypes had a reduced risk of Type 2 diabetes.
1. A method has been devised for the detection after starch-gel electrophoresis of phosphoglycolate phosphatase (PGP) isozymes. 2. PGP isozymes can be detected in all human tissues including red cells, lymphocytes and cultured fibroblasts. The highest activities occur in skeletal muscle and cardiac muscle. 3. PGP is a relatively specific phosphatase which shows enhanced activity in the presence of mercaptoethanol at a neutral pH.4. Six different commonly occurring electrophoretic types of PGP have been identified. Family studies indicate that they are determined by three alleles at an autosomal locus (PGP). 5. The gene frequencies of PGP1, PGP2 and PGP3 in a random sample of Europeans were 0.826, 0.129 and 0.045 respectively. 6. The three-banded isozyme patterns seen in heterozygotes suggest that PGP is a dimeric enzyme.