Genetic polymorphisms related to glucose and triglyceride intolerance.
Explore the source record for details and available documents.
Biomedical subjects
Publications and source records attributed to J Stocks.
Explore the source record for details and available documents.
The allelic frequency of five different restriction fragment length polymorphisms (RFLPs) in the A-1, C-III, A-IV gene region has been determined in Caucasians, Negroes, Indian Asians, and Japanese. The polymorphic sites are with Taq-1 at the 5' end of the A-1 gene, with Msp-1 in the third intron of the A-1 gene, with Pst-1 in the intergenic sequence between the A-1 and C-III genes, with Sst-1 in the 3' non-coding region of the C-III gene, and with Pvu-II in the third intron of the C-III gene. The alleles identified by three of the RFLPs showed large differences in frequency amongst the races, especially between Caucasians and non-Caucasians. Alleles of the Msp-1 polymorphism and Sst-1 polymorphism, which were rare in Caucasians (frequencies 0.03 and 0.01), were more common in Japanese (frequencies 0.37 and 0.35), Indian Asians (frequencies 0.37 and 0.26), and Negroes (frequencies 0.31 and 0.31). In contrast with a Pvu-II polymorphism one allele was rare in Japanese and in Indian Asians (frequency 0.01) but more common in Caucasians (frequency 0.11). Linkage disequilibrium was evident between some of the alleles and a total of seven haplotypes were identified among the different races.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
A polymorphism of the apolipoprotein AII gene (on chromosome 1) was investigated using genomic hybridisation analysis. The two common alleles at this locus were defined by MspI restriction fragments of 3.0 kilobase pairs (M3.0) and 3.7 kilobase pairs (M3.7) respectively. The M3.7 allele was significantly more common (P less than 0.02) in Caucasian subjects who were normo-lipaemic (34%, 20/59) than in those who were hypertriglyceridaemic (16%, 16/98). Serum triglyceride levels were measured in 126 Caucasian subjects with different combinations of disease-associated alleles at the ApoAII and ApoCIII gene loci. Mean serum triglyceride levels were found to be significantly higher (P less than 0.05) in subjects with disease-associated alleles of both the ApoCIII and ApoAII genes, compared with subjects with a disease-associated allele of one or neither locus.
A Japanese group comprising 40 hypertriglyceridaemic and 35 normolipidaemic subjects were genotyped for two intragenic DNA restriction fragment length polymorphisms (RFLPs) at the A-1 and C-III gene loci. An Sst-1 polymorphism is located at the 3' end of the C-III gene and a Msp-1 polymorphism in the third intron of the A-1 gene. The polymorphic restriction sites are 3.8kb apart. The polymorphism with Sst-1 was present at allelic frequencies of 0.67 (S1 allele) and 0.33 (S2 allele), and the polymorphism with Msp-1 was present at allelic frequencies of 0.55 (M1 allele) and 0.45 (M2 allele). The alleles S1, S2, M1, and M2 are in linkage disequilibrium and three haplotypes were identified S1-M1, S1-M2, and S2-M2. Unlike the previously reported association of the S2 allele with hypertriglyceridaemia found in Caucasians there was no difference in the frequency of S2 allele between normolipidaemic and hyperlipidaemic Japanese. However one of the haplotypes S1-M2 was significantly increased in the hypertriglyceridaemic subjects (32% versus 11% P less than 0.025). Thus in Japanese there is an association with genotypes at this locus and hypertriglyceridaemia but with a different haplotype than in Caucasians.
The relationship between plasma HDL-cholesterol subfractions (HDL2 and HDL3), measured using a differential precipitation method, and serum triglycerides, was studied in 402 healthy Caucasian males attending a health screening centre in London. Mean values for HDL2 and HDL3 were 0.42 +/- 0.24 mmol/L and 0.81 +/- 0.15 mmol/L respectively. HDL2 was found to show a stronger negative correlation with serum triglyceride and a stronger positive correlation with total HDL than HDL3. HDL2 also showed a stronger correlation with age than either total HDL or HDL3. Mean levels of HDL2 were 20% higher in subjects over 55 years of age compared with those who were less than 55 years of age. Reference values of HDL2 and HDL3 are presented for different age ranges.
Genetic polymorphisms of apolipoprotein C-III (apo C-III) and insulin were studied in 48 Caucasian post-myocardial infarction patients. 10 patients (21%) had an uncommon allelic variant of the apo A-I/C-III gene cluster (on the long arm of chromosome 11); in 47 control subjects this variant was present in only 2 and in none of those who were normotriglyceridaemic. Distribution of genotypes between post-infarct and normotriglyceridaemic control groups was significantly different and the difference persisted when the normotriglyceridaemic subgroups of these patients were compared. In contrast, there was no difference in distribution of alleles at the highly polymorphic locus on the short arm of chromosome 11 adjacent to the insulin gene.
Three human volunteers were injected with a range of doses of pentosan polysulphate, SP54, i.v. or s.c. A competitive binding assay (CBA) for sulphated polysaccharides was used to detect circulating SP54 after doses as low as 1 mg i.v. and a linear relationship was observed between the peak plasma concentration of SP54 measured by CBA and the administered dose. A comparison was made between the clearance of SP54 measured by CBA and its anticoagulant and lipolytic activities. SP54 was detectable by CBA after doses which caused no alteration in activated partial thromboplastin time (APTT) or anti-factor Xa activity but after which a small increase of lipase activity was measurable. After SP54 at 10 mg i.v. or 100 mg s.c. anti-factor Xa activity was 4-6 times greater than would be expected from the in vitro activity of the concentrations of SP54 measured by CBA. Like heparin and other heparin analogues, SP54 caused an increase in plasma concentrations of platelet factor 4 (PF4) without a concomitant rise in beta-thromboglobulin (beta-TG). It is concluded that the newly developed CBA will provide a more sensitive means than conventional bioassays for the determination of plasma concentrations of SP54.
Two alleles identified by DNA restriction fragment length polymorphisms around the apo A-1/C-III and insulin genes have been shown to be associated with Type IV and V hyperlipidaemia. We have genotyped 19 patients with Type III hyperlipidaemia to establish whether this association is also found in the disorder. Our data show that these associations are not responsible for the majority of cases of Type III hyperlipidaemia, but cannot exclude the possibility that a small proportion (less than 50%) of cases of Type III are caused by interaction between these alleles and the apolipoprotein E2 phenotype.
A total of 167 patients undergoing investigation for suspected coronary artery disease (CAD) were genotyped for restriction fragment length polymorphisms (RFLP) at the apo A-1/C-III locus and the insulin gene locus using cloned human apo A-1 and insulin gene probes. The study group was subdivided into patients with absent or minimal CAD, intermediate CAD and severe obstructive CAD. An Sst-1 polymorphism located in the 3' non-coding region of the apo C-III gene identifies two alleles. One of the alleles (S2) showed a significantly increased frequency in the subjects with severe obstructive CAD (18%) compared with patients with minimal or absent CAD (6%) (P less than 0.025) and normolipidaemic control subjects. This A-1/C-III polymorphism may be a marker for an abnormality in the A-1/C-III genes predisposing to atherosclerosis. In contrast to a previous report, we found no increase in the frequency of the Class 3 insulin alleles in subjects with severe CAD.
Explore the source record for details and available documents.
A DNA sequence polymorphism, revealed by digestion of human DNA with the restriction endonuclease Sst-1 and hybridization with an apolipoprotein A-I complementary DNA clone, has been shown to be located in or close to the 3' noncoding region of the apolipoprotein C-III gene. This polymorphism is found in significantly increased prevalence (P less than 0.001) in Caucasian hypertriglyceridemic subjects compared with race-matched controls, and its distribution in normal individuals of differing racial origins is reported. Furthermore, no alteration of high density lipoprotein or apolipoprotein A-I and apolipoprotein C-III phenotypes was observed in individuals with or without the polymorphism.
We have evaluated a simple dextran sulphate precipitation method for measuring high density lipoprotein cholesterol (HDL) subfractions and have used this method to measure plasma HDL2 and HDL3 in a group of 28 patients with primary gout. These patients were found to have significantly lower levels of plasma HDL and HDL2 than a group of healthy controls, matched for age and sex and of similar body mass index (BMI); no significant difference in mean levels of the HDL3 subfraction was found however. We have confirmed the high prevalence of hypertriglyceridaemia in subjects with gout compared to controls and the mean serum triglyceride levels were significantly higher (P less than 0.01) in the gout group than in controls. We have also shown that subjects with high serum triglyceride levels tend to have low plasma HDL2 concentrations, a finding which is consistent with an inverse relationship between these two parameters. These lipid abnormalities may partly explain the high prevalence of premature atherosclerosis in patients with primary gout.
Explore the source record for details and available documents.
Two gene specific probes have been used to identify polymorphic DNA loci on chromosome 11 close to the insulin and apoprotein A-1 genes in a genetic analysis of hypertriglyceridaemic patients with and without co-existing diabetes. Of the 45 patients studied with both probes, 15 were diabetic of whom nine possessed class 3/3 insulin polymorphism genotypes, compared with none in the non-diabetic group (p less than 0.001; chi 2 test). In contrast, an uncommon apolipoprotein A-1 polymorphism was found to be equally distributed in the diabetic and the non-diabetic patients. No co-segregation of these two particular genetic polymorphisms was found in either patient group. The differing associations of the two disease-related polymorphism genotypes in patients with hypertriglyceridaemia with or without co-existing diabetes may possibly reflect differing aetiologies of the hyperlipidaemia.
Restriction enzyme analysis of the apolipoprotein A-I (apo A-I) gene was performed in two patients with fish eye disease and one with Tangier disease. Despite the marked deficiency of high density lipoprotein and concomitantly of apo A-I in these two conditions, no evidence was found for major deletions or insertions in the apo A-I gene.