Restriction-fragment-length polymorphisms in the A-I-C-III gene complex occurring in a family with hypoalphalipoproteinemia

doi:10.1016/0021-9150(86)90022-5

Atherosclerosis

Volume 62, Issue 1, October 1986, Pages 81-87

https://doi.org/10.1016/0021-9150(86)90022-5 Get rights and content

Abstract

Two restriction-fragment-length polymorphisms in the apolipoprotein A-I-C-III gene complex were defined by digestion with PstI and SacI in a family with hypoalphalipoproteinemia. These polymorphisms established a PstI + /SacI - haplotype which may constitute a linkage marker for this condition within the family.

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Cited by (19)

Influence of polymorphism (RFLP-sstI) at the apolipoprotein C-III gene locus on the lipoprotein metabolism and insulin resistance in essential hypertensive patients. Interaction between gender and genetic polymorphism
2003, Nutrition, Metabolism and Cardiovascular Diseases
Abstract
With respect to the general population, hypertensive patients show an increase in plasma total cholesterol and triglycerides, a decrease in HDL-cholesterol (HDLc) and a higher degree of insulin resistance. Apolipoprotein C-III (apo C-III) plays a regulatory role in the catabolism of triacylglycerol-rich lipoproteins. The S2 allele has been associated with elevated plasma triglycerides concentration, blood pressure and increased risk of myocardial infarction, all of which are characteristic of an insulin resistant state. The aim of this study was to investigate the SstI polymorphism of the apo C-III gene locus on the lipoprotein metabolism, apolipoproteins and basal glucose and insulin levels in essential hypertensive patients. We also examined the influence of the S1S2 allele on blood pressure and the interaction of the mutation at the apo C-III gene and the gender.
We studied 104 essential hypertensive patients (59 males and 45 females) determining the carriers of the S2 allele of the genetic polymorphism in the apo C-III gene by polymerase chain reaction, lipoprotein metabolism by standard laboratory methods and ultracentrifugation, apolipoproteins A-I and B by immunoturbidimetry and basal glucose and insulin levels by enzymatic method and radioimmunoassay, respectively.
The frequency for the carriers of the SstI minor allele S2 (S1S2 genotype) was 0.17. Patients with the rare S2 allele compared with those with S1S1 allele showed higher plasma triglycerides, total cholesterol and apo B (255.9±114.6 vs 135.8±89.1; 250.6±56.6 vs 214.8±47.9 and 128.7±34.8 vs 103.1±28.6 respectively). Furthermore, basal glucose, insulin levels in S2 allele, and the rate Tg-VLDL/HDLc were increased in the same group. Subgroup analysis revealed that the association between these polymorphism and lipoprotein metabolism, apolipoprotein and basal glucose and insulin levels occurred predominantly in females. A study on the effect of the interaction between this mutation with gender revealed an additive effect on changes in total triglycerides levels. However age, blood pressure and body mass index were similar in both groups of patients (S1S1 and S1S2 genotypes).
These results provide evidence of interaction between gender and the SstI polymorphism of the apo C-III on lipoprotein metabolism and insulin resistance in essential hypertensive patients. However, the studied mutation does not contribute to blood pressure levels in essential hypertensive patients (crossover study).
Influence of the ssti polymorphism at the apolipoprotein C-III gene locus on the plasma low-density-lipoprotein-cholesterol response to dietary monounsaturated fat
1997, American Journal of Clinical Nutrition
The plasma lipid response to changes in dietary fat and cholesterol can vary between individuals. The SstI polymorphism, arising from a cytosine to guanosine substitution in the 3' untranslated region of the APOC3 gene distinguishes between two alleles--S1 and S2. The S2 allele has been associated with elevated plasma triacylglycerol, cholesterol, and apolipoprotein (apo) C-III concentrations. In 90 young men we examined the effect of the same mutation on the response of low-density-lipoprotein (LDL) cholesterol to dietary monounsaturated fat. The frequency for the S2 allele was 0.14. Subjects were fed a low-fat diet for 25 d, followed by a diet rich in monounsaturated fatty acid (22% MUFA, 38% total fat) for 28 d; lipoproteins were measured at the end of each diet. There were no significant differences in initial total cholesterol between subjects with the APOC3*S1/APOC3*S1 (S1/S1) and APOC3*S1/APOC3*S2 (S1/S2) genotypes. After consumption of the diet high in MUFA, significant increases in LDL cholesterol (0.13 mmol/L, P < 0.027) were noted in the S1/S1 subjects whereas a significant decrease was observed in the S1/S2 subjects (-0.18 mmol/L, P < 0.046). Significant genotypic effects were seen for diet-induced changes in LDL cholesterol (P < 0.00034), total cholesterol (P < 0.009), and apo B (P < 0.0014). A study of the effect of the interaction between this mutation with that present in position -76 of the APOA1 gene promoter region (G/A) revealed that both mutations had an additive effect on changes in total cholesterol, LDL cholesterol, and apo B induced by diets. Plasma LDL-cholesterol responsiveness to the diet may be explained, at least in part, by variation at the APOC3 gene locus.
The MspI restriction fragment length polymorphism 3′ to the apolipoprotein A-II gene: relationships with lipids, apolipoproteins, and premature coronary artery disease
1992, Atherosclerosis
In previous studies, a restriction fragment length polymorphism (RFLP) has been identified using MspI restriction endonuclease in the 3′ region of the apo A-II gene. The rare variant site for this MspI (M2) has been reported to be associated with higher levels of HDL cholesterol and apo A-II. We have studied the frequency and lipid associations of this RFLP in a population of 168 coronary artery disease (CAD) male and female patients, who had more than 50% narrowing of one or more arteries prior to age 60 years, as well as 255 aged-matched males and females from the Framingham Offspring Study. We also studied 31 kindreds in which the proband had premature CAD. The frequency of the M2 allele was higher in CAD cases (0.20) than in the controls (0.13) (P < 0.05). In general, those subjects carrying the M2 allele had lower HDL cholesterol and apo A-I plasma levels; however, this difference was only significant (P < 0.02 and 0.002, respectively) in females with CAD. No cosegregation of the M2 allele with hypoalphalipoproteinemia was found in 31 kindreds studied. However, in both generations there was a trend for those subjects carrying the M2 allele to have lower HDL cholesterol levels than those carrying the M1 allele. Sequence analysis of the apo A-II gene of subjects homozygous for either the M1 (n = 1) or the M2 allele (n = 2) revealed that this RFLP is due to a T→C single base mutation 528 by 3′ to the apo A-II gene. In the subjects homozygous for the M2 allele no other mutations were found within the coding region of the apo A-II gene that could result in changes in the primary sequence of the protein. These data indicate that the MspI RFLP 3′ to the apo A-II gene is somewhat more frequent in the CAD group. However, there was no significant association between this RFLP and any of the parameters examined. In conclusion, this DNA marker lacks the specificity to be clinically useful for CAD risk assessment in the population studied.
Variation at the apo AI/CIII/A1V gene complex is associated with elevated plasma levels of apo CIII
1991, Atherosclerosis
A number of studies have reported that a variant allele (S2) of the apo AI/CIII/AIV complex is associated with high plasma lipid levels in some populations and furthermore that the frequency of this allele is 2-5-fold higher in patient groups with premature coronary heart disease compared to control groups. This study shows in the healthy ”English“ population that the S2 allele is associated with elevated plasma apo CIII levels but not with low apo Al levels. In addition, it shows that the allele is associated with elevated plasma levels of apo B in men. Regression analysis shows in both men and women that apo CIII levels are positively correlated with plasma triglyceride levels and moreover that they are a stronger predictor of this parameter than apo Al, B or AIV. Apo CIII levels are also an independent predictor of total plasma cholesterol and HDL-cholesterol levels in males and females, respectively. Together these data suggest that a genetic predisposition to develop elevated plasma levels of apo CIII, alone or in combination with elevated plasma apo AIV levels, is the primary defect responsible for the association of the S2 allele with hyperlipidemia and/or premature CHD.
Restriction fragment length polymorphisms of the apolipoprotein A-I, C-III, A-IV gene locus Relationships with lipids, apolipoproteins, and premature coronary artery disease
1991, Atherosclerosis
Data from various laboratories have indicated associations of various alleles determined by RFLPs within or adjacent to several apolipoprotein genes with abnormalities in plasma lipids and/or premature coronary artery disease (CAD). In order to assess such relationships we have examined allele frequencies of 8 different RFLPs within or adjacent to the apo A-I, C-III and A-IV gene complex on the long arm of chromosome 11 (MspI, 5′ to the apo A-I gene; MspI, within the apo A-1 gene; PstI, 3′ to the apo A-I gene; SstI, 3′ to the apo C-III gene; PvuII, within the apo C-III gene; PvuII, 5′ to the apo C-III gene; XbaI, within the apo A-IV gene; and XbaI, 3′ to the apo A-IV gene) in 202 patients with CAD (50% narrowing of one or more coronary arteries) prior to age 60 and 145 normal controls. None of the allele frequencies of these RFLPs were significantly different in cases as compared to controls. With regard to associations with plasma lipids and apolipoprotein levels, the rare allele determined by the absence of the PstI site was associated with elevated triglyceride levels (P < 0.05) in cases, but not in controls. In contrast, the rare MspI allele 5′ to the apo A-I gene was associated with elevated triglyceride levels (P < 0.05) in controls but not in cases. In both cases and controls, subjects with the uncommon SstI allele had triglyceride levels that were 9 and 38% higher than in those without this allele. These differences were significant (P < 0.05) only in controls. Our data indicate that the rare allele determined by the SstI site within this gene complex deserves further study in order to understand its association with elevated triglycerides in Caucasian populations. However, at the present time all these DNA markers lack sufficient specificity to be clinically useful for CAD risk assessment.
Genetic linkage of the human apolipoprotein AI-CIII-AIV gene cluster and the neural cell adhesion molecule (NCAM) gene
1990, Genomics
The genes encoding apolipoproteins AI, CIII, and AIV, three plasma proteins involved in lipid metabolism, are clustered within a 15-kb DNA segment (apoAI-CIII-AIV gene cluster) located on human chromosome 11 at band q23. The gene encoding the neural cell adhesion molecule (NCAM), a cell surface glycoprotein involved in cell-cell recognition during morphogenesis, is also located on chromosome 11, band q23. In this report, 12 previously described restriction fragment length polymorphisms (RFLPs) in the apoAI-CIII-AIV gene cluster were tested for cosegregation with a newly identified BamHI RFLP in the NCAM gene using 13 families. The results show that the apoAI-CIII-AIV gene cluster and the NCAM gene loci are linked with a maximum lod score of 15.9 at a recombination fraction of 0.028. In addition, an approach for the most efficient use of the apoAI-CIII-AIV gene cluster polymorphisms, based on the evaluation of their individual and cumulative heterozygosities, is presented.

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Research paperRestriction-fragment-length polymorphisms in the A-I-C-III gene complex occurring in a family with hypoalphalipoproteinemia

Abstract

Lancet

Amer. J. Med.

Clin. Chim. Acta

Metabolism

Med. Clin. N. Amer.

Biochem. Biophys. Res. Commun.

J. Mol. Biol.

J. Mol. Biol.

J. Lipid Res.

Lancet

J. Lipid Res.

Biochim. Biophys. Acta

Research paper
Restriction-fragment-length polymorphisms in the A-I-C-III gene complex occurring in a family with hypoalphalipoproteinemia