Genetic variation in serum low density lipoproteins and lipid levels in man.

Berg, Kåre; Hames, Curtis G.; Dahlén, G.; Frick, M. H.; I, Krishan

doi:10.1073/pnas.73.3.937

Cited by 67 publications

(30 citation statements)

References 8 publications

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“…A high degree of genetic polymorphism in human LDL has been recognized since 1976, when it was established that allotypic antibodies in the serum of multiply transfused patients are capable of distinguishing allelic variants of LDL (20). These allotypic variants have been shown to be closely linked to DNA polymorphisms in the apoB gene (21).…”

Section: Discussionmentioning

confidence: 99%

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.

Soria

Ludwig

Clarke

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

527

215

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Familial defective apolipoprotein (apo) B-100 is a genetic disease that leads to hypercholesterolemia and to an increased serum concentration of low density lipoproteins that bind defectively to the apoB,E(LDL) receptor. The disorder appears to result from a mutation in the gene for apoB-100. Extensive sequence analysis of the two alleles of one subject heterozygous for the disorder has revealed a previously unreported mutation in the codon for amino acid 3500 that results in the substitution of glutamine for arginine. This same mutant allele occurs in six other, unrelated subjects and in eight affected relatives in two of these families. A partial haplotype of this mutant apoB-100 allele was constructed by sequence analysis and restriction enzyme digestion at positions where variations in the apoB-100 are known to occur. This haplotype is the same in three probands and four affected members of one family and lacks a polymorphic Xba I site whose presence has been correlated with high cholesterol levels. Thus, it appears that the mutation in the codon for amino acid 3500 (CGG----CAG), a CG mutational "hot spot," defines a minor apoB-100 allele associated with defective low density lipoproteins and hypercholesterolemia.

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Section: Discussionmentioning

confidence: 99%

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.

Soria

Ludwig

Clarke

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

527

215

View full text Add to dashboard Cite

show abstract

“…In this table, X2 indicates the presence of the cutting site throughout *Lipid measurements in non-fasting subjects, tAg(y) is associated with high cholesterol and triglyceride. 31 ^Associated with coronary artery disease and peripheral arterial disease (carotids, extremities). §R2 is associated with high very low density lipoproteln B in patient group.…”

mentioning

confidence: 99%

Association of DNA polymorphism at the apolipoprotein B gene locus with coronary heart disease and serum very low density lipoprotein levels.

et al. 1990

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The role of genetic variation at the 3' end of the apolipoprotein B gene locus In the development of coronary heart disease and the regulation of the serum levels of various lipoprotelns was studied by using two common restriction fragment length polymorphisms detected with the enzymes Xba I and EcoR I. A group of 106 male patients with coronary heart disease and 118 matched controls of Austrian origin were Investigated. The frequency of the R2 allele of the EcoR I polymorphism at cDNA position 12 669 defined by the absence of the polymorphic EcoR I cutting site was significantly higher among patients than among controls. The controls with the R2 allele had significantly higher levels of total triglycerides, very low density lipoprotein (VLDL) triglycerides, and VLDL cholesterol than did the controls without this allele. Among the patients, the R2 allele was associated with higher serum VLDL apolipoprotein B levels. The chemical composition of VLDL In Individuals with different genotypes for the EcoR I polymorphism did not differ significantly. For the Xba I polymorphism at cDNA position 7673, no correlation with coronary risk could be demonstrated. Patients and controls homozygous for the X2 allele characterized by the presence of the polymorphic Xba I cutting site showed a higher total and low density lipoprotein cholesterol level than did subjects with the genotype X1X1 or X1X2. This difference, however, was not statistically significant. These findings Indicate that the R2 allele of the EcoR I polymorphism Is associated with the occurrence of coronary heart disease and that variation at the 3' end of the apo B gene Is Involved In the regulation of VLDL metabolism.

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“…This is of particular interest because of a likely association of Ag(x-) with increased serum triglyceride and cholesterol levels. 10 Moreover, an association between the Xbal polymorphism and altered plasma cholesterol and triglyceride levels has been found in an independent study: "Subjects homozygous and heterozygous for the presence of an Xbal restriction site had mean serum triglyceride levels 36% higher (p = 0.02) than those in homozygotes without the restriction site; there was a less substantial difference (p = 0.03) in serum cholesterol." 11 In this regard, a similar calculation was performed.…”

Section: Discussionmentioning

confidence: 99%

Two DNA restriction fragment length polymorphisms associated with Ag(t/z) and Ag(g/c) antigenic sites of human apolipoprotein B.

H¹,

Schumaker²,

Bütler³

et al. 1987

Arteriosclerosis

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Several high frequency restriction fragment length polymorphisms (RFLPs) associated with the human gene for apolipoprotein B have been previously reported by Priestly et al. 1 The EcoRI RFLP here was shown to be very strongly associated with the Ag(t/z) Immunochemlcal polymorphism of human low density llpoprotelns, allowing correct Ag(t/z) phenotyplng of 17 (out of 17 tested) unrelated individuals. The Xbal RFLP was associated with the Ag(g/c) Immunochemlcal polymorphism, permitting correct phenotyplng of 14 (out of 17 tested) unrelated Individuals. Its close association with an RFLP permitted localization of the Ag(t/z) polymorphism to the C-termlnal end of the apolipoprotein B peptlde, and allowed detailed discussion of Its probable molecular basis. (Arteriosclerosis 7:301-305, May/June 1987) B ecause of the central role played by apolipoprotein B (apo B) in the transport of lipids, and especially of cholesterol in low density lipoprotein (LDL), it is possible that a genetic variation in apo B could help explain why some individuals are susceptible to atherosclerosis. Apo B has been cloned, and its entire amino acid sequence has been determined.2 ' 3 This achievement permits the reexamination of previously identified genetic variations at the level of nucleotide sequence.Phenotypic expression of genetic variation in LDL has been studied extensively using antisera against allelic variants of the donors' LDL developed in the sera of multiply transfused patients. Population and family studies have confirmed that these immunochemical polymorphisms are inherited in an autosomal codominant mode, implicating the amino acid sequence variation in a protein component of LDL. The data were analyzed and summarized 4 to indicate the existence of five distinct sites of immunochemical polymorphism: Ag(a1/d), Ag(x/y), Ag(t/z), Ag(g/c), and Ag(h/i). The order of the corresponding five loci along the chromosome remains unknown. (In the terminology employed, 'Ag' means 'antigen group', and 'a1/d' are the two alternate forms of an epitope present at the first-mentioned site; 'x/y' are the two alternate epitopes at the second mentioned site, etc.) Phenotypically, individuals may be Received October 13, 1986; revision accepted January 28, 1987. homozygous or heterozygous at each of these five sites; thus, at the first site, an individual might be a1 ,a1 or d,d or a1 ,d. Therefore, 3 5 = 243 possible human Ag phenotypes exist, of which 44 have been identified. 4A monoclonal antibody against apo B which also recognizes the Ag(g/c) epitope and binds 40 times more tightly to LDL from Ag(c,c) individuals than to LDL from Ag(g,g) individuals has been developed. The existence of this antibody identified the gene for apo B as the general locus for the Ag system; possibly all of the five Ag epitopic pairs represent one or the other of two alternative amino acids at five distinct locations on the polypeptide for this apolipoprotein. 5In this communication, we demonstrate that two previously identified restriction fragment length polymorp...

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Genetic variation in serum low density lipoproteins and lipid levels in man.

Cited by 67 publications

References 8 publications

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.

Association of DNA polymorphism at the apolipoprotein B gene locus with coronary heart disease and serum very low density lipoprotein levels.

Two DNA restriction fragment length polymorphisms associated with Ag(t/z) and Ag(g/c) antigenic sites of human apolipoprotein B.

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