Apolipoprotein B gene haplotypes. Association between Ag and DNA polymorphisms.

H, Y; Ladias, John A. A.; Bütler, R.; Schumaker, Verne N.; Antonarakis, SE; Lusis, Aldons J.; Heinzman, Camilla; Kwiterovich, Peter O.

doi:10.1161/01.atv.8.5.521

Cited by 6 publications

(4 citation statements)

References 17 publications

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“…2 Recently, Ma 3 reported the existence of 14 RFLPs of apo B by using 23 restriction endonucleases and four large cDNA probes covering almost the entire coding sequence of apo B.…”

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confidence: 99%

Bsp 12861 restriction fragment length polymorphism detects Ag(c/g) locus of human apolipoprotein B in all 17 persons studied.

Wang

Bütler

et al. 1989

Arteriosclerosis

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“…2 Recently, Ma 3 reported the existence of 14 RFLPs of apo B by using 23 restriction endonucleases and four large cDNA probes covering almost the entire coding sequence of apo B.…”

mentioning

confidence: 99%

Bsp 12861 restriction fragment length polymorphism detects Ag(c/g) locus of human apolipoprotein B in all 17 persons studied.

Wang

Bütler

et al. 1989

Arteriosclerosis

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“…The probability that a single base substitution will create a restriction site can be calculated to be about V6. 21 Therefore, the chance that all five Ag sites will correspond to restriction sites is only about {Vi) s =1/243. It is difficult to suggest a plausible reason for this intriguing coincidence; however, it is of considerable practical importance.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, most (>97%) alleles from individuals homozygous for the shorter Xba I RFLP (Xl/Xl individuals) are also Ag(y/ y) 32-35 xhe converse is not true, however, since only about 70% of Ag(y)-containing alleles also contain Xba I XI, and it has been shown that different but overlapping subsets of human apo B alleles are being identified by these two markers. 35 The Xba I (Xl/Xl) polymorphism is even more significantly associated than Ag(x-) with elevated cholesterol and triglyceride levels. 32 -34 It is now recognized that there are at least 14 different commonly found haplotypes of apo B that can be distinguished by different combinations of the five Ag epitopes.…”

Section: Discussionmentioning

confidence: 99%

Identification of the base substitution responsible for the Ag(x/y) polymorphism of apolipoprotein B-100.

Butler

Bütler

et al. 1991

Arterioscler Thromb

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The identification of the base substitution responsible for Ag(x/y) completes the description of the antigen group polymorphisms associated with the apolipoprotein B polypeptide. Surprisingly, all five antigen group polymorphisms alter restriction endonuclease cleavage sites and have associated restriction fragment length polymorphisms, thereby providing a convenient alternative for antigen group phenotyping. (Arteriosclerosis and Thrombosis 1991;ll:379-384) T he antigen group (Ag) polymorphisms are a group of 10 epitopes resulting from five single-amino-acid substitutions scattered along the length of the apolipoprotein (apo) B-100 polypeptide. -6 Human alloantibodies recognizing the first of these 10 epitopes were discovered in 1961 7 in the serum of a patient who had responded to multiple blood transfusions by forming antibodies against allelic variants of the donors' serum proteins. This first epitope, A g^) , was soon shown to be associated with the low density lipoprotein (LDL) fraction of serum.8 Subsequent studies identified additional epitopes associated with the LDL, and family studies showed these to be closely linked, since crossing over was never observed.9 As more data were collected, it became possible to group these 10 epitopes into five antithetical pairs, 10 ' 11 that is, pairs of epitopes of which at least one member must be present on the LDL obtained from a single individual. Eventually, the Ag system was shown to be associated with apo B-100, 12 -13 and recently, the underlying nucleotide substitutions responsible for four of the five epitope pairs have been identified and located on the apo B-100 gene.1 -6 Here, we report the position and nature of the fifth and final pair, Ag(x/y). Methods Genome DNA SourceHuman nuclear DNAs were obtained from the white blood cells of 18 individuals as described previously. 14 All these people had been previously Ag phenotyped using a hemoagglutination assay. 15 The five individuals selected for DNA sequencing were donors 4,11,14,15, and 17 listed in Table 3 of Reference 1. Enzymatic Amplification of DNAThe amplification primers used are summarized in Table 1. For convenience in subcloning, the amplification primers were designed to contain a restriction site at the 5' end. The amplification reaction 16 was performed in a final volume of 100 yX, containing 1 fig genomic DNA, 0.5 unit Taq polymerase (Promega, Madison, Wis.) in the reaction buffer supplied by the manufacturer, and primers, as described below. For symmetric amplification, 50 pmoles of each primer was used; for asymmetric amplification, 50 pmoles of one primer and 0.5 pmole of the other were employed. To prevent evaporation, 50 /A mineral oil was layered on top, and then the denaturation step was performed at 95°C for 5 minutes, annealing at 55°C for 45 seconds, and extension at 72°C for 2.5 minutes, for the first cycle. Thirty subsequent cycles were performed for 45 seconds at 95°C for denaturation, 45 seconds at 55°C for annealing, and 25 minutes at 72°C for extension. For the last cycle, ...

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“…9 ' 28 It is to be expected that apo B haplotypes may be more closely linked to serum lipids and apo B than are the individual markers. 15 The Ag(a,/d) epitopic site is one of the five markers used to define the Ag haplotypes; therefore, its characterization and location on the apo B structural DNA and its identification with a restriction site provide information and means of analysis which may prove useful in future studies of the apo B polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein B: the Ag(a1/d) immunogenetic polymorphism coincides with a T-to-C substitution at nucleotide 1981, creating an Alu I restriction site.

Wang

Schlapfer

et al. 1988

Arteriosclerosis

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4 Associated with the Ag system are at least 15 apo B haplotypes, which have been employed in genetic, forensic, ethnological, and epidemiological studies.4 -11 Underlying the Ag system must be corresponding changes in the coding regions of the apo B gene. A number of different apo B cDNA's and the gene have been sequenced, and from these published sequences a list of 60 nucleotide and 39 amino acid differences and one small deletion in the signal peptide has been compiled.12 Some of these nucleotide substitutions result in restriction fragment length polymorphisms (RFLP), and linkage disequilibrium between various RFLP and Ag system loci have been studied. 3812 In the present report a monoclonal antibody 16 was first used to locate Ag(d) to a stretch of 26 amino acid residues on the apo B peptide. Sequencing of the genomic DNA from four individuals was then employed to show that a single base change in this region distinguished individuals who were Ag(a,/ai) from those who were Ag(d/d). The base substitution, which occurs at nucleotide 1981, changes the GTT codon for Val 591, corresponding to the Ag(a,) epitope, to the GCT codon for Ala 591, corresponding to the Ag(d) epitope. The substitution creates an Alul restriction site changing AGTT to AGCT, a fortuitous occurrence that enables the substitution to be identified on Southern blots; perfect correspondence was then found between the Alul RFLP and the Ag(a,/d) genotype for all 17 persons examined. Methods DNA SourcesThe sources of the short fragments of apo B cDNA that were cloned into the pING expression vector were four, long clones spanning the entire coding sequence of apo B: A6c, 17 ABF, SB9, and AB1. 18 The last three were kindly provided

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Apolipoprotein B gene haplotypes. Association between Ag and DNA polymorphisms.

Cited by 6 publications

References 17 publications

Bsp 12861 restriction fragment length polymorphism detects Ag(c/g) locus of human apolipoprotein B in all 17 persons studied.

Bsp 12861 restriction fragment length polymorphism detects Ag(c/g) locus of human apolipoprotein B in all 17 persons studied.

Identification of the base substitution responsible for the Ag(x/y) polymorphism of apolipoprotein B-100.

Apolipoprotein B: the Ag(a1/d) immunogenetic polymorphism coincides with a T-to-C substitution at nucleotide 1981, creating an Alu I restriction site.

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