Apolipoprotein B–Gene DNA Polymorphisms Associated with Myocardial Infarction

Hegele, Robert A.; Huang, Li‐Shin; Herbert, Peter N.; Blum, Conrad B.; Buring, Julie E.; Hennekens, Charles H.; Breslow, Jan L.

doi:10.1056/nejm198612113152403

Cited by 267 publications

(138 citation statements)

References 30 publications

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“…DNA was extracted as described. 22 Screening for known mutations in HL, namely Ϫ480T, V73M, R186H, N193S, S267F, L334F, and T383M, was performed as described 14 -17,23 in 3 subjects from C2T who were known to be deficient in HL activity in postheparin plasma. Genotypes of HL S267F were determined by using polymerase chain reaction amplification and digestion with Hinf I as described.…”

Section: Biochemical and Genetic Determinationsmentioning

confidence: 99%

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Hegele

Breckenridge

Cox

et al. 1998

ATVB

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Abstract-Although naturally occurring loss-of-function mutations in human hepatic lipase (HL) have been described, the biochemical phenotype of heterozygous HL deficiency remains ill defined. This may be due to the relatively small numbers of heterozygous adult carriers of HL mutations in index kindreds. We have identified several new heterozygotes for the catalytically inactive, nonsecreted HL variant S267F in the kindred that was originally ascertained because of hypertriglyceridemia due to the mutant, secreted, circulating apolipoprotein (apo) CII variant apo CII-T. Pairwise comparisons with family controls showed that only the plasma low density lipoprotein triglycerides (LDL TGs) were higher in 11 simple heterozygotes for HL S267F (Pϭ0.002). In contrast, both plasma total TGs and LDL TGs were significantly higher in 12 simple heterozygotes for apo CII-T than in family-matched control subjects (Pϭ0.005 and 0.009, respectively). These findings suggest that the TG content of LDL is increased by heterozygosity for 2 different mutations that affect different proteins involved in lipolysis. However, the mechanisms underlying this compositional change in LDL appear to be different for the 2 mutations, because the total TGs are also elevated in subjects heterozygous for apo CII-T but not in subjects heterozygous for HL S267F. 10 -12 Studies in transgenic rabbits suggest that HL overexpression can result in reduced plasma HDL and IDL and in reduced atherosclerosis. 4 In contrast, disruption of HL in mice can result in increased HDL and, on an APOE-deficient background, increased ␤-migrating VLDL but reduced atherosclerosis. 13 The relevance of such results to human lipoprotein metabolism is unclear.Most patients with HL deficiency due to HL mutations have been ascertained on the basis of dyslipidemia. However, among carriers of HL mutations associated with loss of function, such as R186H, S267F, L334F, and T383M, there are disparities in both the biochemical phenotype and the association with atherosclerosis susceptibility.14 -17 For example, in a Canadian family, compound heterozygotes for HL S267F and T383M had (1) combined hyperlipidemia, (2) TG enrichment of LDL and HDL, (3) ␤-migrating VLDL, (4) impaired chylomicron remnant metabolism, and (5) early coronary heart disease.14 However, the limited number of subjects in this family made it difficult to conclude whether simple heterozygotes had a discrete phenotype. In a Finnish family, compound heterozygotes for L334F and T383M did not have ␤-migrating VLDL but did have TG enrichment of LDL and HDL.15 Also, Finnish heterozygotes for an HL allele that carried R186H and L334F appeared to have TG enrichment of LDL and HDL.16 Homozygosity for a splice-site mutation in HL intron I was associated with hypertriglyceridemia and coronary heart disease; however, there was no obvious biochemical phenotype among heterozygotes. 17The disparity among the results of studies of phenotype in heterozygotes for loss-of-function mutations in HL has many possible explanations. First, ...

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Section: Biochemical and Genetic Determinationsmentioning

confidence: 99%

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Hegele

Breckenridge

Cox

et al. 1998

ATVB

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“…32 The model likelihoods on these pedigree data were approximated by the Pedigree Analysis Program (PAP) developed by Hasstedt. 53 ' 54 Hypothesis testing of nested models used the likelihood ratio criterion.…”

Section: Complex Segregation Analysismentioning

confidence: 99%

Genetic predictors of FCHL in four large pedigrees. Influence of ApoB level major locus predicted genotype and LDL subclass phenotype.

Jarvik

Brunzell

Austin

et al. 1994

Arterioscler Thromb

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The genetic basis of familial combined hyperlipidemia (FCHL) has eluded investigators for 20 years, despite the apparent segregation of FCHL as an autosomal dominant disorder affecting 1% to 2% of individuals. Etiologic heterogeneity and additive effects of traits controlled by other genetic loci have been suggested. Two traits have been implicated in FCHL. The first is the predominance of a small, dense low-density lipoprotein (LDL), LDL subclass phenotype B, which segregates as a mendelian trait. The second is a mendelian locus with large effects on apolipoprotein (apo) B levels that is defined by complex segregation analysis (predicted apoB level genotype). This study shows that these factors F amilial combined hyperlipidemia (FCHL) is characterized by variable expression of hypercholesterolemia and hypertriglyceridemia in a given family, with either or both present in affected individuals.1 FCHL is associated with an excess risk of coronary artery disease (CAD) and was first reported by Goldstein et al 1 in 1973 in pedigrees ascertained through men who were survivors of myocardial infarction; over 10% of those probands were considered to have FCHL. One half to one third of familial premature CAD 2 and at least 10% of all premature CAD 1 -3 are ascribed to FCHL. This disorder is estimated to affect 1% to 2% of those in the populations studied and may be responsible for 5% of myocardial infarctions.1 While the inheritance of FCHL was originally described as consistent with an autosomal dominant disorder with full penetrance by the end of the third decade, 1 formal segregation analysis, adjusting for ascertainment, has not been reported. 4 Thus, the mode of inheritance remains uncertain.Efforts to refine the phenotype of FCHL have led to the observation that elevated levels of apolipoprotein Received May 4, 1994; revision accepted July 19, 1994. O 1994 American Heart Association, Inc.appear to be separate genetic effects, both of which aid in the prediction of FCHL in four large pedigrees. The results suggest that FCHL may be best predicted by a threshold model in which apoB level genotype and LDL subclass phenotype each act to increase the risk of FCHL. Heterogeneity in the transmission of apoB levels among families is suggested, supporting the etiologic heterogeneity of FCHL. These results emphasize the advantages inherent in the study of large pedigrees when disease heterogeneity is suspected.

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“…This result, combined with the finding that the concentration required for 50% competition was lower with E~/~ LDL than with E V LDL (although not significantly so), suggests that the presence of a Lys residue at position 4,154 does not alter the function of the LDL-receptor-binding domain of apo B-100. In support of this, an association between plasma cholesterol concentration and the EcoBl polymorphism could not be demonstrated in two populations, one in Boston 5 and the other in London. 4 A possible explanation for the association in the population between CAD and the EcoRl polymorphism is that the polymorphism affects the susceptibility of LDL to modification by peroxidation in the vicinity of the arterial wall.…”

Section: Discussionmentioning

confidence: 96%

Does the EcoRI polymorphism in the human apolipoprotein B gene affect the binding of low density lipoprotein to the low density lipoprotein receptor?

Gallagher

Myant

1992

Arterioscler Thromb

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(apo B) gene detected with the restriction enzyme EcoRl gives rise to two codominant apo B alleles, one with the EcoRl recognition site (E + ) and the other without it (E"). 1 The E + allele encodes glutamic acid (Glu) at residue 4,154 in apo B-100 (the protein component of low density lipoprotein [LDL]), while the E" allele encodes lysine (Lys) at this position. The EcoRl polymorphism in the apo B gene, which corresponds to the t/z polymorphism of the Ag system, 2 appears to be universally present in humans, with the E" allele occurring at a frequency of between 0.10 and 0.15 in most human populations (see Reference 3). We 4 and others 56 have shown that the frequency of the E" allele is significantly higher in men with coronary artery disease (CAD) than in healthy men from the same population.The major pathway for removal of LDL from the plasma is mediated by high-affinity binding of the apo From the MRC Lipoprotein Team,

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Apolipoprotein B–Gene DNA Polymorphisms Associated with Myocardial Infarction

Cited by 267 publications

References 30 publications

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Genetic predictors of FCHL in four large pedigrees. Influence of ApoB level major locus predicted genotype and LDL subclass phenotype.

Does the EcoRI polymorphism in the human apolipoprotein B gene affect the binding of low density lipoprotein to the low density lipoprotein receptor?

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