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Background: Recently, we localized the Human Poliovirus Receptor Related 2 Gene (PRR2) 17kb centromeric to the gene for apolipoprotein E (APOE). Common polymorphisms in the latter have been found, in some studies, to be related to coronary heart disease (CHD) but the PRR2 gene has not been studied in this context. Here, we examined relationships between a PRR2 Sau96I (A/G) polymorphism, the epsilon2, 3 and 4 alleles of APOE and CHD., Design and Methods: Consecutive Caucasian patients (n = 640) < 50 years with angiographically documented coronary obstructive disease and/or with unequivocal myocardial infarction were compared with 624 control subjects, aged 30-50 years, randomly selected from the community and without a history of CHD., Results: An excess of PRR2-A homozygotes was observed in cases (20% vs. 15%; OR 1.4, CI 1.04-1.86, P = 0.026) particularly in those with single vessel disease (OR 1.7, CI 1.2-2.4, P <0.01). The A allele was in linkage disequilibrium with the epsilon4 allele and the G allele with the epsilon2. Overrepresentation of the A allele and underrepresentation of the G allele in the CHD group did not reach significance (P = 0.054). While the epsilon2 allele was underrepresented in the CHD group (OR 0.64, CI 0.46-0.89, P = 0.009), the epsilon4 allele was not significantly overrepresented., Conclusion: The relationship between the PRR2 Sau96I (A/G) polymorphism and early onset coronary artery disease may be due to linkage disequilibrium with the APOE gene and underrepresentation, or a protective effect, of the epsilon2 allele. Alternatively, since A allele homozygosity is particularly overrepresented, the relationship could be more direct, perhaps through a viral association.

Compared with apolipoprotein E3 (apoE3), apoE2 is less effective in mediating the binding of lipoproteins to the low-density lipoprotein (LDL) receptor. The influence of the E4 isoform, which is associated with adverse effects on plasma lipids and coronary heart disease, is less clear. We compared the ability of very low density lipoprotein (VLDL) and LDL from paired E4/4 and E3/3 subjects to compete against 125I-labeled LDL for binding with the LDL receptor on cultured fibroblasts and Hep G2 cells. The concentrations of VLDL or LDL required to inhibit binding of 125I-LDL by 50% (IC50, microgram apoB/ml) were determined, and results were assessed in terms of an IC50 ratio, E4/4 IC50 relative to E3/3 IC50, to reduce the influence of interassay variability. In Hep G2 cells, E4/4 VLDL was more effective than E3/3 VLDL in competing for the LDL receptor, the IC50 ratio being lower than unity (0.73 +/- 0.31, P < 0.05, two-tailed t-test). IC50 values themselves were marginally lower in E4/4 than E3/3 subjects (3.7 +/- 1.3 vs. 6.1 +/- 3.7, P < 0.08). However, there was no difference between E4/4 and E3/3 VLDL in competing for the LDL receptor on fibroblasts or between E4/4 and E3/3 LDL in competing for the LDL receptor on either cell type. These results suggest that inheritance of apoE4 is associated with an increased affinity of VLDL particles for LDL receptors on hepatocytes and may partly explain the influence of the E4 isoform on lipid metabolism.

We aimed to examine the effect of genetic polymorphisms of apolipoprotein B-100 (apoB) signal peptide and apolipoprotein E (apoE) on the hepatic secretion of very low density lipoprotein (VLDL) apoB in 29 men with visceral obesity. We studied apoB secretion using a primed (1 mg/kg), constant (1 mg/kg/h) intravenous infusion of [1-(13)C]leucine. The isotopic enrichment of VLDL apoB was determined using gas chromatography-mass spectrometry (GCMS). A multi-compartmental model was used to estimate the fractional turnover rate of VLDL apoB. Genotypes for the apoB signal peptide length polymorphism, 27 amino acid (SP27) and 24 amino acid (SP24), and apoE genotypes were determined using polymerase chain reaction. In subjects who were not apoE2 carriers and were homozygous for the SP27 of the apoB signal peptide, the hepatic secretion of VLDL apoB was significantly higher than in subjects who were not apoE2 carriers and were either heterozygous or homozygous for the SP24 allele (31.3 +/- 11.8 mg/kg fat-free mass/day, n = 8 vs. 16.9 +/- 12.2 mg/kg fat-free mass/day, n = 13, P = 0.01). In subjects who were not apoE4 carriers and were either heterozygous or homozygous for the apoB SP24 allele, the hepatic secretion of VLDL apoB was significantly lower than in subjects who were not apoE4 carriers and were homozygous for the SP27 allele (15.8 +/- 12.9 mg/kg fat-free mass/day, n = 13 vs. 27.4 +/- 11.5 mg/kg fat-free mass/day, n = 7, P = 0.03). The data suggest that in men with visceral obesity, the apoB signal peptide and apoE genotypes appear to be involved in the hepatic secretion of apoB.

Through the sequencing of a 42kb cosmid clone we describe a new gene, designated PEREC1, located approximately 1.5kb centromeric of the human apolipoprotein (APO) E-C2 cluster. The combination of dotplot analysis, predicted coding potential and interrogation of the Expressed Sequence Tag (EST) database determined the genomic organisation of PEREC1. Sequence alignment with multiple overlapping ESTs confirmed the predicted splice sites. The predicted cDNA and amino acid sequences of PEREC1 have extensive similarity to the Caenorhabditis elegans protein, C18E9.6. Conserved structural and functional motifs have been defined by combining nucleotide and amino acid analyses to identify third base degeneracy and therefore selection at the protein level. The Poliovirus Receptor Related Protein2 gene (PRR2), previously mapped to chromosome 19q13.2 by Fluorescent In-Situ Hybridisation, has also been located approximately 17kb centromeric of APO E.

The genetic predisposition to inclusion body myositis (IBM) is probably multifactorial. The deposition of the beta-amyloid protein is a characteristic histological feature of both IBM and Alzheimer's disease (AD). The epsilon 4 allele of apolipoprotein E (APO E) has been strongly associated with familial and late-onset AD. We therefore compared the APO E allele frequencies in a group of 14 patients with IBM with those in a group of patients with other inflammatory muscle diseases and in the general population. The frequency of the epsilon 4 allele in IBM was increased (0.29) compared with that in patients with other inflammatory muscle diseases (0.15) and the general population (0.13) (p < 0.05). These data suggest that APO E genotype may be one of the factors involved in determining the predisposition to the development of IBM.

Background: An insertion/deletion (I/D) polymorphism in the gene for angiotensin-converting enzyme (ACE) has been associated with myocardial infarction and other cardiac pathology. There is evidence for a role of the renin-angiotensin system in cell growth and in the repair of damaged arterial walls, so the ACE gene was postulated to be a candidate gene affecting the important clinical problem of restenosis after percutaneous transluminal balloon coronary angioplasty (PTCA). Because restenosis is influenced by the apolipoprotein E (apoE) genotype, the possibility of a relation between ACE and apoE genotypes and restenosis was also sought., Methods and Results: Subjects (< 70 years of age) were prospectively followed and had coronary angiography 6 months after PTCA to determine the presence or absence of restenosis. Those who had angiography earlier and did not have restenosis (> or = 50% loss of gain at PTCA plus > or = 50% luminal diameter stenosis) also had angiography at 6 months. The whole group (n = 207) had a higher DD genotype frequency than did 136 population control subjects (38% versus 26%, P < .02); in PTCA patients, the frequency was the same in those with and without prior myocardial infarction. The distribution of ACE genotypes was not different in the 88 patients with and 119 patients without restenosis, while the epsilon 4/4 genotype was more frequent in those with restenosis (8 of 88 versus 3 of 118, P < .05). There was no effect of the ACE genotype in noncarriers of the epsilon 4 allele, but there was a significant effect in epsilon 4 carriers (P < .005). The combined D and epsilon 4 carrier state showed a 16-fold increase in the odds ratio for restenosis (P < .02). Multiple linear regression examining the loss of lumen as a continuous variable showed significant independent effects of the ACE and apoE genotypes., Conclusions: Overall, the ACE genotype had no clear influence on restenosis, but there was an interaction between ACE and apoE genotypes. The combined carrier state for the D and apoE epsilon 4 alleles substantially increased restenosis. For loss of lumen as a continuous variable, there were significant effects of both ACE and apoE genotypes. While the observations may not affect current management, they no doubt have implications in pathophysiology.

Conventional coronary risk factors have not consistently been found to be related to restenosis after coronary angioplasty. Apolipoprotein E (apo E) gene polymorphism and/or plasma apo(a) levels were determined in 195 subjects undergoing prospective follow up and angiographic study 6 months after elective balloon angioplasty of a previously untreated coronary obstruction. Restenosis (stenosis > or = 50% plus loss of > or = 50% of initial gain) had occurred in 59 of 150 subjects for whom E genotypes were available. The apo epsilon 4 allele frequency in those with restenosis was higher than those without (0.20 vs. 0.10, P < 0.01), attributable to an excess of epsilon 4 homozygotes in the restenosis group (5 of 59 vs. 1 of 91, P < 0.04). Restenosis was not related to plasma apo(a) and the apo epsilon 4 allele was not associated with elevated levels of apo(a) as has been reported elsewhere. No relationship was found between E genotype and serum lipid and lipoprotein levels; paradoxically, LDL cholesterol was significantly lower and HDL cholesterol higher in those with restenosis. In conclusion, homozygosity for apolipoprotein epsilon 4 appears to be an important determinant of restenosis after coronary angioplasty.

We have compared apolipoprotein E gene polymorphism in 91 Australian men aged 30-50 who had been referred for coronary angioplasty and in 172 healthy younger men. 5 of the 19 patients who were less than 40 years of age were homozygous for the epsilon 4 allele, representing a 16-fold increase in prevalence compared with controls. In patients aged 40-50 the epsilon 4 allele frequency was 60% higher than it was in controls. Inheritance of epsilon 4 seems to confer risk of premature ischaemic heart disease in males, homozygotes being especially at risk at a younger age.