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Effects of three genetic loci in a pedigree with multiple lipoprotein phenotypes
M Emi1, R M Hegele, P N Hopkins
1Howard Hughes Medical Institute, University of Utah Health Sciences Center, Salt Lake City.
Insights
Genetic defects in LDL receptor and apo B genes cause hyperlipoproteinemia and hypobetalipoproteinemia. Interactions between LDL receptor and apo E2 alleles lead to type III dyslipoproteinemia, revealing complex lipoprotein inheritance patterns.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Disease
Background:
- Familial hypercholesterolemia and other dyslipoproteinemias are significant risk factors for coronary artery disease.
- Understanding the genetic basis of lipoprotein disorders is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the genetic defects underlying plasma lipoprotein abnormalities in an extended family.
- To determine the phenotypic effects of combined genetic variations in apolipoprotein B, apolipoprotein E, and the LDL receptor.
Main Methods:
- Utilized molecular markers to track gene segregation for apolipoprotein (apo) B, apo E, and the low-density lipoprotein (LDL) receptor.
- Performed linkage analysis to associate specific genetic loci with lipoprotein phenotypes.
- Conducted DNA sequence analysis to identify specific apolipoprotein E2 allele variants.
Main Results:
- Elevated LDL cholesterol and hypobetalipoproteinemia (HBLP) phenotypes were linked to defects at the LDL receptor and apo B loci, respectively.
- An individual with both a defective LDL receptor allele and an HBLP-linked apo B allele exhibited a normal lipoprotein phenotype.
- Seven individuals with a defective LDL receptor allele and apo E2 alleles developed type III dyslipoproteinemia (DLPIII).
- The identified apo E2 alleles were the common E2 158 (Arg to Cys) variant.
Conclusions:
- Genetic defects in the LDL receptor and apo B contribute to distinct lipoprotein disorders.
- A potential gene-environment interaction exists between abnormal LDL receptor alleles and apo E2, leading to DLPIII expression.
- The presence of a single copy of apo E2 can precipitate DLPIII in conjunction with LDL receptor defects.
Abstract:
In the course of familial investigations of coronary artery disease, we identified an extended kinship in which several members were affected with type IIa hyperlipoproteinemia (HLPIIa), type III dyslipoproteinemia (DLPIII), or hypobetalipoproteinemia (HBLP). To study the genetic defects responsible for plasma lipoprotein abnormalities in this pedigree and to investigate the phenotypic effect of different genotypic combinations, we used molecular markers for apolipoprotein (apo) B, apo E, and the low density lipoprotein (LDL) receptor to characterize segregation at each locus. Linkage analysis showed that elevated LDL cholesterol levels and the HBLP phenotype were due to defects at the LDL receptor and the apo B loci, respectively. One pedigree member, who inherited both an LDL receptor allele linked with elevated LDL cholesterol levels and an apo B allele linked with HBLP, had a normal lipoprotein phenotype. Seven patients who simultaneously inherited the defective LDL receptor allele and one or two apo E2 alleles manifested DLPIII. The E2 alleles in this pedigree were shown by DNA sequence analysis to be the common E2 158 (arginine----cysteine) allele. These findings suggested a possible interaction between the abnormal LDL receptor and apo E2 alleles, resulting in the expression of DLPIII in the presence of a single copy of ago E2.