Elevated plasma levels of apolipoprotein B (apo B100) and low density lipoprotein (LDL) are associated with a higher risk for atherosclerotic coronary heart disease, a leading cause of mortality in the industrialized world. Apo B is required for the secretion of very low-density lipoproteins (VLDL) from the liver and is the mandatory protein constituent of both plasma VLDL and LDL. Overproduction of apo B is a major characteristics of familial combined hyperlipidemia (FCHL), a prevalent disease with heterogeneous genetic basis. Genetic studies have shown that plasma apo B levels are controlled by unknown major genes. The investigators hypothesize that plasma apoB levels are controlled, in part by the secretion rate of apo B-containing lipoproteins, which is genetically regulated. To determine the genetic basis of plasma apo B levels, we have chosen to use the human apo B only in the liver. The preliminary studies provided evidence of genetic control of hepatic B-100 secretion resulting in varying plasma human apo B levels in F1 offspring from crosses between a congenic HuBTg and various inbred mouse strains. Further genetic studies in crosses between C57BL/6 and 129/Sv have identified two novel major quantitative trait loci (QTL) (designated apo B regulator loci), which account for a majority of genetic variance of plasma human apo B levels in these crosses. The long-term goal of the proposal is to clone and characterize one of the major apo B regulator genes. This gene will be a novel regulator affecting the pathways involved in the assembly and secretion of apo B-containing lipoproteins and is a strong candidate gene for FCHL. It is also a potential target for therapeutic intervention. The goals will be achieved through the following aims.
Aim 1 : Generation and characterization of partial congenic HuBTg mouse lines containing chromosomal intervals regulating plasma human apo B levels. Specific breeding strategies will be used to generate interval-specific partial congenic lines (i.e., incipient congenics) for fine mapping and biochemical characterization.
Aim 2 : High resolution mapping of the interval containing a major apo B regulator locus using interval-specific incipient congenics. The incipient congenic line with a greater effect on the plasma apo B levels will be selected for fine mapping.
Aim 3 : Identification and characterization of transcripts within the critical interval containing the apo B regulator locus. A BAC contig containing the critical interval will be analyzed and transcripts identified. Allelic variants for the candidate gene will be identified and tested for their functional significance.
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