Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/7/2007
Publication Date: 11/8/2007
Citation: Santos, R.D., Schaefer, E., Asztalos, B.F., Polisecki, E., Wang, J., Hegele, R.A., Martinez, L.R., Miname, M.H., Rochitte, C.E., Daluz, P.L., Maranhao, R.C. 2007. Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency. Journal of Lipid Research. 49:349-357. Interpretive Summary: The major cholesterol carrying particles in the bloodstream are known as low density lipoproteins or LDL. High levels of LDL cholesterol (> 160 mg/dl) have been associated with an increased risk of heart disease, a leading cause of death and disability in our society. Another cholesterol carrying particle in the bloodstream is known as high density lipoprotein cholesterol. Low levels of high density lipoprotein (HDL) cholesterol (< 40 mg/dl in men and < 50 mg/dl in women) have also been associated with an increased risk of coronary heart disease. LDL is known to deposit cholesterol in tissues, while HDL is known to remove it for return to the liver and excretion from the body. We identified two brothers that had very low HDL cholesterol levels of < 5 mg/dl (normal > 40 mg/dl). They were found to have no detectable apolipoprotein (apo) A-I, the major protein of HDL in their plasma. We found that they had a defect in the gene responsible for making this protein. They inherited the same defect from each of their parents, who were first cousins. Therefore they were homozygotes for this mutation. In this family we identified 8 carriers or heterozygotes that had plasma HDL cholesterol and apoA-I levels that were 50% of normal, and we also identified 2 normal unaffected family members with normal plasma HDL cholesterol and apoA-I levels. The two brothers both had severe heart disease requiring bypass surgery at the ages of 38 and 39 years. We also showed that despite the fact that the index cases had no apoA-I in HDL, they had relatively normal amounts of HDL particles containing apoA-IV and apoE which comprise about 5 – 10% of HDL particles in normal people. The data indicates that lack of HDL and apoA-I is associated with severe premature heart disease, and that there are other HDL particles in the bloodstream that do not contain apoA-I. It has clearly been shown that lowering elevated blood cholesterol ( > 240 mg/dl) and elevated low density lipoprotein (LDL) cholesterol ( > 160 mg/dl) with diet and statin medications can reduce the risk of heart disease. However there are many people who receive such treatment who go on to develop heart disease or to have a recurrent event. Many of these people have a low high density lipoprotein (HDL) cholesterol level ( < 40 mg/dl). Here we have identified a family with absence of the major protein of HDL, known as apolipoprotein (apo) A-I. These people developed heart disease in their late thirties, and the disease can be picked with computed tomography (CT) imaging of calcium in the heart as well as with intravenous CT angiography. We have also shown that if one does not have apoA-I in HDL, one can still have small amounts of other HDL particles containing proteins known as apoA-IV and apoE. Our studies support the view that low HDL cholesterol, like high LDL cholesterol, is a potent risk factor for premature heart disease. Moreover we need to develop better strategies to treat low HDL cholesterol levels.
Technical Abstract: Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon 22, QX, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small a-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow a migrating apoA-IV- and apoEcontaining HDL, while in the eight heterozygotes, there was loss of large a-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II a-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.