|Tai, E Shyong|
Submitted to: Clinical Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/23/2002
Publication Date: 1/1/2003
Citation: TAI, E., ADICONIS, X., ORDOVAS, J.M., CARMENA-RAMON, R., REAL, J., CORELLA, D., ASCASO, J., CARMENA, R. POLYMORPHISMS AT THE SRBI LOCUS ARE ASSOCIATED WITH LIPOPROTEIN LEVELS IN SUBJECTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA. Clinical Genetics. 2003;63:53-58.
Interpretive Summary: Genetics play an important role in the risk of coronary heart disease. Some individuals are at exceptionally high risk for this disease due to mutations in genes that are crucial for the metabolism of lipoproteins, such as the case with familial hypercholesterolemia due to mutations in the low density lipoprotein receptor. However, even within subjects that have these mutations, there is a lot of variability in the disease risk that could be in part due to some environmental factors, but also due to the presence of other genetic factors that can protect or make worse the course of the disease. At this regard, we have examined mutations in another receptor involved in lipoprotein metabolism, known as Scavenger receptor, class B, type 1 (SRBI), also known as HDL-receptor. Specifically, we have examined the association of three common mutations at the SRBI gene in subjects who were heterozygous for familial hypercholesterolemia (FH). In agreement with animal model studies, the effect of these polymorphisms over blood lipids suggests a role for the SRBI in the metabolism of low density lipoproteins in humans. This receptor may constitute a back up mechanism to low density lipoprotein (LDL) receptor mediated uptake of these atherogenic lipoproteins, which could be particularly relevant in subjects with high levels of these particles in the blood, such as those occurring in patients with FH.
Technical Abstract: Scavenger receptor, class B, type 1 (SRBI) is a promising candidate gene involved in the pathophysiology of atherosclerosis. We have examined the association of three common polymorphisms at the SRBI locus in 77 subjects who were heterozygous for familial hypercholesterolemia (FH). The alleles represented by polymorphisms in exon 1 and exon 8 were associated with variation in plasma concentrations of fasting triglyceride (TG). Mean plasma TG concentrations for homozygotes for the most common allele, heterozygotes and homozygotes for the less common allele were 85+/-6, 111+/-9 and 135+/-22 mg/dl (p=0.011) for exon 1, and 96+/-11, 86+/-6 and 134+/-13 mg/dl (p=0.007) for exon 8, after adjustment for age, sex and body mass index. In addition, the exon 8 polymorphism was associated with increased total cholesterol (320+/-15, 340+/-8 and 388 +/-18 mg/dl, p=0.015), VLDL cholesterol (18+/-2.9, 15.7+/-1.6 and 33.4+/-3.9 mg/dl, p<0.001) and LDL cholesterol (251+/-15, 270+/-8 and 312+/-10 mg/dl, p=0.041) concentrations. In agreement with animal studies, our data also suggest a role for the SRBI in the metabolism of apolipoprotein B containing lipoproteins in humans. This pathway may constitute a back up mechanism to low density lipoprotein (LDL) receptor mediated pathways for the catabolism of these lipoproteins, which could be particularly relevant in subjects with high levels of apolipoprotein B-containing lipoproteins, such as those occurring in patients with FH.