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Familial hypercholesteroloemia (FH) is a common autosomal codominant hereditary disease caused by defects in the LDL receptor (LDLR) gene, and one of the most common characteristics of affected subjects is premature coronary heart disease (CHD). In heterozygous FH patients, the clinical expression of FH is highly variable in terms of the severity of hypercholesteroloemia and the age of onset and severity of CHD. Identification of mutations in the ATP binding cassette transporter 1 (ARCA 1) gene in patients with Tangier disease, who exhibit reduced HDL cholesterol and apolipoprotein Al concentrations and premature coronary atherosclerosis, has led us to hypothesise that ABCA 1 could play a key role in the onset of premature CHD in FH. In order to know if the presence of the R2 19K variant in the ABCA i gene could be a protective factor for premature CHD in FH, we have determined the presence of this genetic variant by amplification by PCR and restriction analysis in a group of 374 FH subjects, with and without premature CHD. The K allele of the R2 19K variant was significantly more frequent in FH subjects without premature CHD (0.32, 95% Cl 0.27 to 0.37) than in FH subjects with premature CHD (0.25, 95% Cl 0.21 to 0.29) (p<0.05), suggesting that the genetic variant R219K in ABCA1 could influence the development and progression of atherosclerosis in FH subjects. Moreover, the K allele of the R2 19K polymorphism seems to modify CHD risk without important modification of plasma HDL-C levels, and it appears to be more protective for smokers than non-smokers.
Epidemiological studies have shown a strong inverse relationship between HDL cholesterol (HDL-C) levels and coronary heart disease (CHD), (1 2) low concentration of HDL-C in plasma is considered an independent risk factor for premature atherosclerosis. Many genetic and environmental factors influence plasma HDL-C levels and the causes that contribute to low HDL-C values are heterogeneous. The identification of ATP binding cassette transporter 1 (AECAl)(3 4) and the fact that mutations in the ABCAI gene are the cause of Tangier disease and familial HDL deficiency, both of them characterised by low plasma levels of HDL-C and apolipoprotein (apo) A-I, and increased risk of premature coronary atherosclerosis, suggests that ABCAI is a protein that plays a key role in regulating plasma HDL-C and apo A-I metabolism. (5-7) ABCAI is a membrane transporter protein that stimulates cholesterol and phospholipid efflux to apo A-I. This step is one of the first stages in the reverse cholesterol transport (RCT), which media tes the cholesterol catabolism from peripheral cells back to the liver. Therefore, ABCAI has been considered as a rate limiting step in the production of HDL. (8)
Familial hypercholesterolaemia (FR) is a common autosomal codominant disease caused by defects in the LDL receptor (LDLR) gene. Affected subjects have raised plasma levels of total and LDL cholesterol and a very high risk of premature coronary heart disease. (9) In heterozygous FR patients, the clinical expression of FR is highly variable in terms of the severity of hypercholesterolaemia and the age of onset and severity of CHD, even in subjects sharing the same LDLR gene defect. (10 11) Therefore, the phenotype of such patients is clearly influenced by other genes and/or environmental factors (12-14) and several studies have been carried out to elucidate this issue. (15-19)
One of the genes that could be involved in the manifestation of CHD at a young age is ABCAI. (20) Recently, common polymorphisms in the ABCAI gene have been shown to affect plasma levels of HDL-C and CHD risk (21 22) and therefore they could be genetic risk factors for coronary atherosclerosis in FH.
In order to discover if the presence of the R219K polymorphism in the ABCA1 gene plays a protective role for premature CHD in FH, we have analysed this genetic variant in a group of FR subjects. In this work, we report that the common variant R219K in the ABCAI gene is significantly more frequent in FH subjects without premature CHD than in FR subjects with premature CHD, suggesting that genetic variation in ABCAI influences the atherosclerosis process in FR subjects.
MATERIAL AND METHODS
The Spanish FR Register was established in 1999 and currently consists of 989 confirmed FH patients using the diagnosis criteria of the MedPed programme (>8 points). (23 24) From this registry, we selected those heterozygous FR subjects with a proven premature coronary event before 55 or 65 years old for men and women, respectively, who constituted the premature CRD group (216 subjects). Coronary events included were myocardial infarction, coronary angioplasty, and coronary bypass surgery. We also selected those heterozygous FR subjects, older than 55 or 65 years for men and women, respectively, and free of any cardiovascular disease, as a control group (158 subjects).
All procedures were in accordance with the Helsinki Declaration of 1975, as revised in 1983. Informed consent was obtained from every person studied.
Fasting blood samples were drawn for measurements of total plasma cholesterol, HDL-C, and triglycerides. Measurements were performed with commercially available …