Novel polymorphisms in promoter region of ATP binding cassette transportergene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy

Identification of mutations in the ATP binding cassette transporter (ABCA1) gene in patients with Tangier disease, who exhibit reduced HDL cholesterol (HDL-C) and apolipoprotein Al (apoA1) levels and premature coronary athero sclerosis, has led to the hypothesis that common polymorphisms in the ABCA1 gene could determine HDL-C and apoA1 levels and the risk of coronary ather osclerosis in the general population. We sequenced a 660-bp 5 ' fragment of the ABCA1 gene in 24 subjects and identified 3 novel polymorphisms: -477C/ T, -419A/C, and -320G/C. We developed assays, genotyped 372 participants in the prospective Lipoprotein Coronary Atherosclerosis Study (LCAS), and det ermined the association of the variants with fasting plasma lipids and indi ces of quantitative coronary angiograms obtained at baseline and 2.5 years after randomization to fluvastatin or placebo. Distribution of -477C/T and -320G/C genotypes were 127 CC, 171 CT, and 74 TT and 130 GG, 168 GC, and 75 CIC, respectively, and were in complete linkage disequilibrium (P <0.0001) . Data for -477C/T are presented. The -419A/C variant was uncommon (present in 1 of 63 subjects). Heterozygous subjects had a modest reduction in HDL- C (P=0.09) and apoA1 (P=0.05) levels and a lesser response of apoA1 to trea tment with fluvastatin (P=0.04). The mean number of coronary lesions causin g 30% to 75% diameter stenosis was greater in subjects with the TT genotype (3.1 +/-2.1) or CT genotype (2.9 +/-1.9) than in subjects with the CC geno type (2.2 +/-1.8) (P=0.002). Similarly, compared with subjects with the CC genotype, greater numbers of subjects with the TT or CT genotype had greate r than or equal to1 coronary lesion (P=0.001). No association between the g enotypes and progression of coronary atherosclerosis or clinical events was detected. We conclude that ABCA1 genotypes are potential risk factors for coronary atherosclerosis in the general population.