A study of the relationship between ABCA I gene polymorphisms, plasma lipid levels and risk of atherosclerosis

Abstract

To test the hypothesis that ABCA1 gene common variants are genetic factors that influence lipid levels and coronary heart disease in the general population, DNA from 1164 patients with angiographically confirmed coronary heart disease were genotyped for a number of polymorphisms in the ABCA1 gene.

In patients not on statin treatment, HDL-cholesterol levels were associated with the 1883M polymorphism, with carriers of the M allele having higher HDL-cholesterol levels than non-carriers (p=0.001), and there was a trend towards higher HDL-cholesterol levels in carries of the 1 allele of the V8251 polymorphism (p=0.05). In the sample as a whole and in patients on statin treatment, there was an association between HDL-cholesterol levels nada the R1587K polymorphism, such that homozygotes of the K allele of the R1587K had the lowest mean level, compared with individuals of other genotype for this polymorphism (p=0.028 in the sample as a whole and p=0.030 in patients on statin treatment).

There was an association between the -407 G>C polymorphism and age of onset of symptomatic CAD, age of onset being lowest patients homozygous for the -407G allele, intermediate in heterozygotes, highest in those who were homozygous for the -407C allele (p=0.002). Age of onset of CAD was also found to be associated with the -565 C>T and -278 G>C polymorphisms (p=0.01 and p=0.007 respectively) which were in linkage disequilibrium with the -407 G>C polymorphism.

Functional studies showed that cells transfected with a plasmid expressing the 825I variant had a higher rate of apoA1-mediated cholesterol efflux with a lower rate of cholesterol laden foam cell formation, compared with cells transfected with a plasmid expressing the wild-type ABCA1 (825V). The studies also showed that cells expressing the 219K variant had a lower rate of cholesterol laden foam cell formation than cells expressing the ABCA1 wild-type (219R).

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