Cerebrovascular atherosclerosis in type III hyperlipidemia is modulated by variation in the apolipoprotein A5 gene

Type III Hyperlipoproteinemia is a rare lipid disorder with a frequency of 1-5 in 5000. It is characterized by the accumulation of triglyceride rich lipoproteins and patients are at increased risk of developping atherosclerosis. Type III HLP is strongly associated with the homozygous presence of the ε2 allele of the APOE gene. However only about 10% of subjects with APOE2/2 genotype develop hyperlipidemia and it is therefore assumed that further genetic and environmental factors are necessary for the expression of disease. It has recently been shown that variation in the APOA5 gene is one of these co-factors. The aim of this study is to investigate the development of cerebrovascular athero?sclerosis in patients with Type III hyperlipopro?teinemia (Type III HLP) and the role of variation in the APOA5 gene as a risk factor.

60 patients with type III hyperlipidemia and ApoE2/2 genotype were included in the study after informed consent. The presence of cerebrovascular atherosclerosis was investigated using B-mode ultrasonography of the carotid artery. Serum lipid levels were measured by standard procedures.The APOE genotype and the 1131T>C and S19W SNPs in the APOA5 gene and the APOC3 sstI SNP were determined by restriction isotyping. Allele frequencies were determined by gene counting and compared using Fisher's exact test. Continuous variables were compared using the Mann Whitney test. A p value of 0.05 or below was considered statistically significant. Analysis was performed using Statistica 7 software.

The incidence of the APOA5 SNPs, -1131T>C and S19W and the APOC3 sstI SNP were determined as a potential risk modifier. After correction for conventional risk factors, the C allele of the -1131T>C SNP in the APOA5 gene was associated with an increased risk for the development of carotid plaque in patients with Type III HLP with an odds ratio of 3.69. Evaluation of the genotype distribution was compatible with an independent effect of APOA5.

The development of atherosclerosis in patients with Type III HLP is modulated by variation in the APOA5 gene.