Polymorphisms Associated With Cholesterol and Risk of Cardiovascular Events

Abstract

Conclusion: A genotype score of validated single-nucleotide polymorphisms (SNPs) of LDL or HDL cholesterol is an independent risk factor for cardiovascular (CV) disease. Summary: There are single-nucleotide polymorphisms (SNPs) associated with blood levels of low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol. These polymorphisms modestly affect lipid levels. The authors studied whether a combination of SNPs can contribute to risk of CV disease. Single-nucleotide polymorphisms at nine loci in 5414 subjects were studied. The patients were derived from a CV cohort of the Malmö Diet and Cancer Study. Initially associations between SNPs and HDL and LDL cholesterol were validated. A genotype score based on the number of unfavorable alleles was developed. A Cox proportional-hazards model was then used to determine the time to the first CVevent in relationship to the genotype score. Levels of either LDL or HDL cholesterol all were associated with all nine of the SNPs. The level of LDL cholesterol increased from 152 to 171 mg/dl with increasing genotype score. HDL cholesterol decreased from 60 mg/dl to 51 mg/dl when increasing genotype score. At a median follow up of 10.6 years 238 subjects had a first CV event. Genotype score was associated with the first CVevent in the model when adjusted for covariances including baseline lipid levels (P < 0.001). Genotype score did not improve clinical risk projection. There was improvement in risk classification with the use of models that included the genotype score. Comment: Single measurements of blood lipid levels may not accurately reflect effects of lifetime exposure to elevated cholesterol. Genotypes, however, are invariant over time and can be precisely measured on a single assay. It may be therefore, that a panel of polymorphisms associated with levels of HDL or LDL cholesterol may eventually provide more precise prediction of cardiovascular outcomes than LDL or HDL levels alone. In this study the authors assign equal weight to genotype score for each unfavorable allele regardless of the effect of each on cholesterol levels. Therefore, the effects of various alleles may have been over- or under-estimated. Future research will clarify the true effect on cholesterol levels of each unfavorable allele.