New study uses gene variants to predict cardiovascular risk

March 22, 2008 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Genome-wide studies have identified a number of gene variants that are associated with altered levels of HDL and LDL cholesterol. Researchers have now tested whether inheritance of these gene variants might predict future cardiovascular events, independently of lipoprotein levels. The study, published in the New England Journal of Medicine, suggests that evaluation of an individual’s genetic profile might aid in cardiovascular risk stratification.

The gene variants are called single-nucleotide polymorphisms (SNPs), sequence differences among alleles of a gene that might or might not have known effects on expression or function of the encoded protein. Many SNPs of genes associated with lipoprotein metabolism have been characterized, some of which appear to have effects on lipoprotein level. Researchers asked whether 9 different SNPs at 9 different genes can be used in combination to assess individual's risk. The SNPs chosen occurred in genes for apolipoprotein B, apolipoprotein E, HMG CoA Reductase, LDL receptor, proprotein convertase subtilisin/kexin type 9, ATP-binding cassette subfamily A member 1, cholesteryl ester transfer protein, hepatic lipase, & lipoprotein lipase.

SNPs were sequenced from 5414 patients from the Malmö Diet and Cancer Study. The mean age was 58 years, 59% were women, and all were of European ancestry. Median follow up was 10.6 years. The prespecified end point was a composite of myocardial infarction, ischemic stroke, or death from coronary heart disease. A genotype score was calculated based on how many copies of risk-associated SNPs an individual had (highest possible score of 9 SNPs x 2 alleles = 18). Genotype scores were compared to baseline LDL and HDL levels adjusted for age, sex, and diabetes status. There was a statistically significant association between genotype score and lipoprotein level. Mean LDL / HDL values were 152 / 60 mg/dL for those with genotype score less than 6, and 172 / 51 mg/dL for those with genotype score of >13. In multivariate analysis, the genotype score was statistically associated with time to the first cardiovascular event, with a relative risk of 1.15 per unfavorable allele copy (CI 1.07–1.24), p<0.001). Incorporating genotype score into a prediction model along with established coronary heart disease risk factors did not, however, improve the ability to predict the primary outcome.

The authors propose that a genetic risk assessment might add information in addition to a point measurement of lipoprotein level because the genetic approach can better assess lifetime risk. For complex continuous traits such as lipoprotein levels, the genetic contribution to phenotype comprises the effects of multiple genes in combination. As more and more associations are uncovered, our ability to individualize treatments and risk assessments will expand greatly. The authors or this study took a simplistic, almost proof-of-concent approach – they analyzed candidate SNPs in genes with known functions in lipoprotein metabolism, and weighted each SNP equally. In this way, the concept is clear and the promise of this approach is obvious.