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Polymorphisms associated with cholesterol and risk of cardiovascular events. |
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Notes for this articleRisk factor identification in the 21st century will be changing many of the current ways we practice. The current paper by Kathiresan et al points out the use of single nucleotide polymorphisms (SNPs) with associated links to LDL/HDL cholesterol levels and cardiovascular events. In this study of 5414 patients over a 10 year period in the Malmo Diet and Cancer Study, SNPs at nine loci were evaluated and then correlated to lipid values with clinical cardiovascular events. They used a genotype scoring system that represented the number of unfavorable alleles. The alleles that were selected correlated to LDL and HDL cholesterol. The nine alleles used were APOB rs693, APOE cluster rs4420638, HMGCR rs12654264, LDLR rs1529729, PCSK9 rs11591147, ABCA1 rs3890182, CETP rs1800775, LIPC rs1800588, and LPL rs328. Certainly, to the clinician these look somewhat foreign but to the research scientist there more common. I would strongly suggest you look at this impressive paper in the journal, but for a short summary they were able to predict cardiovascular events by the genotype score along with the correlation with both HDL and LDL levels. Patients with greater than 13 genotype score at 10 years had 8-9% cardiovascular event rate vs less than 6 genotypes approximately 2-3%. The higher the number of unfavorable alleles, the higher the LDL level and lower HDL. This correlation was found to be significant. In summary, if genotyping becomes easy to obtain at a reasonable cost, it would help further risk stratify patients and possibly lead to early beneficial treatments.--Robert J. Chilton, DO
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Posting History AbstractBACKGROUND: Common single-nucleotide polymorphisms (SNPs) that are associated with blood low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol modestly affect lipid levels. We tested the hypothesis that a combination of such SNPs contributes to the risk of cardiovascular disease. METHODS: We studied SNPs at nine loci in 5414 subjects from the cardiovascular cohort of the Malmö Diet and Cancer Study. We first validated the association between SNPs and either LDL or HDL cholesterol and subsequently created a genotype score on the basis of the number of unfavorable alleles. We used Cox proportional-hazards models to determine the time to the first cardiovascular event in relation to the genotype score. RESULTS: All nine SNPs showed replication of an association with levels of either LDL or HDL cholesterol. With increasing genotype scores, the level of LDL cholesterol increased from 152 mg to 171 mg per deciliter (3.9 to 4.4 mmol per liter), whereas HDL cholesterol decreased from 60 mg to 51 mg per deciliter (1.6 to 1.3 mmol per liter). During follow-up (median, 10.6 years), 238 subjects had a first cardiovascular event. The genotype score was associated with incident cardiovascular disease in models adjusted for covariates including baseline lipid levels (P<0.001). The use of the genotype score did not improve the clinical risk prediction, as assessed by the C statistic. However, there was a significant improvement in risk classification with the use of models that included the genotype score, as compared with those that did not include the genotype score. CONCLUSIONS: A genotype score of nine validated SNPs that are associated with modulation in levels of LDL or HDL cholesterol was an independent risk factor for incident cardiovascular disease. The score did not improve risk discrimination but did modestly improve clinical risk reclassification for individual subjects beyond standard clinical factors.
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