Year: 2009
Type: editorial
Abstract: Despite several observational studies showing that lipoprotein(a), or Lp(a), is associated with myocardial infarction (MI) 1,2 , only circumstantial evidence exists regarding the causal nature of this association.Observational epidemiological studies, even with a sound prospective design, can provide hints to disease pathogenesis when the effect size is modest but cannot provide definitive evidence for causal relationships.Much of the current understanding of the causal factors in cardiovascular disease, such as the role of LDL, has been confirmed by randomized clinical trials (RCT) 3,4 .However, RCTs are not always feasible.In the case of Lp(a), the modest effect size and the lack of specific Lp(a) lowering therapy are major obstacles to obtaining causal evidence for its role in cardiovascular disease.In this issue of JAMA, Kamstrup and colleagues 5 provide insights using a "Mendelian randomization" approach and provide evidence for the causal role of Lp(a) in MI.This study elegantly demonstrates how Mendelian randomization can be used to improve the evidence for causality from observational studies and highlights the advantages and limitations of such an approach.The study by Kamstrup et al., can be viewed as a form of natural "randomized trial" of plasma Lp(a) level on myocardial infarction, with a few important differences from traditional clinical trials.Instead of using drug therapy to decrease plasma Lp(a) levels, genetic variation in the lipoprotein apo(a) gene, LPA, that controls plasma levels of Lp(a) are used."Randomization", which minimizes the effect of confounding variables, is achieved through the random assortment of these LPA gene variants from parents to offspring that occurs duringgamete formation and conception.In this way, because LPA variants are randomly assigned, they are unlikely to associate with other nongenetic factors, such as lifestyle factors, that could act as confounders, thereby providing an unbiased assessment of the role of Lp(a) in MI.Lp(a) represents an excellent example of a genetic exposure that can be evaluated using the Mendelian randomization approach.Such an approach requires highly accurate quantitation of the triangulation of three associations: LPA gene variants and serum Lp(a) levels, serum Lp(a) levels and myocardial infarction, and LPA gene variants and myocardial infarction.Much of the population variation (30-60%) in Lp(a) levels is explained by the number of copy number variants, known as KIV-2 repeats, a form of structural variation, in the LPA gene 5, 6 .With increasing number of KIV-2 repeats in the LPA gene, plasma levels of Lp(a) are reduced.In the Copenhagen City Heart Study (CCHS), the authors demonstrate that this
Source: JAMA
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funder: National Institutes of Health
Award: G4705346009
OpenAlex ID: W2071135141