Mendelian randomization: Its impact on cardiovascular disease

Abstract

Cardiovascular diseases and their risk factors are inheritable. Single nucleotide polymorphisms in the human genome are found in around 1 in 1000 base pairs, and this may affect the genetic variety of individuals. During meiosis, any genetic information is randomized and is independent of other characteristics. In a Mendelian randomization study (MRS), a genetic variant associated with biomarker is used as a proxy for the biomarker, and the outcomes are compared between the groups harboring the effect alleles and a group with the reference allele. An MRS using variants of both rare and modest effect sizes and variants of common and lower effect sizes provides an understanding of risk factors and their causality of cardiovascular disease; for example, an individual possessing an allele associated with lower low-density lipoprotein cholesterol (LDL-C) exhibits lower risk of coronary artery disease (CAD). Moreover, the log-transformed reduction rates of CAD are linearly correlated with the reduction value of LDL-C. High-density lipoprotein (HDL) removes cholesteryl esters from peripheral tissues, including atherosclerotic plaque to the liver. Numerous epidemiological studies have shown that HDL-cholesterol (HDL-C) levels are inversely associated with the frequency of the occurrence of CAD. However, genetic variants, which are only associated with higher HDL-C levels, do not decrease the frequency of myocardial infarction. This fact shows that HDL-C level is not a cause but a biomarker of CAD. Discoveries of rare variants in Mendelian disorders resulted in the successful development of drugs for the general population. An MRS may also predict the pharmacological effectiveness and adverse side effects of novel drugs targeting specific molecules. An MRS could become a standard process to be performed before the development of novel drugs. Furthermore, future guidelines for the prevention of CAD should consider the genetic information of individuals, which will result in precision medicine for cardiovascular diseases.

Keywords: Mendelian randomization study; Randomized controlled trial; Risk factor.