How effective is the PRS in stratifying for CAD risk? Does genetic risk respond to treatment? This will provoke at least two questions. This enables one to determine the risk for CAD any time after birth and initiate early prevention. Risk due to one’s DNA is determined at the time of conception and does not change in one’s lifetime. Short of treating everyone with increased plasma cholesterol, knowing 50% will not benefit but be exposed to the same side effects and cost, why not risk stratify using the PRS. Plasma cholesterol, a primary causative factor for CAD, also increases with age but already exceeds the recommended level of 70 mg/dL in men and women by the fourth decade. ![]() The conventional risk factors are age-dependent and often not increased to provide risk stratification until the fifth or sixth decade. Secondly, CAD, which starts early in life, develops gradually and is more effectively prevented by early prevention. It is claimed 50% of individuals will experience at least 1 cardiac event in their lifetime. Primary prevention is also effective but limited due to a lack of means to detect those at increased risk. Secondary prevention of the clinical sequelae of CAD has been very effective. The genetic risk for CAD is proportional to the number of genetic risk variants inherited, so can be expressed as a single number referred to as a Polygenic Risk Score (PRS).ĬONVENTIONAL RISK FACTORS FOR CAD ARE LESS THAN ADEQUATE TO STRATIFY FOR PRIMARY PREVENTIONĪ major interest is whether the PRS would effectively improve risk stratification for CAD. The mechanism mediating the risk for CAD is unknown for over half of the genetic risk variants. Thus, the risk is mediated by increasing or decreasing the expression of protein-coding genes. Each genetic risk variant imparts minimal increased risk for CAD with over 80% occurring in non-protein-coding regions of the genome. The formation of international consortia led by CARDIoGRAMplusC4D enabled sample sizes of hundreds of thousands leading to the discovery of hundreds of genetic risk variants predisposing to CAD. Utilizing GWAS and SNPs as markers, the first genetic risk variant for CAD was discovered on the short arm (p) of chromosome 9 (9p21). claim that 80% of individual human attributes are due to these SNPs. ![]() Included within the 1% are SNPs of which the number has remained fairly constant at about 5 million per genome. The human DNA sequence is 99% identical with the remaining 1% being unique sequences responsible for the individual distinguishing features. ![]() HapMap Project mapped and annotated millions of single nucleotide polymorphisms (SNPs) which provided the DNA markers necessary to pursue genome-wide association studies (GWAS). Recent scientific contributions predominantly, the Human Genome and HapMap Projects, enabled us to pursue the discovery of the DNA variants contributing to polygenic disorders. Genetic linkage analysis of pedigree’s provided the golden era for discovering genes responsible for single-gene disorders but was inappropriate for polygenic disorders. Unlike single-gene disorders, the phenotype of common disorders such as CAD is due to multiple genes interacting with multiple acquired factors. DISCOVERY OF GENETIC RISK VARIANTS PREDISPOSING TO CAD
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