Common Variants for Cardiovascular Disease
Clinical Utility Confirmed
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Article, see p 2091
The increase in sample size of genome-wide association study (GWAS) meta-analyses has led to the identification now of >150 common variants/single-nucleotide polymorphisms (SNPs) that are robustly associated with cardiovascular disease (CVD), coronary heart disease (CHD), or CVD traits such as coronary calcification (http://www.ebi.ac.uk/gwas/). For example, in 2013, the CARDIoGRAMplusC4D Consortium, with 63 746 cases with coronary artery disease and 130 681 controls,1 identified 15 novel loci, taking the number of statistically robust CVD SNPs to 46, with a further 104 SNPs associated with CVD at a 5% false discovery rate. Together, these variants explained ≈10.6% of CVD heritability. Many of these loci identified are known to be involved in lipid metabolism,2 as would be expected from our knowledge of the importance of dyslipidemia in the development of CVD, with 12 of 46 CARDIoGRAMplusC4D SNPs showing a significant association with a lipid trait.
These SNPs, located throughout the human genome, are common (frequency >5% for all), with the odds ratio for disease ranging from ≈30% higher risk for carriers of top-ranking GWAS risk variants at the chromosome 9p CDKN2A/2B locus to only 7% to 8% higher risk for carriers of SNPs at the loci for PCSK9 (chromosome 2) or for HNF1A (chromosome 12). Because all of these odds ratios are modest, questions arise as to what the potential clinical utility of these SNPs is and how we can use these genetic tools to explore the inherited contribution to CVD.
Given the relatively small effect sizes associated with these risk loci, it is unsurprising that the addition of 1 variant into a classic risk factor (CRF) risk score does not result in improved predictive ability.3 This has led to the development of so-called genetic risk scores (GRSs) for which SNPs at independent loci are combined. A GRS …