Genome-wide association study for residualized-apolipoprotein B elucidates the role of apolipoprotein B in coronary artery disease risk
Zhang, S. K.; Koyama, S.; Bellomo, T. R.; Haidermota, S.; Hornsby, W.; Honigberg, M. C.; Ellinor, P. T.; Natarajan, P.
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Apolipoprotein B (apoB) has emerged as a more accurate predictor of coronary artery disease risk relative to standard lipid measurements like low-density lipoprotein cholesterol (LDL-C). Here, we sought to characterize the clinical associations and genetics underlying apoB and LDL-C discordance. We derived a residualized-apoB phenotype, defined as observed minus expected apoB for an individual given their LDL-C level, in 239,144 individuals in the UK and Mass General Brigham Biobanks. Higher residualized-apoB was independently associated with increased risk of myocardial infarction (hazard ratio = 1.30 per standard deviation change, {Delta}R2 = 10%). Genome-wide association analyses identified 137 significant loci for residualized-apoB, including 16 unique genomic loci significant only in residualized-apoB in our study and 2 loci not previously described in lipid studies. Key loci implicated genes involved in lipid metabolism and cardiovascular disease (i.e. NPR2, RORA) and were also linked to other metabolic traits, suggesting broader metabolic relevance.
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