Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

Abstract

Summary Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, the role of inheritance is substantially greater1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3–8 whereas common variants at more than 45 loci have been associated with MI risk in the population9–15. Here, we evaluate the contribution of rare mutations to MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes where rare coding-sequence mutations were more frequent in cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare, damaging mutations (3.1% of cases versus 1.3% of controls) were at 2.4-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). This sequence-based estimate of the proportion of early MI cases due to LDLR mutations is remarkably similar to an estimate made more than 40 years ago using total cholesterol16. At apolipoprotein A-V (APOA5), carriers of rare nonsynonymous mutations (1.4% of cases versus 0.6% of controls) were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C318,19. When combined, these observations suggest that, beyond LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

“…This becomes even more apparent since we also detected a missense variant in the LPL gene, which led to a 20% reduction in LPL activity, to be associated with increased risk for CAD (Stitziel et al , 2016). The findings for LPL and ANGPTL4 confirm recent results for two other regulators of LPL activity, APOA5 and APOC3, in that rare APOA5 mutations increase both plasma triglyceride levels and risk of CAD (Do et al , 2015), whereas rare loss‐of‐function mutations in the APOC3 gene have opposite effects (The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, 2014). Taken together, LPL activity seems to have a central role in triglyceride metabolism (Fig 3A) and consecutively CAD risk (Fig 4).…”

The effect of phenotypic outliers and non-normality on rare-variant association testing

“…1 Recently, there has been a deepening interest in evaluating the extent to which rare variants contribute to variation in complex traits and diseases. [2][3][4][5][6][7][8][9] This has motivated development of statistical methods for testing rare-variant associations at the gene level. [10][11][12][13][14][15][16] Although these methods are useful for increasing statistical power to detect associations relative to single-variant analyses, valid well-powered statistical analyses are contingent on careful examination of phenotypes and underlying assumptions.…”

High Triglycerides Are Associated With Increased Cardiovascular Events, Medical Costs, and Resource Use: A Real‐World Administrative Claims Analysis of Statin‐Treated Patients With High Residual Cardiovascular Risk

“…Epidemiologic studies have shown that elevated triglycerides correlate with elevated cardiovascular risk,4, 5 and the American Heart Association has long recognized that elevated triglycerides are an important marker of cardiovascular risk 6. More recently, genetic,7, 8, 9, 10, 11, 12, 13 genome‐wide analysis,14, 15, 16, 17 and mendelian randomization18, 19, 20, 21, 22 studies have suggested a causal role for triglycerides as a modifiable risk factor in the development and progression of ASCVD. Analyses from clinical data have demonstrated that lower on‐treatment triglycerides correlate with reduced cardiovascular risk 23, 24…”