Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance(1,2). When MI occurs early in life, genetic inheritance is a major component to risk(1). Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk inindividual families(3-8), whereas common variants at more than 45 loci have been associated with MI risk in the population(9-15). Here we evaluate how rare mutations contribute to early-onset 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 inmales and <= 60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol(16). Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations 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 lipase(15,17) and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction / Do, R; Stitziel, No; Won, Hh; Jørgensen, Ab; Duga, S; Angelica Merlini, P; Kiezun, A; Farrall, M; Goel, A; Zuk, O; Guella, I; Asselta, R; Lange, La; Peloso, Gm; Auer, Pl; NHLBI Exome Sequencing, Project; Girelli, D; Martinelli, N; Farlow, Dn; DePristo, Ma; Roberts, R; Stewart, Af; Saleheen, D; Danesh, J; Epstein, Se; Sivapalaratnam, S; Hovingh, Gk; Kastelein, Jj; Samani, Nj; Schunkert, H; Erdmann, J; Shah, Sh; Kraus, We; Davies, R; Nikpay, M; Johansen, Ct; Wang, J; Hegele, Ra; Hechter, E; Marz, W; Kleber, Me; Huang, J; Johnson, Ad; Li, M; Burke, Gl; Gross, M; Liu, Y; Assimes, Tl; Heiss, G; LangeEM, ; Folsom, Ar; Taylor, Ha; Olivieri, O; Hamsten, A; Clarke, R; Reilly, Df; Yin, W; Rivas, Ma; Donnelly, P; Rossouw, Je; Psaty, Bm; Herrington, Dm; Wilson, Jg; Rich, Ss; Bamshad, Mj; Tracy, Rp; Cupples, La; Rader, Dj; Reilly, Mp; Spertus, Ja; Cresci, S; Hartiala, J; Tang, Wh; Hazen, Sl; Allayee, H; Reiner, Ap; Carlson, Cs; Kooperberg, C; Jackson, Rd; Boerwinkle, E; Lander, Es; Schwartz, Sm; Siscovick, Ds; McPherson, R; Tybjaerg-Hansen, A; Abecasis, Gr; Watkins, H; Nickerson, Da; Ardissino, D; Sunyaev, Sr; O'Donnell, Cj; Altshuler, D; Gabriel, S; Kathiresan, S. - In: NATURE. - ISSN 1476-4687. - 518:7537(2015), pp. 102-106. [10.1038/nature13917]

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

Ardissino D;
2015

Abstract

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance(1,2). When MI occurs early in life, genetic inheritance is a major component to risk(1). Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk inindividual families(3-8), whereas common variants at more than 45 loci have been associated with MI risk in the population(9-15). Here we evaluate how rare mutations contribute to early-onset 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 inmales and <= 60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol(16). Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations 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 lipase(15,17) and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2883849
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