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 None., 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., Lange EM., 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.
Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. 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 in males 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. 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 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.