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

ABSTRACT: 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.

SUBMITTER: Do R

PROVIDER: S-EPMC4319990 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Do Ron R Stitziel Nathan O NO Won Hong-Hee HH Jørgensen Anders Berg AB Duga Stefano S Angelica Merlini Pier P Kiezun Adam A Farrall Martin M Goel Anuj A Zuk Or O Guella Illaria I Asselta Rosanna R Lange Leslie A LA Peloso Gina M GM Auer Paul L PL Girelli Domenico D Martinelli Nicola N Farlow Deborah N DN DePristo Mark A MA Roberts Robert R Stewart Alexander F R AF Saleheen Danish D Danesh John J Epstein Stephen E SE Sivapalaratnam Suthesh S Hovingh G Kees GK Kastelein John J JJ Samani Nilesh J NJ Schunkert Heribert H Erdmann Jeanette J Shah Svati H SH Kraus William E WE Davies Robert R Nikpay Majid M Johansen Christopher T CT Wang Jian J Hegele Robert A RA Hechter Eliana E Marz Winfried W Kleber Marcus E ME Huang Jie J Johnson Andrew D AD Li Mingyao M Burke Greg L GL Gross Myron M Liu Yongmei Y Assimes Themistocles L TL Heiss Gerardo G Lange Ethan M EM Folsom Aaron R AR Taylor Herman A HA Olivieri Oliviero O Hamsten Anders A Clarke Robert R Reilly Dermot F DF Yin Wu W Rivas Manuel A MA Donnelly Peter P Rossouw Jacques E JE Psaty Bruce M BM Herrington David M DM Wilson James G JG Rich Stephen S SS Bamshad Michael J MJ Tracy Russell P RP Cupples L Adrienne LA Rader Daniel J DJ Reilly Muredach P MP Spertus John A JA Cresci Sharon S Hartiala Jaana J Tang W H Wilson WH Hazen Stanley L SL Allayee Hooman H Reiner Alex P AP Carlson Christopher S CS Kooperberg Charles C Jackson Rebecca D RD Boerwinkle Eric E Lander Eric S ES Schwartz Stephen M SM Siscovick David S DS McPherson Ruth R Tybjaerg-Hansen Anne A Abecasis Goncalo R GR Watkins Hugh H Nickerson Deborah A DA Ardissino Diego D Sunyaev Shamil R SR O'Donnell Christopher J CJ Altshuler David D Gabriel Stacey S Kathiresan Sekar S

Nature 20141210 7537

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 ...[more]

PMID: 25487149

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Project description:BACKGROUND: Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. OBJECTIVE: To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. DESIGN: DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. RESULTS: Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients. CONCLUSION: For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease.

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

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

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