TY - JOUR T1 - Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. JF - Am J Hum Genet Y1 - 2014 A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Voorman, Arend A1 - Morrison, Alanna C A1 - Stitziel, Nathan O A1 - Brody, Jennifer A A1 - Khetarpal, Sumeet A A1 - Crosby, Jacy R A1 - Fornage, Myriam A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Feitosa, Mary F A1 - Davies, Gail A1 - Huffman, Jennifer E A1 - Manichaikul, Ani A1 - Davis, Brian A1 - Lohman, Kurt A1 - Joon, Aron Y A1 - Smith, Albert V A1 - Grove, Megan L A1 - Zanoni, Paolo A1 - Redon, Valeska A1 - Demissie, Serkalem A1 - Lawson, Kim A1 - Peters, Ulrike A1 - Carlson, Christopher A1 - Jackson, Rebecca D A1 - Ryckman, Kelli K A1 - Mackey, Rachel H A1 - Robinson, Jennifer G A1 - Siscovick, David S A1 - Schreiner, Pamela J A1 - Mychaleckyj, Josyf C A1 - Pankow, James S A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Harris, Tamara B A1 - Taylor, Kent D A1 - Stafford, Jeanette M A1 - Reynolds, Lindsay M A1 - Marioni, Riccardo E A1 - Dehghan, Abbas A1 - Franco, Oscar H A1 - Patel, Aniruddh P A1 - Lu, Yingchang A1 - Hindy, George A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - Melander, Olle A1 - Orho-Melander, Marju A1 - Loos, Ruth J F A1 - Duga, Stefano A1 - Merlini, Piera Angelica A1 - Farrall, Martin A1 - Goel, Anuj A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Shah, Svati H A1 - Kraus, William E A1 - Li, Mingyao A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - McPherson, Ruth A1 - Watkins, Hugh A1 - Ardissino, Diego A1 - Zhang, Qunyuan A1 - Wang, Judy A1 - Tsai, Michael Y A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Lange, Leslie A A1 - Starr, John M A1 - Rudan, Igor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Ordovas, Jose M A1 - Levy, Daniel A1 - Chen, Y-D Ida A1 - Reiner, Alexander P A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Borecki, Ingrid B A1 - Liu, Yongmei A1 - Gudnason, Vilmundur A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Rice, Kenneth A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar A1 - Cupples, L Adrienne KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Animals KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Code KW - Genetic Variation KW - Humans KW - Linear Models KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Microtubule-Associated Proteins KW - Middle Aged KW - Phenotype KW - Sequence Analysis, DNA KW - Subtilisins KW - Triglycerides AB -

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract ER - TY - JOUR T1 - Loss-of-function mutations in APOC3, triglycerides, and coronary disease. JF - N Engl J Med Y1 - 2014 A1 - Crosby, Jacy A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Crosslin, David R A1 - Stitziel, Nathan O A1 - Lange, Leslie A A1 - Lu, Yingchang A1 - Tang, Zheng-Zheng A1 - Zhang, He A1 - Hindy, George A1 - Masca, Nicholas A1 - Stirrups, Kathleen A1 - Kanoni, Stavroula A1 - Do, Ron A1 - Jun, Goo A1 - Hu, Youna A1 - Kang, Hyun Min A1 - Xue, Chenyi A1 - Goel, Anuj A1 - Farrall, Martin A1 - Duga, Stefano A1 - Merlini, Pier Angelica A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Olivieri, Oliviero A1 - Martinelli, Nicola A1 - Yin, Wu A1 - Reilly, Dermot A1 - Speliotes, Elizabeth A1 - Fox, Caroline S A1 - Hveem, Kristian A1 - Holmen, Oddgeir L A1 - Nikpay, Majid A1 - Farlow, Deborah N A1 - Assimes, Themistocles L A1 - Franceschini, Nora A1 - Robinson, Jennifer A1 - North, Kari E A1 - Martin, Lisa W A1 - DePristo, Mark A1 - Gupta, Namrata A1 - Escher, Stefan A A1 - Jansson, Jan-Håkan A1 - Van Zuydam, Natalie A1 - Palmer, Colin N A A1 - Wareham, Nicholas A1 - Koch, Werner A1 - Meitinger, Thomas A1 - Peters, Annette A1 - Lieb, Wolfgang A1 - Erbel, Raimund A1 - König, Inke R A1 - Kruppa, Jochen A1 - Degenhardt, Franziska A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Ballantyne, Christie M A1 - Abecasis, Goncalo A1 - Ordovas, Jose M A1 - Melander, Olle A1 - Watkins, Hugh A1 - Orho-Melander, Marju A1 - Ardissino, Diego A1 - Loos, Ruth J F A1 - McPherson, Ruth A1 - Willer, Cristen J A1 - Erdmann, Jeanette A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Deloukas, Panos A1 - Schunkert, Heribert A1 - Wilson, James G A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Lin, Dan-Yu A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Nickerson, Deborah A A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Reiner, Alex P A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar KW - African Continental Ancestry Group KW - Apolipoprotein C-III KW - Coronary Disease KW - European Continental Ancestry Group KW - Exome KW - Genotype KW - Heterozygote KW - Humans KW - Liver KW - Mutation KW - Risk Factors KW - Sequence Analysis, DNA KW - Triglycerides AB -

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.

METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)).

CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

VL - 371 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24941081?dopt=Abstract ER - TY - JOUR T1 - Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. JF - Nature Y1 - 2015 A1 - Do, Ron A1 - Stitziel, Nathan O A1 - Won, Hong-Hee A1 - Jørgensen, Anders Berg A1 - Duga, Stefano A1 - Angelica Merlini, Pier A1 - Kiezun, Adam A1 - Farrall, Martin A1 - Goel, Anuj A1 - Zuk, Or A1 - Guella, Illaria A1 - Asselta, Rosanna A1 - Lange, Leslie A A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Farlow, Deborah N A1 - DePristo, Mark A A1 - Roberts, Robert A1 - Stewart, Alexander F R A1 - Saleheen, Danish A1 - Danesh, John A1 - Epstein, Stephen E A1 - Sivapalaratnam, Suthesh A1 - Hovingh, G Kees A1 - Kastelein, John J A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Erdmann, Jeanette A1 - Shah, Svati H A1 - Kraus, William E A1 - Davies, Robert A1 - Nikpay, Majid A1 - Johansen, Christopher T A1 - Wang, Jian A1 - Hegele, Robert A A1 - Hechter, Eliana A1 - März, Winfried A1 - Kleber, Marcus E A1 - Huang, Jie A1 - Johnson, Andrew D A1 - Li, Mingyao A1 - Burke, Greg L A1 - Gross, Myron A1 - Liu, Yongmei A1 - Assimes, Themistocles L A1 - Heiss, Gerardo A1 - Lange, Ethan M A1 - Folsom, Aaron R A1 - Taylor, Herman A A1 - Olivieri, Oliviero A1 - Hamsten, Anders A1 - Clarke, Robert A1 - Reilly, Dermot F A1 - Yin, Wu A1 - Rivas, Manuel A A1 - Donnelly, Peter A1 - Rossouw, Jacques E A1 - Psaty, Bruce M A1 - Herrington, David M A1 - Wilson, James G A1 - Rich, Stephen S A1 - Bamshad, Michael J A1 - Tracy, Russell P A1 - Cupples, L Adrienne A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Spertus, John A A1 - Cresci, Sharon A1 - Hartiala, Jaana A1 - Tang, W H Wilson A1 - Hazen, Stanley L A1 - Allayee, Hooman A1 - Reiner, Alex P A1 - Carlson, Christopher S A1 - Kooperberg, Charles A1 - Jackson, Rebecca D A1 - Boerwinkle, Eric A1 - Lander, Eric S A1 - Schwartz, Stephen M A1 - Siscovick, David S A1 - McPherson, Ruth A1 - Tybjaerg-Hansen, Anne A1 - Abecasis, Goncalo R A1 - Watkins, Hugh A1 - Nickerson, Deborah A A1 - Ardissino, Diego A1 - Sunyaev, Shamil R A1 - O'Donnell, Christopher J A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Kathiresan, Sekar KW - Age Factors KW - Age of Onset KW - Alleles KW - Apolipoproteins A KW - Case-Control Studies KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Heterozygote KW - Humans KW - Male KW - Middle Aged KW - Mutation KW - Myocardial Infarction KW - National Heart, Lung, and Blood Institute (U.S.) KW - Receptors, LDL KW - Triglycerides KW - United States AB -

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.

VL - 518 IS - 7537 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract ER - TY - JOUR T1 - Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. JF - J Am Coll Cardiol Y1 - 2016 A1 - Khera, Amit V A1 - Won, Hong-Hee A1 - Peloso, Gina M A1 - Lawson, Kim S A1 - Bartz, Traci M A1 - Deng, Xuan A1 - van Leeuwen, Elisabeth M A1 - Natarajan, Pradeep A1 - Emdin, Connor A A1 - Bick, Alexander G A1 - Morrison, Alanna C A1 - Brody, Jennifer A A1 - Gupta, Namrata A1 - Nomura, Akihiro A1 - Kessler, Thorsten A1 - Duga, Stefano A1 - Bis, Joshua C A1 - van Duijn, Cornelia M A1 - Cupples, L Adrienne A1 - Psaty, Bruce A1 - Rader, Daniel J A1 - Danesh, John A1 - Schunkert, Heribert A1 - McPherson, Ruth A1 - Farrall, Martin A1 - Watkins, Hugh A1 - Lander, Eric A1 - Wilson, James G A1 - Correa, Adolfo A1 - Boerwinkle, Eric A1 - Merlini, Piera Angelica A1 - Ardissino, Diego A1 - Saleheen, Danish A1 - Gabriel, Stacey A1 - Kathiresan, Sekar AB -

BACKGROUND: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement.

OBJECTIVES: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.

METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.

RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.

CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.

VL - 67 IS - 22 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27050191?dopt=Abstract ER -