Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease

被引：782

作者：

Crosby, Jacy ^{[1
,2
]}

Peloso, Gina M. ^{[5
,6
,7
,11
]}

Auer, Paul L. ^{[12
]}

Crosslin, David R. ^{[13
,14
]}

Stitziel, Nathan O. ^{[20
,21
]}

Lange, Leslie A. ^{[22
]}

Lu, Yingchang ^{[26
]}

Tang, Zheng-zheng ^{[23
]}

Zhang, He ^{[28
,29
,30
]}

Hindy, George ^{[34
]}

Masca, Nicholas ^{[39
,40
]}

Stirrups, Kathleen ^{[41
]}

Kanoni, Stavroula ^{[41
]}

Do, Ron ^{[5
,6
,7
,11
]}

Jun, Goo ^{[31
]}

Hu, Youna ^{[31
]}

Kang, Hyun Min ^{[31
]}

Xue, Chenyi ^{[29
]}

Goel, Anuj ^{[42
]}

Farrall, Martin ^{[42
]}

Duga, Stefano ^{[47
]}

Merlini, Pier Angelica ^{[48
]}

Asselta, Rosanna ^{[47
]}

Girelli, Domenico ^{[49
]}

Olivieri, Oliviero ^{[49
]}

Martinelli, Nicola ^{[49
]}

Yin, Wu ^{[8
]}

Reilly, Dermot ^{[8
]}

Speliotes, Elizabeth ^{[28
,29
,32
]}

Fox, Caroline S. ^{[51
,52
]}

Hveem, Kristian ^{[53
,54
]}

Holmen, Oddgeir L. ^{[53
,55
]}

Nikpay, Majid ^{[56
]}

Farlow, Deborah N. ^{[11
]}

Assimes, Themistocles L. ^{[57
]}

Franceschini, Nora ^{[24
]}

Robinson, Jennifer ^{[58
,59
]}

North, Kari E. ^{[24
,25
]}

Martin, Lisa W. ^{[60
]}

DePristo, Mark ^{[11
]}

Gupta, Namrata ^{[11
]}

Escher, Stefan A. ^{[35
]}

Jansson, Jan-Hakan ^{[37
,38
]}

Van Zuydam, Natalie ^{[43
]}

Palmer, Colin N. A. ^{[43
]}

Wareham, Nicholas ^{[44
]}

Koch, Werner ^{[61
,62
,64
]}

Meitinger, Thomas ^{[63
]}

Peters, Annette ^{[64
,65
]}

Lieb, Wolfgang ^{[66
]}

机构：

[1] Univ Texas Houston, Dept Biostat Bioinformat & Syst Biol, Grad Sch Biomed Sci, Houston, TX USA

[2] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[3] Baylor Coll Med, Houston, TX 77030 USA

[4] Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA

[5] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[6] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[8] Merck Sharp & Dohme Ltd, Boston, MA USA

[9] Tufts Univ, Nutr & Genom Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA

[10] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[11] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[12] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA

[13] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[14] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA

[15] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[16] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA

[17] Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA

[18] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA

[19] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA

[20] Washington Univ, Sch Med, Dept Med, Cardiovasc Div, St Louis, MO 63130 USA

[21] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63130 USA

[22] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[23] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA

[24] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[25] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA

[26] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA

[27] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA

[28] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[29] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[30] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[31] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[32] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA

[33] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[34] Lund Univ, Dept Clin Sci, Clin Res Ctr, Malmo, Sweden

[35] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden

[36] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[37] Skelleftea Hosp, Dept Med, Skelleftea, Sweden

[38] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden

[39] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[40] Natl Inst Hlth Res Leicester, Cardiovasc Biomed Res Unit, Leicester, Leics, England

[41] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England

[42] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Wellcome Trust Ctr Human Genet, Oxford, England

[43] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland

[44] Addenbrookes Hosp, Med Res Council Epidemiol Unit, Inst Metab Sci, Cambridge, England

[45] Wellcome Trust Sanger Inst, Cambridge, England

[46] Univ Leeds, Sch Med, Div Epidemiol, Leeds LS2 9JT, W Yorkshire, England

[47] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, Milan, Italy

[48] Osped Niguarda Ca Granda, Div Cardiol, Milan, Italy

[49] Univ Verona, Dept Med, Sch Med, I-37100 Verona, Italy

[50] Azienda Osped Univ Parma, Div Cardiol, Parma, Italy

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2014年 / 371卷 / 01期

关键词：

APOLIPOPROTEIN C-III; CARDIOVASCULAR-DISEASE; PLASMA TRIGLYCERIDES; RICH LIPOPROTEINS; RARE VARIANTS; PCSK9; ASSOCIATIONS; INHIBITION; CAPTURE; DESIGN;

D O I：

10.1056/NEJMoa1307095

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-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 = 4x10(-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.)

引用

页码：22 / 31

页数：10

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