Genetic Regulation of Serum Phytosterol Levels and Risk of Coronary Artery Disease

被引：138

作者：

Teupser, Daniel ^{[1
,2
]}

Baber, Ronny ^{[1
]}

Ceglarek, Uta ^{[1
,2
]}

Scholz, Markus ^{[2
,3
]}

Illig, Thomas ^{[8
]}

Gieger, Christian ^{[8
]}

Holdt, Lesca M. ^{[1
]}

Leichtle, Alexander ^{[1
]}

Greiser, Karin H. ^{[13
]}

Huster, Dominik ^{[4
]}

Linsel-Nitschke, Patrick ^{[15
]}

Schaefer, Arne ^{[17
,18
]}

Braund, Peter S. ^{[19
,20
]}

Tiret, Laurence ^{[21
]}

Stark, Klaus ^{[22
]}

Raaz-Schrauder, Dorette ^{[23
]}

Fiedler, Georg M. ^{[1
]}

Wilfert, Wolfgang ^{[1
]}

Beutner, Frank ^{[1
,2
]}

Gielen, Stephan ^{[2
,5
]}

Grosshennig, Anika ^{[15
,16
]}

Koenig, Inke R. ^{[16
]}

Lichtner, Peter ^{[9
]}

Heid, Iris M. ^{[8
,10
]}

Kluttig, Alexander ^{[13
]}

El Mokhtari, Nour E. ^{[24
]}

Rubin, Diana ^{[17
,18
]}

Ekici, Arif B. ^{[25
]}

Reis, Andre ^{[25
]}

Garlichs, Christoph D. ^{[23
]}

Hall, Alistair S. ^{[26
]}

Matthes, Gert ^{[6
]}

Wittekind, Christian ^{[7
]}

Hengstenberg, Christian ^{[22
]}

Cambien, Francois ^{[21
]}

Schreiber, Stefan ^{[17
,18
]}

Werdan, Karl ^{[14
]}

Meitinger, Thomas ^{[9
,12
]}

Loeffler, Markus ^{[2
,3
]}

Samani, Nilesh J. ^{[19
,20
]}

Erdmann, Jeanette ^{[15
]}

Wichmann, H. -Erich ^{[8
,11
]}

Schunkert, Heribert ^{[15
]}

Thiery, Joachim ^{[1
,2
]}

机构：

[1] Univ Leipzig, Inst Lab Med Clin Chem & Mol Diagnost, Leipzig, Germany

[2] Univ Leipzig, Leipzig Res Ctr Civilizat Dis LIFE, Leipzig, Germany

[3] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany

[4] Univ Leipzig, Dept Med 2, Leipzig, Germany

[5] Univ Leipzig, Ctr Heart, Dept Internal Med Cardiol, Leipzig, Germany

[6] Univ Leipzig, Inst Transfus Med, Leipzig, Germany

[7] Univ Leipzig, Inst Pathol, Leipzig, Germany

[8] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany

[9] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[10] Univ Regensburg, Med Ctr, Dept Epidemiol & Prevent Med, Regensburg, Germany

[11] Univ Munich, Inst Med Informat Biometry & Epidemiol, D-80539 Munich, Germany

[12] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany

[13] Univ Halle Wittenberg, Inst Med Epidemiol Biostat & Informat, Halle, Saale, Germany

[14] Univ Halle Wittenberg, Dept Med 3, Halle, Saale, Germany

[15] Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany

[16] Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany

[17] Univ Klinikum Schleswig Holstein, Inst Klin Mol Biol, Kiel, Germany

[18] Univ Klinikum Schleswig Holstein, Dept Internal Med 1, Kiel, Germany

[19] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England

[20] Univ Leicester, Glenfield Hosp, Leicester Natl Inst Hlth Res, Biomed Res Unit Cardiovasc Dis, Leicester, Leics, England

[21] Univ Paris, Univ Paris 06, Inst Natl Sante & Rech Med Unite INSERM, Mixte Rech UMR S937, F-75252 Paris, France

[22] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany

[23] Univ Hosp Erlangen, Dept Cardiol & Angiol, Erlangen, Germany

[24] Kreiskrankenhaus Rendsburg, Innere Med Klin, Rendsburg, Germany

[25] Univ Erlangen Nurnberg, Inst Human Genet, D-8520 Erlangen, Germany

[26] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England

来源：

CIRCULATION-CARDIOVASCULAR GENETICS | 2010年 / 3卷 / 04期

关键词：

coronary disease; genes; genetics; lipids; GENOME-WIDE ASSOCIATION; MYOCARDIAL-INFARCTION; BLOOD-GROUPS; HEART-DISEASE; PLANT STEROL; CHOLESTEROL; ABCG5; SUSCEPTIBILITY; POLYMORPHISMS; MONICA/KORA;

D O I：

10.1161/CIRCGENETICS.109.907873

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD). Methods and Results-A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n = 1495) with subsequent replication in 2 additional samples (n = 1157 and n = 1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P = 1.6 x 10(-50) and 6.2 x 10(-25), respectively; n = 4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P = 0.009). Effects at the ABO locus were related to SNP rs657152 (combined P = 9.4 x 10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P = 2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P = 9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P = 1.3 x 10(-5)). Conclusion-Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD. (Circ Cardiovasc Genet. 2010;3:331-339.)

引用

页码：331 / 339

页数：9

共 49 条

[11] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[12] Genomic control, a new approach to genetic-based association studies [J].

Devlin, B ;

Roeder, K ;

Wasserman, L .

THEORETICAL POPULATION BIOLOGY, 2001, 60 (03) :155-166

[13] SLC2A9 influences uric acid concentrations with pronounced sex-specific effects [J].

Doering, Angela ;

Gieger, Christian ;

Mehta, Divya ;

Gohlke, Henning ;

Prokisch, Holger ;

Coassin, Stefan ;

Fischer, Guido ;

Henke, Kathleen ;

Klopp, Norman ;

Kronenberg, Florian ;

Paulweber, Bernhard ;

Pfeufer, Arne ;

Rosskopf, Dieter ;

Voelzke, Henry ;

Illig, Thomas ;

Meitinger, Thomas ;

Wichmann, H-Erich ;

Meisinger, Christa .

NATURE GENETICS, 2008, 40 (04) :430-436

[14] New susceptibility locus for coronary artery disease on chromosome 3q22.3 [J].

Erdmann, Jeanette ;

Grosshennig, Anika ;

Braund, Peter S. ;

Koenig, Inke R. ;

Hengstenberg, Christian ;

Hall, Alistair S. ;

Linsel-Nitschke, Patrick ;

Kathiresan, Sekar ;

Wright, Ben ;

Tregouet, David-Alexandre ;

Cambien, Francois ;

Bruse, Petra ;

Aherrahrou, Zouhair ;

Wagner, Arnika K. ;

Stark, Klaus ;

Schwartz, Stephen M. ;

Salomaa, Veikko ;

Elosua, Roberto ;

Melander, Olle ;

Voight, Benjamin F. ;

O'Donnell, Christopher J. ;

Peltonen, Leena ;

Siscovick, David S. ;

Altshuler, David ;

Merlini, Piera Angelica ;

Peyvandi, Flora ;

Bernardinelli, Luisa ;

Ardissino, Diego ;

Schillert, Arne ;

Blankenberg, Stefan ;

Zeller, Tanja ;

Wild, Philipp ;

Schwarz, Daniel F. ;

Tiret, Laurence ;

Perret, Claire ;

Schreiber, Stefan ;

El Mokhtari, Nour Eddine ;

Schaefer, Arne ;

Maerz, Winfried ;

Renner, Wilfried ;

Bugert, Peter ;

Klueter, Harald ;

Schrezenmeir, Juergen ;

Rubin, Diana ;

Ball, Stephen G. ;

Balmforth, Anthony J. ;

Wichmann, H-Erich ;

Meitinger, Thomas ;

Fischer, Marcus ;

Meisinger, Christa .

NATURE GENETICS, 2009, 41 (03) :280-282

[15] Customary use of plant sterol and plant stanol enriched margarine is associated with changes in serum plant sterol and stanol concentrations in humans [J].

Fransen, Heidi P. ;

de Jong, Nynke ;

Wolfs, Marion ;

Verhagen, Hans ;

Verschuren, W. M. Monique ;

Luetjohann, Dieter ;

von Bergmann, Klaus ;

Plat, Jogchum ;

Mensink, Ronald P. .

JOURNAL OF NUTRITION, 2007, 137 (05) :1301-1306

[16] ABO BLOOD-GROUP AND CARDIOVASCULAR DISEASE - FRAMINGHAM STUDY [J].

GARRISON, RJ ;

HAVLIK, RJ ;

HARRIS, RB ;

FEINLEIB, M ;

KANNEL, WB ;

PADGETT, SJ .

ATHEROSCLEROSIS, 1976, 25 (2-3) :311-318

[17] Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface [J].

Graf, GA ;

Li, WP ;

Gerard, RD ;

Gelissen, I ;

White, A ;

Cohen, JC ;

Hobbs, HH .

JOURNAL OF CLINICAL INVESTIGATION, 2002, 110 (05) :659-669

[18] Cardiovascular disease, risk factors and heart rate variability in the elderly general population: Design and objectives of the CARdiovascular disease, Living and Ageing in Halle (CARLA) Study [J].

Greiser K.H. ;

Kluttig A. ;

Schumann B. ;

Kors J.A. ;

Swenne C.A. ;

Kuss O. ;

Werdan K. ;

Haerting J. .

BMC Cardiovascular Disorders, 5 (1)

[19] Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption and insulin sensitivity [J].

Gylling, H ;

Hallikainen, M ;

Pihlakamäki, J ;

Ågren, J ;

Laakso, M ;

Rajaratnam, RA ;

Rauramaa, R ;

Miettinen, TA .

JOURNAL OF LIPID RESEARCH, 2004, 45 (09) :1660-1665

[20] KORA -: A research platform for population based health research [J].

Holle, R ;

Happich, M ;

Löwel, H ;

Wichmann, HE .

GESUNDHEITSWESEN, 2005, 67 :S19-S25

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