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

[21] High copper selectively alters lipid metabolism and cell cycle machinery in the mouse model of Wilson disease [J].

Huster, Dominik ;

Purnat, Tina D. ;

Burkhead, Jason L. ;

Ralle, Martina ;

Fiehn, Oliver ;

Stuckert, Franziska ;

Olson, N. Erik ;

Teupser, Daniel ;

Lutsenko, Svetlana .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (11) :8343-8355

[22] Phytosterols and vascular disease [J].

John, Saji ;

Sorokin, Alexey V. ;

Thompson, Paul D. .

CURRENT OPINION IN LIPIDOLOGY, 2007, 18 (01) :35-40

[23] ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin [J].

Kajinami, K ;

Brousseau, ME ;

Nartsupha, C ;

Ordovas, JM ;

Schaefer, EJ .

JOURNAL OF LIPID RESEARCH, 2004, 45 (04) :653-656

[24] Common variants at 30 loci contribute to polygenic dyslipidemia [J].

Kathiresan, Sekar ;

Willer, Cristen J. ;

Peloso, Gina M. ;

Demissie, Serkalem ;

Musunuru, Kiran ;

Schadt, Eric E. ;

Kaplan, Lee ;

Bennett, Derrick ;

Li, Yun ;

Tanaka, Toshiko ;

Voight, Benjamin F. ;

Bonnycastle, Lori L. ;

Jackson, Anne U. ;

Crawford, Gabriel ;

Surti, Aarti ;

Guiducci, Candace ;

Burtt, Noel P. ;

Parish, Sarah ;

Clarke, Robert ;

Zelenika, Diana ;

Kubalanza, Kari A. ;

Morken, Mario A. ;

Scott, Laura J. ;

Stringham, Heather M. ;

Galan, Pilar ;

Swift, Amy J. ;

Kuusisto, Johanna ;

Bergman, Richard N. ;

Sundvall, Jouko ;

Laakso, Markku ;

Ferrucci, Luigi ;

Scheet, Paul ;

Sanna, Serena ;

Uda, Manuela ;

Yang, Qiong ;

Lunetta, Kathryn L. ;

Dupuis, Josee ;

de Bakker, Paul I. W. ;

O'Donnell, Christopher J. ;

Chambers, John C. ;

Kooner, Jaspal S. ;

Hercberg, Serge ;

Meneton, Pierre ;

Lakatta, Edward G. ;

Scuteri, Angelo ;

Schlessinger, David ;

Tuomilehto, Jaakko ;

Collins, Francis S. ;

Groop, Leif ;

Altshuler, David .

NATURE GENETICS, 2009, 41 (01) :56-65

[25] Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants [J].

Kathiresan, Sekar ;

Altschuler, David ;

Anand, Sonia ;

Ardissino, Diego ;

Asselta, Rosanna ;

Ball, Stephen G. ;

Balmforth, Anthony J. ;

Berger, Klaus ;

Berglund, Goran ;

Bernardi, Francesco ;

Bernardinelli, Luisa ;

Berzuini, Carlo ;

Braund, Peter S. ;

Burnett, Mary-Susan ;

Burtt, Noel ;

Cambien, Francois ;

Casari, Giorgio ;

Celli, Patrizia ;

Chen, Zhen ;

Corrocher, Roberto ;

Daly, Mark J. ;

Deloukas, Panos ;

Devaney, Joe ;

Do, Ron ;

Duga, Stefano ;

Elosua, Roberto ;

Engert, James C. ;

Epstein, Stephen E. ;

Erdmann, Jeanette ;

Ferrario, Maurizio ;

Fetiveau, Raffaela ;

Fischer, Marcus ;

Friedlander, Yechiel ;

Gabriel, Stacey B. ;

Galli, Michele ;

Gianniny, Lauren ;

Girelli, Domenico ;

Grosshennig, Anika ;

Guiducci, Candace ;

Hakonarson, Hakon H. ;

Hall, Alistair S. ;

Havulinna, Aki S. ;

Hengstenberg, Christian ;

Hirschhorn, Joel N. ;

Holm, Hilma ;

Huge, Andreas ;

Kent, Kenneth M. ;

Konig, Inke R. ;

Korn, Joshua M. ;

Li, Mingyao .

NATURE GENETICS, 2009, 41 (03) :334-341

[26] Polymorphisms of the P-selectin gene and risk of myocardial infarction in men and women in the ECTIM extension study [J].

Kee, F ;

Morrison, C ;

Evans, AE ;

McCrum, E ;

McMaster, D ;

Dallongeville, J ;

Nicaud, V ;

Poirier, O ;

Cambien, F .

HEART, 2000, 84 (05) :548-551

[27] New reference intervals for thyrotropin and thyroid hormones based on national academy of clinical biochemistry criteria and regular ultrasonography of the thyroid [J].

Kratzsch, J ;

Fiedler, GM ;

Leichtle, A ;

Brügel, M ;

Buchbinder, S ;

Otto, L ;

Sabri, O ;

Matthes, G ;

Thiery, J .

CLINICAL CHEMISTRY, 2005, 51 (08) :1480-1486

[28] PopGen: Population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships [J].

Krawczak, M ;

Nikolaus, S ;

von Eberstein, H ;

Croucher, PJP ;

El Mokhtari, NE ;

Schreiber, S .

COMMUNITY GENETICS, 2006, 9 (01) :55-61

[29] Rapid quantification of free and esterified phytosterols in human serum using APPI-LC-MS/MS [J].

Lembcke, J ;

Ceglarek, U ;

Fiedler, GM ;

Baumann, S ;

Leichtle, A ;

Thiery, J .

JOURNAL OF LIPID RESEARCH, 2005, 46 (01) :21-26

[30] The population-based acute myocardial infarction (AMI) registry of the MONICA/KORA study region of Augsburg [J].

Löwel, H ;

Meisinger, C ;

Heier, M ;

Hörmann, A .

GESUNDHEITSWESEN, 2005, 67 :S31-S37

← 1 2 3 4 5 →