Genetic analysis of atherosclerosis identifies a major susceptibility locus in the major histocompatibility complex of mice

被引：14

作者：

Grainger, Andrew T. ^{[1
]}

Jones, Michael B. ^{[2
]}

Li, Jing ^{[2
]}

Chen, Mei-Hua ^{[2
]}

Manichaikul, Ani ^{[3
]}

Shi, Weibin ^{[1
,2
]}

机构：

[1] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA

[2] Univ Virginia, Dept Radiol & Med Imaging, Charlottesville, VA USA

[3] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA

来源：

ATHEROSCLEROSIS | 2016年 / 254卷

关键词：

Atherosclerosis; Major histocompatibility complex; Quantitative trait locus; Mice; QUANTITATIVE TRAIT LOCI; CORONARY-HEART-DISEASE; CAROTID ATHEROSCLEROSIS; DEFICIENT MICE; INTERCROSS; MOUSE; C57BL/6; ASSOCIATION; BALB/CJ; DEATH;

D O I：

10.1016/j.atherosclerosis.2016.10.011

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background and aims: Recent genome-wide association studies (GWAS) have identified over 50 significant loci containing common variants associated with coronary artery disease. However, these variants explain only 26% of the genetic heritability of the disease, suggesting that many more variants remain to be discovered. Here, we examined the genetic basis underlying the marked difference between SM/J-Apoe(-/-) and BALB/cJ-Apoe(-/-) mice in atherosclerotic lesion formation. Methods: 206 female F-2 mice generated from an intercross between the two Apoe(-/-) strains were fed 12 weeks of western diet. Atherosclerotic lesion sizes in the aortic root were measured and 149 genetic markers genotyped across the entire genome. Results: A significant locus, named Ath49 (LOD score: 4.18), for atherosclerosis was mapped to the H2 complex [mouse major histocompatibility complex (MHC)] on chromosome 17. Bioinformatic analysis identified 12 probable candidate genes, including Tnfrsf21, Adgrf1, Adgrf5, Mep1a, and Pla2g7. Corresponding human genomic regions of Ath49 showed significant association with coronary heart disease. Five suggestive loci on chromosomes 1, 4, 5, and 8 for atherosclerosis were also identified. Atherosclerotic lesion sizes were significantly correlated with HDL but not with non-HDL cholesterol, triglyceride or glucose levels in the F2 cohort. Conclusions: We have identified the MHC as a major genetic determinant of atherosclerosis, highlighting the importance of inflammation in atherogenesis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

引用

页码：124 / 132

页数：9

共 33 条

[1] The nature and identification of quantitative trait loci: a community's view [J].

Abiola, O ;

Angel, JM ;

Avner, P ;

Bachmanov, AA ;

Belknap, JK ;

Bennett, B ;

Blankenhorn, EP ;

Blizard, DA ;

Bolivar, V ;

Brockmann, GA ;

Buck, KJ ;

Bureau, JF ;

Casley, WL ;

Chesler, EJ ;

Cheverud, JM ;

Churchill, GA ;

Cook, M ;

Crabbe, JC ;

Crusio, WE ;

Darvasi, A ;

de Haan, G ;

Demant, P ;

Doerge, RW ;

Elliott, RW ;

Farber, CR ;

Flaherty, L ;

Flint, J ;

Gershenfeld, H ;

Gu, JPGJ ;

Gu, WK ;

Himmelbauer, H ;

Hitzemann, R ;

Hsu, HC ;

Hunter, K ;

Iraqi, FA ;

Jansen, RC ;

Johnson, TE ;

Jones, BC ;

Kempermann, G ;

Lammert, F ;

Lu, L ;

Manly, KF ;

Matthews, DB ;

Medrano, JF ;

Mehrabian, M ;

Mittleman, G ;

Mock, BA ;

Mogil, JS ;

Montagutelli, X ;

Morahan, G .

NATURE REVIEWS GENETICS, 2003, 4 (11) :911-916

[2] Association Between Family History and Coronary Heart Disease Death Across Long-Term Follow-Up in Men The Cooper Center Longitudinal Study [J].

Bachmann, Justin M. ;

Willis, Benjamin L. ;

Ayers, Colby R. ;

Khera, Amit ;

Berry, Jarett D. .

CIRCULATION, 2012, 125 (25) :3092-3098

[3] Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease [J].

Banerjee, Sanjita ;

Jin, Ge ;

Bradley, S. Gaylen ;

Matters, Gail L. ;

Gailey, Ryan D. ;

Crisman, Jacqueline M. ;

Bond, Judith S. .

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2011, 300 (02) :G273-G282

[4] Cosegregation of Aortic Root Atherosclerosis and Intermediate Lipid Phenotypes on Chromosomes 2 and 8 in an Intercross of C57BL/6 and BALBc/ByJ Low-Density Lipoprotein Receptor-/- Mice [J].

Burkhardt, Ralph ;

Suendermann, Simon ;

Ludwig, Doris ;

Ceglarek, Uta ;

Holdt, Lesca M. ;

Thiery, Joachim ;

Teupser, Daniel .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2011, 31 (04) :775-U143

[5]

Dansky HM, 2002, GENETICS, V160, P1599

[6] Large-scale association analysis identifies new risk loci for coronary artery disease [J].

Deloukas, Panos ;

Kanoni, Stavroula ;

Willenborg, Christina ;

Farrall, Martin ;

Assimes, Themistocles L. ;

Thompson, John R. ;

Ingelsson, Erik ;

Saleheen, Danish ;

Erdmann, Jeanette ;

Goldstein, Benjamin A. ;

Stirrups, Kathleen ;

Koenig, Inke R. ;

Cazier, Jean-Baptiste ;

Johansson, Asa ;

Hall, Alistair S. ;

Lee, Jong-Young ;

Willer, Cristen J. ;

Chambers, John C. ;

Esko, Tonu ;

Folkersen, Lasse ;

Goel, Anuj ;

Grundberg, Elin ;

Havulinna, Aki S. ;

Ho, Weang K. ;

Hopewell, Jemma C. ;

Eriksson, Niclas ;

Kleber, Marcus E. ;

Kristiansson, Kati ;

Lundmark, Per ;

Lyytikainen, Leo-Pekka ;

Rafelt, Suzanne ;

Shungin, Dmitry ;

Strawbridge, Rona J. ;

Thorleifsson, Gudmar ;

Tikkanen, Emmi ;

Van Zuydam, Natalie ;

Voight, Benjamin F. ;

Waite, Lindsay L. ;

Zhang, Weihua ;

Ziegler, Andreas ;

Absher, Devin ;

Altshuler, David ;

Balmforth, Anthony J. ;

Barroso, Ines ;

Braund, Peter S. ;

Burgdorf, Christof ;

Claudi-Boehm, Simone ;

Cox, David ;

Dimitriou, Maria ;

Do, Ron .

NATURE GENETICS, 2013, 45 (01) :25-U52

[7] Mendelian randomization of blood lipids for coronary heart disease [J].

Holmes, Michael V. ;

Asselbergs, Folkert W. ;

Palmer, Tom M. ;

Drenos, Fotios ;

Lanktree, Matthew B. ;

Nelson, Christopher P. ;

Dale, Caroline E. ;

Padmanabhan, Sandosh ;

Finan, Chris ;

Swerdlow, Daniel I. ;

Tragante, Vinicius ;

van Iperen, Erik P. A. ;

Sivapalaratnam, Suthesh ;

Shah, Sonia ;

Elbers, Clara C. ;

Shah, Tina ;

Engmann, Jorgen ;

Giambartolomei, Claudia ;

White, Jon ;

Zabaneh, Delilah ;

Sofat, Reecha ;

McLachlan, Stela ;

Doevendans, Pieter A. ;

Balmforth, Anthony J. ;

Hall, Alistair S. ;

North, Kari E. ;

Almoguera, Berta ;

Hoogeveen, Ron C. ;

Cushman, Mary ;

Fornage, Myriam ;

Patel, Sanjay R. ;

Redline, Susan ;

Siscovick, David S. ;

Tsai, Michael Y. ;

Karczewski, Konrad J. ;

Hofker, Marten H. ;

Verschuren, W. Monique ;

Bots, Michiel L. ;

van der Schouw, Yvonne T. ;

Melander, Olle ;

Dominiczak, Anna F. ;

Morris, Richard ;

Ben-Shlomo, Yoav ;

Price, Jackie ;

Kumari, Meena ;

Baumert, Jens ;

Peters, Annette ;

Thorand, Barbara ;

Koenig, Wolfgang ;

Gaunt, Tom R. .

EUROPEAN HEART JOURNAL, 2015, 36 (09) :539-+

[8] MASSIVE XANTHOMATOSIS AND ATHEROSCLEROSIS IN CHOLESTEROL-FED LOW-DENSITY-LIPOPROTEIN RECEPTOR-NEGATIVE MICE [J].

ISHIBASHI, S ;

GOLDSTEIN, JL ;

BROWN, MS ;

HERZ, J ;

BURNS, DK .

JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (05) :1885-1893

[9] Quantitative trait locus analysis of carotid atherosclerosis in an intercross between C57BL/6 and C3H apolipoprotein E-deficient mice [J].

Li, Qiongzhen ;

Li, Yuhua ;

Zhang, Zhimin ;

Gilbert, Timothy R. ;

Matsumoto, Alan H. ;

Dobrin, Seth E. ;

Shi, Weibin .

STROKE, 2008, 39 (01) :166-173

[10] Variation in Type 2 Diabetes-Related Phenotypes among Apolipoprotein E-Deficient Mouse Strains [J].

Liu, Shuiping ;

Li, Jing ;

Chen, Mei-Hua ;

Liu, Zhenqi ;

Shi, Weibin .

PLOS ONE, 2015, 10 (05)

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