Skip to main content
SpringerLink
Log in

ADAMTS7 locus confers high cross-race risk for development of coronary atheromatous plaque

  • Original Article
  • Published:
Molecular Genetics and Genomics Aims and scope Submit manuscript

Abstract

Genome-wide association studies of coronary artery disease (CAD) have recently identified a new susceptibility locus, ADAMTS7, in subjects of European ancestry. However, the significance of this locus in Chinese populations has not been identified. Therefore, this study was designed to evaluate the effect of rs3825807, a non-synonymous variant in the prodomain of the ADAMTS7 protease, on CAD risk and atherosclerosis severity in a Chinese population. We performed genetic association analyses in two independent case–control cohorts, which included a total of 8154 participants. Additionally, the association between the ADAMTS7 rs3825807 genotype and the proportion of CAD patients with 3- and 1-vessel disease was tested. We found that ADAMTS7 rs3825807 was associated with susceptibility to CAD in a Chinese population [odds ratio (OR) = 1.15, 95 % confidence interval (CI) = 1.05–1.26, P = 0.002]. The association remained significant after adjusting for clinical covariates (adjusted OR = 1.12, 95 % CI = 1.02–1.24, P = 0.02). Among 3741 angiographically documented CAD patients, the rs3825807 risk allele showed a significant association with disease severity (P = 0.04, trend P = 0.02). Additionally, 3-vessel disease demonstrated a strong and direct association with ADAMTS7 rs3825807 gene dosage (P = 0.02). Overall, our findings indicate that the significant associations observed between this coding variant in ADAMTS7 and the risk of CAD development are cross-ethnic, and the gene dosage is consistent with the degree of coronary atheromatous burden.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Bauer RC, Tohyama J, Cui J, Cheng L, Yang J, Zhang X, Ou K, Paschos GK, Zheng XL, Parmacek MS, Rader DJ, Reilly MP (2015) Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice. Circulation 131(13):1202–1213

    Article  PubMed  CAS  Google Scholar 

  • CARDIoGRAMplusC4D Consortium (2013) Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 45(1):25–33

    Google Scholar 

  • Coronary Artery Disease (C4D) Genetics Consortium (2011) A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 43(4):339–344

    Article  Google Scholar 

  • Edwards SL, Beesley J, French JD, Dunning AM (2013) Beyond GWASs: illuminating the dark road from association to function. Am J Hum Genet 93(5):779–797

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani SS, Wong ND, Woo D, Turner MB (2013) Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127(1):e6–e245

    Article  PubMed  Google Scholar 

  • Guo F, Lai Y, Tian Q, Lin EA, Kong L, Liu C (2010) Granulin-epithelin precursor binds directly to ADAMTS-7 and ADAMTS-12 and inhibits their degradation of cartilage oligomeric matrix protein. Arthritis Rheum 62(7):2023–2036

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hanby HA, Zheng XL (2013) Biochemistry and physiological functions of ADAMTS7 metalloprotease. Adv Biochem 1(3):43

    Article  CAS  Google Scholar 

  • Kessler T, Zhang L, Liu Z, Yin X, Huang Y, Wang Y, Fu Y, Mayr M, Ge Q, Xu Q, Zhu Y, Wang X, Schmidt K, de Wit C, Erdmann J, Schunkert H, Aherrahrou Z, Kong W (2015) ADAMTS-7 inhibits re-endothelialization of injured arteries and promotes vascular remodeling through cleavage of thrombospondin-1. Circulation 131(13):1191–1201

    Article  PubMed  CAS  Google Scholar 

  • Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler SP, Sabio H, Bouhassira EE, Upshaw JD Jr, Ginsburg D, Tsai HM (2001) Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413(6855):488–494

    Article  PubMed  CAS  Google Scholar 

  • Liu CJ, Kong W, Ilalov K, Yu S, Xu K, Prazak L, Fajardo M, Sehgal B, Di Cesare PE (2006) ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein. FASEB J 20(7):988–990

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Liu L, Cao Y, Cui G, Li Z, Sun J, Zhang L, Chen C, Wang Y, Wang P, Ding H, Wang DW (2013a) Association analysis of polymorphisms in ROCK2 with cardiovascular disease in a Chinese population. PLoS One 8(1):e53905

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Liu L, Yang X, Wang H, Cui G, Xu Y, Wang P, Yuan G, Wang X, Ding H, Wang DW (2013b) Association between variants of EXT2 and type 2 diabetes: a replication and meta-analysis. Hum Genet 132(2):139–145

    Article  PubMed  CAS  Google Scholar 

  • Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O’Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA 3rd, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De Leon FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2095–2128

    Article  PubMed  Google Scholar 

  • Lu X, Wang L, Chen S, He L, Yang X, Shi Y, Cheng J, Zhang L, Gu CC, Huang J, Wu T, Ma Y, Li J, Cao J, Chen J, Ge D, Fan Z, Li Y, Zhao L, Li H, Zhou X, Chen L, Liu D, Chen J, Duan X, Hao Y, Wang L, Lu F, Liu Z, Yao C, Shen C, Pu X, Yu L, Fang X, Xu L, Mu J, Wu X, Zheng R, Wu N, Zhao Q, Li Y, Liu X, Wang M, Yu D, Hu D, Ji X, Guo D, Sun D, Wang Q, Yang Y, Liu F, Mao Q, Liang X, Ji J, Chen P, Mo X, Li D, Chai G, Tang Y, Li X, Du Z, Liu X, Dou C, Yang Z, Meng Q, Wang D, Wang R, Yang J, Schunkert H, Samani NJ, Kathiresan S, Reilly MP, Erdmann J, Coronary ADG-WR, Meta-Analysis C, Peng X, Wu X, Liu D, Yang Y, Chen R, Qiang B, Gu D (2012) Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease. Nat Genet 44(8):890–894

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Luan Y, Kong L, Howell DR, Ilalov K, Fajardo M, Bai XH, Di Cesare PE, Goldring MB, Abramson SB, Liu CJ (2008) Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin. Osteoarthritis Cartilage 16(11):1413–1420

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Maouche S, Schunkert H (2012) Strategies beyond genome-wide association studies for atherosclerosis. Arterioscler Thromb Vasc Biol 32(2):170–181

    Article  PubMed  CAS  Google Scholar 

  • Patel RS, Ye S (2013) ADAMTS7: a promising new therapeutic target in coronary heart disease. Expert Opin Ther Targets 17(8):863–867

    Article  PubMed  CAS  Google Scholar 

  • Pu X, Xiao Q, Kiechl S, Chan K, Ng FL, Gor S, Poston RN, Fang C, Patel A, Senver EC, Shaw-Hawkins S, Willeit J, Liu C, Zhu J, Tucker AT, Xu Q, Caulfield MJ, Ye S (2013) ADAMTS7 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-disease-associated variant. Am J Hum Genet 92(3):366–374

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Rawlings ND, Barrett AJ, Bateman A (2012) MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucl Acids Res 40(database issue): D343–D350

  • Reilly MP, Li M, He J, Ferguson JF, Stylianou IM, Mehta NN, Burnett MS, Devaney JM, Knouff CW, Thompson JR, Horne BD, Stewart AF, Assimes TL, Wild PS, Allayee H, Nitschke PL, Patel RS, Martinelli N, Girelli D, Quyyumi AA, Anderson JL, Erdmann J, Hall AS, Schunkert H, Quertermous T, Blankenberg S, Hazen SL, Roberts R, Kathiresan S, Samani NJ, Epstein SE, Rader DJ (2011) Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 377(9763):383–392

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Riessen R, Fenchel M, Chen H, Axel DI, Karsch KR, Lawler J (2001) Cartilage oligomeric matrix protein (thrombospondin-5) is expressed by human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 21(1):47–54

    Article  PubMed  CAS  Google Scholar 

  • Roberts R, Stewart AF (2012) Genes and coronary artery disease: where are we? J Am Coll Cardiol 60(18):1715–1721

    Article  PubMed  CAS  Google Scholar 

  • Sasayama S (2008) Heart disease in Asia. Circulation 118(25):2669–2671

    Article  PubMed  Google Scholar 

  • Schunkert H, Erdmann J, Samani NJ (2010) Genetics of myocardial infarction: a progress report. Eur Heart J 31(8):918–925

    Article  PubMed  Google Scholar 

  • Schunkert H, Konig IR, Kathiresan S, Reilly MP, Assimes TL, Holm H, Preuss M, Stewart AF, Barbalic M, Gieger C, Absher D, Aherrahrou Z, Allayee H, Altshuler D, Anand SS, Andersen K, Anderson JL, Ardissino D, Ball SG, Balmforth AJ, Barnes TA, Becker DM, Becker LC, Berger K, Bis JC, Boekholdt SM, Boerwinkle E, Braund PS, Brown MJ, Burnett MS, Buysschaert I, Carlquist JF, Chen L, Cichon S, Codd V, Davies RW, Dedoussis G, Dehghan A, Demissie S, Devaney JM, Diemert P, Do R, Doering A, Eifert S, Mokhtari NE, Ellis SG, Elosua R, Engert JC, Epstein SE, de Faire U, Fischer M, Folsom AR, Freyer J, Gigante B, Girelli D, Gretarsdottir S, Gudnason V, Gulcher JR, Halperin E, Hammond N, Hazen SL, Hofman A, Horne BD, Illig T, Iribarren C, Jones GT, Jukema JW, Kaiser MA, Kaplan LM, Kastelein JJ, Khaw KT, Knowles JW, Kolovou G, Kong A, Laaksonen R, Lambrechts D, Leander K, Lettre G, Li M, Lieb W, Loley C, Lotery AJ, Mannucci PM, Maouche S, Martinelli N, McKeown PP, Meisinger C, Meitinger T, Melander O, Merlini PA, Mooser V, Morgan T, Muhleisen TW, Muhlestein JB, Munzel T, Musunuru K, Nahrstaedt J, Nelson CP, Nothen MM, Olivieri O, Patel RS, Patterson CC, Peters A, Peyvandi F, Qu L, Quyyumi AA, Rader DJ, Rallidis LS, Rice C, Rosendaal FR, Rubin D, Salomaa V, Sampietro ML, Sandhu MS, Schadt E, Schafer A, Schillert A, Schreiber S, Schrezenmeir J, Schwartz SM, Siscovick DS, Sivananthan M, Sivapalaratnam S, Smith A, Smith TB, Snoep JD, Soranzo N, Spertus JA, Stark K, Stirrups K, Stoll M, Tang WH, Tennstedt S, Thorgeirsson G, Thorleifsson G, Tomaszewski M, Uitterlinden AG, van Rij AM, Voight BF, Wareham NJ, Wells GA, Wichmann HE, Wild PS, Willenborg C, Witteman JC, Wright BJ, Ye S, Zeller T, Ziegler A, Cambien F, Goodall AH, Cupples LA, Quertermous T, Marz W, Hengstenberg C, Blankenberg S, Ouwehand WH, Hall AS, Deloukas P, Thompson JR, Stefansson K, Roberts R, Thorsteinsdottir U, O’Donnell CJ, McPherson R, Erdmann J, Samani NJ (2011) Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 43(4):333–338

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Somerville RP, Longpre JM, Apel ED, Lewis RM, Wang LW, Sanes JR, Leduc R, Apte SS (2004) ADAMTS7B, the full-length product of the ADAMTS7 gene, is a chondroitin sulfate proteoglycan containing a mucin domain. J Biol Chem 279(34):35159–35175

    Article  PubMed  CAS  Google Scholar 

  • van Setten J, Isgum I, Smolonska J, Ripke S, de Jong PA, Oudkerk M, de Koning H, Lammers JW, Zanen P, Groen HJ, Marike Boezen H, Postma DS, Wijmenga C, Viergever MA, Mali WP, de Bakker PI (2013) Genome-wide association study of coronary and aortic calcification implicates risk loci for coronary artery disease and myocardial infarction. Atherosclerosis 228(2):400–405

    Article  PubMed  Google Scholar 

  • Wang L, Zheng J, Bai X, Liu B, Liu CJ, Xu Q, Zhu Y, Wang N, Kong W, Wang X (2009) ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries. Circ Res 104(5):688–698

    Article  PubMed  CAS  Google Scholar 

  • Wang L, Wang X, Kong W (2010) ADAMTS-7, a novel proteolytic culprit in vascular remodeling. Sheng Li Xue Bao 62(4):285–294

    PubMed  CAS  Google Scholar 

  • Wang F, Xu CQ, He Q, Cai JP, Li XC, Wang D, Xiong X, Liao YH, Zeng QT, Yang YZ, Cheng X, Li C, Yang R, Wang CC, Wu G, Lu QL, Bai Y, Huang YF, Yin D, Yang Q, Wang XJ, Dai DP, Zhang RF, Wan J, Ren JH, Li SS, Zhao YY, Fu FF, Huang Y, Li QX, Shi SW, Lin N, Pan ZW, Li Y, Yu B, Wu YX, Ke YH, Lei J, Wang N, Luo CY, Ji LY, Gao LJ, Li L, Liu H, Huang EW, Cui J, Jia N, Ren X, Li H, Ke T, Zhang XQ, Liu JY, Liu MG, Xia H, Yang B, Shi LS, Xia YL, Tu X, Wang QK (2011) Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nat Genet 43(4):345–349

    Article  PubMed  CAS  Google Scholar 

  • Zeller T, Blankenberg S, Diemert P (2012) Genomewide association studies in cardiovascular disease–an update 2011. Clin Chem 58(1):92–103

    Article  PubMed  CAS  Google Scholar 

  • Zhang Q, Huang M, Wang X, Xu X, Ni M, Wang Y (2012) Negative effects of ADAMTS-7 and ADAMTS-12 on endplate cartilage differentiation. J Orthop Res 30(8):1238–1243

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are particularly grateful to all volunteers for participating in the present study and to the medical personnel of Tongji Hospital and The Second Hospital of Hebei Medical University for their kind assistance in collecting the data and samples.

Author information

Author notes

    Authors and Affiliations

    1. Division of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China

      Ling You & Wei Cui

    2. Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

      Lun Tan, Lei Liu, Rufei Shen, Sandip Chaugai & Dao Wen Wang

    Authors
    1. Ling You
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Lun Tan
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Lei Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Rufei Shen
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Sandip Chaugai
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Dao Wen Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Wei Cui
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Dao Wen Wang or Wei Cui.

    Ethics declarations

    Funding

    This study was funded by the research grants from National ‘973’ Project (2012CB518004), and National Nature Science Foundation of China (30930039, 81100066).

    Conflict of interest

    Ling You, Lun Tan, Lei Liu, Rufei Shen, Sandip Chaugai, Dao Wen Wang, Wei Cui declares that he/she has no conflict of interest.

    Ethical approval

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

    Additional information

    Communicated by Q. Wang.

    L. You and L. Tan contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 13 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    You, L., Tan, L., Liu, L. et al. ADAMTS7 locus confers high cross-race risk for development of coronary atheromatous plaque. Mol Genet Genomics 291, 121–128 (2016). https://doi.org/10.1007/s00438-015-1092-9

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00438-015-1092-9

    Keywords

    Search

    Navigation