Molecular Biology Reports

, Volume 41, Issue 9, pp 5645–5663

Genetic predisposition to calcific aortic stenosis and mitral annular calcification

  • Anton G. Kutikhin
  • Arseniy E. Yuzhalin
  • Elena B. Brusina
  • Anastasia V. Ponasenko
  • Alexey S. Golovkin
  • Olga L. Barbarash


Valvular calcification precedes the development of valvular stenosis and may represent an important early phenotype for valvular heart disease. It is known that development of valvular calcification is likely to occur among members of a family. However, the knowledge about the role of genomic predictive markers in valvular calcification is still elusive. Aims of this review are to assess the impact of gene polymorphisms on risk and severity of aortic stenosis and mitral annular calcification. According to the results of the investigations carried out, all polymorphisms may be divided into the three groups conferring the level of evidence of their association with valvular stenosis. It is possible to conclude that apoB (XbaI, rs1042031, and rs6725189), ACE (rs4340), IL10 (rs1800896 and rs1800872), and LPA (rs10455872) gene polymorphisms may be associated with valvular calcific stenosis with a relatively high level of evidence. A number of other polymorphisms, such as PvuII polymorphism within the ORα gene, rs1042636 polymorphism within the CaSR gene, rs3024491, rs3021094, rs1554286, and rs3024498 polymorphisms within the IL10 gene, rs662 polymorphism within the PON1 gene, rs2276288 polymorphism within the MYO7A gene, rs5194 polymorphism within the AGTR1 gene, rs2071307 polymorphism within the ELN gene, rs17659543 and rs13415097 polymorphisms within the IL1F9 gene may correlate with a risk of calcific valve stenosis with moderate level of evidence. Finally, rs1544410 polymorphism within the VDR gene, E2 and E4 alleles within the apoE gene, rs6254 polymorphism within the PTH gene, and rs1800871 polymorphism within the IL10 gene may be associated with aortic stenosis with low level of evidence.


Valvular calcification Heart valves Aortic stenosis Mitral annular calcification Gene polymorphisms Genetic predisposition 



Single nucleotide polymorphism


Vitamin D receptor




Low-density lipoprotein


Transforming growth factor


Oestrogen receptor alpha


Odds ratio


Confidence interval




Angiotensin-converting enzyme




Calcium-sensing receptor


Connective tissue growth factor


Fibroblast growth factor




Myosin VIIA


Angiotensinogen receptor






Polypeptide N-acetylgalactosaminyltransferase 2


Lipoprotein lipase


ATP-binding cassette sub-family A member 1


Apolipoprotein A-V


Scavenger receptor class B member 1


Hepatic triglyceride lipase


Cholesterol ester transfer protein


Lecithin-cholesterol acyltransferase


Endothelial triglyceride lipase


Apolipoprotein C-IV


Phospholipid transfer protein


High-density lipoprotein


Polymerase chain reaction–restriction fragment length polymorphism


Kringle IV type 2


Genome-wide association studies


  1. 1.
    Carabello BA, Paulus WJ (2009) Aortic stenosis. Lancet 373:956–966CrossRefPubMedGoogle Scholar
  2. 2.
    Cosmi JE, Kort S, Tunick PA, Rosenzweig BP, Freedberg RS, Katz ES, Applebaum RM, Kronzon I (2002) The risk of the development of aortic stenosis in patients with “benign” aortic valve thickening. Arch Intern Med 162:2345–2347CrossRefPubMedGoogle Scholar
  3. 3.
    Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS (1999) Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 341:142–147CrossRefPubMedGoogle Scholar
  4. 4.
    Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC), European Association for Cardio-Thoracic Surgery (EACTS), Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schäfers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M (2012) Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 33:2451–2496CrossRefGoogle Scholar
  5. 5.
    Li C, Xu S, Gotlieb AI (2011) The response to valve injury. A paradigm to understand the pathogenesis of heart valve disease. Cardiovasc Pathol 20:183–190CrossRefPubMedGoogle Scholar
  6. 6.
    Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, Simmons CA, Masters KS, Mathieu P, O’Brien KD, Schoen FJ, Towler DA, Yoganathan AP, Otto CM (2011) Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aorticvalve disease—2011 update. Circulation 124:1783–1791PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM (1997) Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 29:630–634CrossRefPubMedGoogle Scholar
  8. 8.
    Roberts WC, Ko JM (2005) Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation 111:920–925CrossRefPubMedGoogle Scholar
  9. 9.
    Otto CM, O’Brien KD (2001) Why is there discordance between calcific aortic stenosis and coronary artery disease? Heart 85:601–602PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Fox CS, Vasan RS, Parise H, Levy D, O’Donnell CJ, D’Agostino RB, Benjamin EJ, Framingham Heart Study (2003) Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study. Circulation 107:1492–1496CrossRefPubMedGoogle Scholar
  11. 11.
    Roberts WC (1986) The senile cardiac calcification syndrome. Am J Cardiol 58:572–574CrossRefPubMedGoogle Scholar
  12. 12.
    Bella JN, Tang W, Kraja A, Rao DC, Hunt SC, Miller MB, Palmieri V, Roman MJ, Kitzman DW, Oberman A, Devereux RB, Arnett DK (2007) Genome-wide linkage mapping for valve calcification susceptibility loci in hypertensive sibships: the Hypertension Genetic Epidemiology Network Study. Hypertension 49:453–460CrossRefPubMedGoogle Scholar
  13. 13.
    Lamba V, Lamba J, Yasuda K, Strom S, Davila J, Hancock ML, Fackenthal JD, Rogan PK, Ring B, Wrighton SA, Schuetz EG (2003) Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J Pharmacol Exp Ther 307:906–922CrossRefPubMedGoogle Scholar
  14. 14.
    Tierney MJ, Medcalf RL (2001) Plasminogen activator inhibitor type 2 contains mRNA instability elements within exon 4 of the coding region. Sequence homology to coding region instability determinants in other mRNAs. J Biol Chem 276:13675–13684PubMedGoogle Scholar
  15. 15.
    Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12:205–216CrossRefPubMedGoogle Scholar
  16. 16.
    Thomas KH, Meyn P, Suttorp N (2006) Single nucleotide polymorphism in 5′-flanking region reduces transcription of surfactant protein B gene in H441 cells. Am J Physiol Lung Cell Mol Physiol 291:L386–L390CrossRefPubMedGoogle Scholar
  17. 17.
    Zysow BR, Lindahl GE, Wade DP, Knight BL, Lawn RM (1995) C/T polymorphism in the 5′ untranslated region of the apolipoprotein(a) gene introduces an upstream ATG and reduces in vitro translation. Arterioscler Thromb Vasc Biol 15:58–64CrossRefPubMedGoogle Scholar
  18. 18.
    Ortlepp JR, Hoffmann R, Ohme F, Lauscher J, Bleckmann F, Hanrath P (2001) The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis. Heart 85:635–638PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Thakkinstian A, D’Este C, Eisman J, Nguyen T, Attia J (2004) Meta-analysis of molecular association studies: vitamin D receptor gene polymorphisms and BMD as a case study. J Bone Miner Res 19:419–428CrossRefPubMedGoogle Scholar
  20. 20.
    Avakian SD, Annicchino-Bizzacchi JM, Grinberg M, Ramires JA, Mansura AP (2001) Apolipoproteins AI, B, and E polymorphisms in severe aortic valve stenosis. Clin Genet 60:381–384CrossRefPubMedGoogle Scholar
  21. 21.
    Aalto-Setälä K, Tikkanen MJ, Taskinen MR, Nieminen M, Holmberg P, Kontula K (1988) XbaI and c/g polymorphisms of the apolipoprotein B gene locus are associated with serum cholesterol and LDL-cholesterol levels in Finland. Atherosclerosis 74:47–54CrossRefPubMedGoogle Scholar
  22. 22.
    Peacock R, Dunning A, Hamsten A, Tornvall P, Humphries S, Talmud P (1992) Apolipoprotein B gene polymorphisms, lipoproteins and coronary atherosclerosis: a study of young myocardial infarction survivors and healthy population-based individuals. Atherosclerosis 92:151–164CrossRefPubMedGoogle Scholar
  23. 23.
    Nordström P, Glader CA, Dahlén G, Birgander LS, Lorentzon R, Waldenström A, Lorentzon M (2003) Oestrogen receptor alpha gene polymorphism is related to aortic valve sclerosis in postmenopausal women. J Intern Med 254:140–146CrossRefPubMedGoogle Scholar
  24. 24.
    Mendelsohn ME, Karas RH (1994) Estrogen and the blood vessel wall. Curr Opin Cardiol 9:619–626CrossRefPubMedGoogle Scholar
  25. 25.
    Nicholson AC, Hajjar DP (1992) Transforming growth factor-beta up-regulates low density lipoprotein receptor-mediated cholesterol metabolism in vascular smooth muscle cells. J Biol Chem 267:25982–25987PubMedGoogle Scholar
  26. 26.
    Novaro GM, Sachar R, Pearce GL, Sprecher DL, Griffin BP (2003) Association between apolipoprotein E alleles and calcific valvular heart disease. Circulation 108:1804–1808CrossRefPubMedGoogle Scholar
  27. 27.
    Ortlepp JR, Schmitz F, Mevissen V, Weiss S, Huster J, Dronskowski R, Langebartels G, Autschbach R, Zerres K, Weber C, Hanrath P, Hoffmann R (2004) The amount of calcium-deficient hexagonal hydroxyapatite in aortic valves is influenced by gender and associated with genetic polymorphisms in patients with severe calcific aortic stenosis. Eur Heart J 25:514–522CrossRefPubMedGoogle Scholar
  28. 28.
    Davutoglu V, Nacak M (2005) Influence of angiotensin-converting enzyme gene insertion/deletion polymorphism on rheumatic valve involvement, valve severity and subsequent valve calcification. J Heart Valve Dis 14:277–281PubMedGoogle Scholar
  29. 29.
    Ortlepp JR, Pillich M, Mevissen V, Krantz C, Kimmel M, Autschbach R, Langebartels G, Erdmann J, Hoffmann R, Zerres K (2006) APOE alleles are not associated with calcific aortic stenosis. Heart 92:1463–1466PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Ertas FS, Hasan T, Ozdol C, Gulec S, Atmaca Y, Tulunay C, Karabulut H, Kocum HT, Dincer I, Kose KS, Erol C (2007) Relationship between angiotensin-converting enzyme gene polymorphism and severity of aortic valve calcification. Mayo Clin Proc 82:944–950CrossRefPubMedGoogle Scholar
  31. 31.
    Schmitz F, Ewering S, Zerres K, Klomfass S, Hoffmann R, Ortlepp JR (2009) Parathyroid hormone gene variant and calcific aortic stenosis. J Heart Valve Dis 18:262–267PubMedGoogle Scholar
  32. 32.
    Turkmen F, Ozdemir A, Sevinc C, Eren PA, Demiral S (2009) Calcium-sensing receptor gene polymorphisms and cardiac valvular calcification in patients with chronic renal failure: a pilot study. Hemodial Int 13:176–180CrossRefPubMedGoogle Scholar
  33. 33.
    Gaudreault N, Ducharme V, Lamontagne M, Guauque-Olarte S, Mathieu P, Pibarot P, Bossé Y (2011) Replication of genetic association studies in aortic stenosis in adults. Am J Cardiol 108:1305–1310CrossRefPubMedGoogle Scholar
  34. 34.
    Tangri N, Alam A, Wooten EC, Huggins GS (2011) Lack of association of Klotho gene variants with valvular and vascular calcification in Caucasians: a candidate gene study of the Framingham Offspring Cohort. Nephrol Dial Transplant 26:3998–4002PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Moura LM, Faria S, Brito M, Pinto FJ, Kristensen SD, Barros IM, Rajamannan N, Rocha-Gonçalves F (2012) Relationship of PON1 192 and 55 gene polymorphisms to calcific valvular aortic stenosis. Am J Cardiovasc Dis 2:123–132PubMedCentralPubMedGoogle Scholar
  36. 36.
    Ellis SG, Dushman-Ellis S, Luke MM, Murugesan G, Kottke-Marchant K, Ellis GM, Griffin B, Tuzcu EM, Hazen S (2012) Pilot candidate gene analysis of patients ≥60 years old with aortic stenosis involving a tricuspid aortic valve. Am J Cardiol 110:88–92CrossRefPubMedGoogle Scholar
  37. 37.
    Helske S, Lindstedt KA, Laine M, Mäyränpää M, Werkkala K, Lommi J, Turto H, Kupari M, Kovanen PT (2004) Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol 44:1859–1866CrossRefPubMedGoogle Scholar
  38. 38.
    Ducharme V, Guauque-Olarte S, Gaudreault N, Pibarot P, Mathieu P, Bossé Y (2013) NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis. J Heart Valve Dis 22:142–149PubMedGoogle Scholar
  39. 39.
    Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, Kerr KF, Pechlivanis S, Budoff MJ, Harris TB, Malhotra R, O’Brien KD, Kamstrup PR, Nordestgaard BG, Tybjaerg-Hansen A, Allison MA, Aspelund T, Criqui MH, Heckbert SR, Hwang SJ, Liu Y, Sjogren M, van der Pals J, Kälsch H, Mühleisen TW, Nöthen MM, Cupples LA, Caslake M, Di Angelantonio E, Danesh J, Rotter JI, Sigurdsson S, Wong Q, Erbel R, Kathiresan S, Melander O, Gudnason V, O’Donnell CJ, Post WS, CHARGE Extracoronary Calcium Working Group (2013) Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 368:503–512PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG (2014) Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 63:470–477CrossRefPubMedGoogle Scholar
  41. 41.
    Arsenault BJ, Dubé MP, Brodeur MR, de Oliveira Moraes AB, Lavoie V, Kernaleguen AE, Guauque-Olarte S, Mathieu P, Pibarot P, Messika-Zeitoun D, Bossé Y, Rhainds D, Rhéaume E, Tardif JC (2014) Evaluation of links between high-density lipoprotein genetics, functionality, and aortic valve stenosis risk in humans. Arterioscler Thromb Vasc Biol 34:457–462CrossRefPubMedGoogle Scholar
  42. 42.
    Yuzhalin AE, Kutikhin AG (2012) Integrative systems of genomic risk markers for cancer and other diseases: future of predictive medicine. Cancer Manag Res 4:131–135PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Anton G. Kutikhin
    • 1
    • 2
    • 3
  • Arseniy E. Yuzhalin
    • 4
  • Elena B. Brusina
    • 1
    • 3
  • Anastasia V. Ponasenko
    • 1
  • Alexey S. Golovkin
    • 1
  • Olga L. Barbarash
    • 1
  1. 1.Research Institute for Complex Issues of Cardiovascular Diseases Under the Siberian Branch of the Russian Academy of Medical SciencesKemerovoRussian Federation
  2. 2.Central Research LaboratoryKemerovo State Medical AcademyKemerovoRussian Federation
  3. 3.Department of EpidemiologyKemerovo State Medical AcademyKemerovoRussian Federation
  4. 4.Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK

Personalised recommendations