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Genetic predisposition to calcific aortic stenosis and mitral annular calcification

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Abstract

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.

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Abbreviations

SNP:

Single nucleotide polymorphism

VDR:

Vitamin D receptor

apo:

Apolipoprotein

LDL:

Low-density lipoprotein

TGF:

Transforming growth factor

ORα:

Oestrogen receptor alpha

OR:

Odds ratio

CI:

Confidence interval

IL:

Interleukin

ACE:

Angiotensin-converting enzyme

PTH:

Parathormone

CaSR:

Calcium-sensing receptor

CTGF:

Connective tissue growth factor

FGF:

Fibroblast growth factor

PON:

Paraoxonase

MYO7A:

Myosin VIIA

AGTR:

Angiotensinogen receptor

ELN:

Elastin

LPA:

Lipoprotein(a)

GALTN2:

Polypeptide N-acetylgalactosaminyltransferase 2

LPL:

Lipoprotein lipase

ABCA1:

ATP-binding cassette sub-family A member 1

APOA5:

Apolipoprotein A-V

SCARB1:

Scavenger receptor class B member 1

LIPC:

Hepatic triglyceride lipase

CETP:

Cholesterol ester transfer protein

LCAT:

Lecithin-cholesterol acyltransferase

LIPG:

Endothelial triglyceride lipase

APOC4:

Apolipoprotein C-IV

PLTP:

Phospholipid transfer protein

HDL:

High-density lipoprotein

PCR–RFLP:

Polymerase chain reaction–restriction fragment length polymorphism

KIV-2:

Kringle IV type 2

GWAS:

Genome-wide association studies

References

  1. Carabello BA, Paulus WJ (2009) Aortic stenosis. Lancet 373:956–966

    Article  PubMed  Google Scholar 

  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 162:2345–2347

    Article  PubMed  Google Scholar 

  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 341:142–147

    Article  CAS  PubMed  Google Scholar 

  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 33:2451–2496

    Article  Google Scholar 

  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 20:183–190

    Article  PubMed  Google Scholar 

  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 124:1783–1791

    Article  PubMed Central  PubMed  Google Scholar 

  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 29:630–634

    Article  CAS  PubMed  Google Scholar 

  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 111:920–925

    Article  PubMed  Google Scholar 

  9. Otto CM, O’Brien KD (2001) Why is there discordance between calcific aortic stenosis and coronary artery disease? Heart 85:601–602

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 107:1492–1496

    Article  PubMed  Google Scholar 

  11. Roberts WC (1986) The senile cardiac calcification syndrome. Am J Cardiol 58:572–574

    Article  CAS  PubMed  Google Scholar 

  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 49:453–460

    Article  CAS  PubMed  Google Scholar 

  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 307:906–922

    Article  CAS  PubMed  Google Scholar 

  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 276:13675–13684

    CAS  PubMed  Google Scholar 

  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 12:205–216

    Article  CAS  PubMed  Google Scholar 

  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–L390

    Article  CAS  PubMed  Google Scholar 

  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 15:58–64

    Article  CAS  PubMed  Google Scholar 

  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 85:635–638

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 19:419–428

    Article  CAS  PubMed  Google Scholar 

  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 60:381–384

    Article  CAS  PubMed  Google Scholar 

  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 74:47–54

    Article  PubMed  Google Scholar 

  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 92:151–164

    Article  CAS  PubMed  Google Scholar 

  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 254:140–146

    Article  PubMed  Google Scholar 

  24. Mendelsohn ME, Karas RH (1994) Estrogen and the blood vessel wall. Curr Opin Cardiol 9:619–626

    Article  CAS  PubMed  Google Scholar 

  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 267:25982–25987

    CAS  PubMed  Google Scholar 

  26. Novaro GM, Sachar R, Pearce GL, Sprecher DL, Griffin BP (2003) Association between apolipoprotein E alleles and calcific valvular heart disease. Circulation 108:1804–1808

    Article  CAS  PubMed  Google Scholar 

  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 25:514–522

    Article  CAS  PubMed  Google Scholar 

  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 14:277–281

    PubMed  Google Scholar 

  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 92:1463–1466

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 82:944–950

    Article  CAS  PubMed  Google Scholar 

  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 18:262–267

    PubMed  Google Scholar 

  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 13:176–180

    Article  PubMed  Google Scholar 

  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 108:1305–1310

    Article  CAS  PubMed  Google Scholar 

  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 26:3998–4002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 2:123–132

    PubMed Central  CAS  PubMed  Google Scholar 

  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 110:88–92

    Article  CAS  PubMed  Google Scholar 

  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 44:1859–1866

    Article  CAS  PubMed  Google Scholar 

  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 22:142–149

    PubMed  Google Scholar 

  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 368:503–512

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 63:470–477

    Article  CAS  PubMed  Google Scholar 

  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 34:457–462

    Article  CAS  PubMed  Google Scholar 

  42. Yuzhalin AE, Kutikhin AG (2012) Integrative systems of genomic risk markers for cancer and other diseases: future of predictive medicine. Cancer Manag Res 4:131–135

    Article  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Research Institute for Complex Issues of Cardiovascular Diseases Under the Siberian Branch of the Russian Academy of Medical Sciences, Sosnovy Blvd 6, 650002, Kemerovo, Russian Federation

    Anton G. Kutikhin, Elena B. Brusina, Anastasia V. Ponasenko, Alexey S. Golovkin & Olga L. Barbarash

  2. Central Research Laboratory, Kemerovo State Medical Academy, Voroshilova Street 22a, 650029, Kemerovo, Russian Federation

    Anton G. Kutikhin

  3. Department of Epidemiology, Kemerovo State Medical Academy, Voroshilova Street 22a, 650029, Kemerovo, Russian Federation

    Anton G. Kutikhin & Elena B. Brusina

  4. Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK

    Arseniy E. Yuzhalin

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  1. Anton G. Kutikhin
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Kutikhin, A.G., Yuzhalin, A.E., Brusina, E.B. et al. Genetic predisposition to calcific aortic stenosis and mitral annular calcification. Mol Biol Rep 41, 5645–5663 (2014). https://doi.org/10.1007/s11033-014-3434-9

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