PERİODONTAL HASTALIKLARDA GENETİK POLİMORFİZMLERİN ROLÜ

Yıl 2012, Cilt: 1 Sayı: 3, 154 - 163, 31.12.2012

Burak Doğan, Gizem Torumtay Yener Özat

Öz

Periodontoloji disiplini, periodontal hastalık patogenezine olan bakış açısını salt mikrobiyal dental plak esaslı ekseninden çıkarmış, enfeksiyon ile konak yanıtı arasındaki çok değişkenli ve karmaşık etkileşim biçiminde geliştirmiştir. Periodontal hastalık patogenezine ait bilinmeyenleri cevaplayabilmek için konak immün yanıtı ile periodontopatik bakteriler arasındaki etkileşimin dinamiklerini bilmek ve bu karmaşık süreçte rol aldığı düşünülen diğer etkenleri analiz etmek gereklidir. Her ne kadar bakteriyel plak varlığı periodontitisin başlaması için gerekli ise de, plak miktarının hastalık şiddeti ile mutlaka korelasyon göstermediği ve bireysel faktörlerin klinik tabloda belirleyici olduğu bilinmektedir. Periodontal hastalığın çağdaş tanımında bakteriyel etiyolojiden çok, konak yanıtı vurgulanmaktadır. Literatürdeki pek çok çalışma ile konak immün yanıtındaki bireyler arası değişkenlik ve pek çok patolojideki genetik bileşen varlığı ortaya konmuştur. İmmün hücre gelişiminde, antijen hücre sunumunda veya non-spesifik immün yanıtta rol alan inflamatuvar medyatörlerdeki genetik varyasyonlar, periodontitis de dahil olmak üzere belli durumlar için risk faktörü olabilir. Bu açıdan bakıldığında periodontitis, fenotipi etkilenen bireydeki genetik yapı ve çevresel etkenler ile şekillenen karmaşık bir genetik hastalık olarak dikkate alınabilir. Dolayısı ile periodontitis ile ilişkili genetik duyarlılık profilinin haritasının çıkarılmasının, tanı yöntemleri ve bireysel tedavi stratejileri geliştirmek açısından getiri sağlayacağı öngörülebilir. Bu sistematik olmayan derlemenin amacı, periodontal hastalıklarda genetik polimorfizmlerin olası rolünün altını çizmek ve ilişkilendirme çalışmalarındaki yöntemler ile ilgili tartışmaları gözden geçirmekti.

Anahtar Kelimeler

Periodontal hastalık, gen polimorfizmi

THE ROLE OF GENETIC POLYMORPHISMS IN PERIODONTAL DISEASES

Öz

Discipline of periodontology shifted the understanding of periodontal disease pathogenesis from solely microbial dental plaque based axis to complex, multi-variate interplay between infection and host response. It is essential to initialize the dynamics of the interaction between the host immune response and periodontopathic bacteria, and to analyse other factors possibly playing role in this complex process. Where the existence of bacterial plaque is a pre-requirement for the initiation of periodontitis, it is well known that amount of plaque does not necessarily correlate with disease severity and individual factors are determinative on clinical presentation. Rather than bacterial aetiology, host response in more emphasized in modern definition of periodontal disease. A sum of researches in the literature has revealed the inter-individual variability regarding host immune response and influence of genetic components in numerous pathologic conditions. Genetic variations in immune cell development, antigen cell presentation or inflammatory mediators of non-spesific immune response could be the risk factors for certain conditions, including periodontitis. From this point of view, periodontitis could be considered as a complex genetic disease with a phenotype configured through the genetic make-up and environmental factors in the affected individual. Therefore, it could be foreseen that mapping of the genetic suspectibility profile related with periodontitis might be very valuable for developing diagnostic techniques and individual treatment strategies. The aim of this non-systematic review was to underline the possible role of genetic polymorphisms in periodontal diseases and to revise the discussions on the methods for association studies.

Anahtar Kelimeler

Periodontal disease, genetic polymorphism

Kaynakça

• 1. Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol. 1996;1(1):821-78.
• 2. Kinane DF, Shiba H, Hart TC. The genetic basis of periodontitis. Periodontol 2000. 2005;39:91-117.
• 3. Michalowicz BS, Aeppli D, Virag JG et al:. Periodontal findings in adult twins. J Periodontol. 1991;62(5):293-9.
• 4. Michalowicz BS, Diehl SR, Gunsolley JC et al:. Evidence of a substantial genetic basis for risk of adult periodontitis. J Periodontol. 2000;71(11):1699-707.
• 5. Corey LA, Nance WE, Hofstede P, Schenkein HA. Self-reported periodontal disease in a Virginia twin population. J Periodontol. 1993;64(12):1205-8.
• 6. Boughman JA, Astemborski JA, Suzuki JB. Phenotypic assessment of early onset periodontitis in sibships. J Clin Periodontol. 1992;19(4):233-9.
• 7. Marazita ML, Burmeister JA, Gunsolley JC, Koertge TE, Lake K, Schenkein HA. Evidence for autosomal dominant inheritance and race-specific heterogeneity in early-onset periodontitis. J Periodontol. 1994;65(6):623-30.
• 8. Li Y, Xu L, Hasturk H, Kantarci A, DePalma SR, Van Dyke TE. Localized aggressive periodontitis is linked to human chromosome 1q25. Hum Genet. 2004;114(3):291-7.
• 9. Laine ML, Loos BG, Crielaard W. Gene polymorphisms in chronic periodontitis. Int J Dent. 2010;2010:324719.
• 10. Kornman KS, Crane A, Wang HY et al:. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol. 1997;24(1):72-7.
• 11. Diehl SR, Wang Y, Brooks CN et al:. Linkage disequilibrium of interleukin-1 genetic polymorphisms with early-onset periodontitis. J Periodontol. 1999;70(4):418-30.
• 12. Ishihara Y, Nishihara T, Kuroyanagi T et al:. Gingival crevicular interleukin-1 and interleukin-1 receptor antagonist levels in periodontally healthy and diseased sites. J Periodontal Res. 1997;32(6):524-9.
• 13. Moreira PR, Costa JE, Gomez RS, Gollob KJ, Dutra WO. The IL1A (-889) gene polymorphism is associated with chronic periodontal disease in a sample of Brazilian individuals. J Periodontal Res. 2007;42(1):23-30.
• 14. Kobayashi T, Ito S, Kuroda T et al:. The interleukin-1 and Fcgamma receptor gene polymorphisms in Japanese patients with rheumatoid arthritis and periodontitis. J Periodontol. 2007;78(12):2311-8.
• 15. Berdeli A, Emingil G, Gurkan A, Atilla G, Kose T. Association of the IL-1RN2 allele with periodontal diseases. Clin Biochem. 2006;39(4):357-62.
• 16. Laine ML, Farre MA, Gonzalez G et al:. Polymorphisms of the interleukin-1 gene family, oral microbial pathogens, and smoking in adult periodontitis. J Dent Res. 2001;80(8):1695-9.
• 17. Parkhill JM, Hennig BJ, Chapple IL, Heasman PA, Taylor JJ. Association of interleukin-1 gene polymorphisms with early-onset periodontitis. J Clin Periodontol. 2000;27(9):682-9.
• 18. Schulz S, Machulla HK, Altermann W et al:. Genetic markers of tumour necrosis factor alpha in aggressive and chronic periodontitis. J Clin Periodontol. 2008;35(6):493-500.
• 19. Tervonen T, Raunio T, Knuuttila M, Karttunen R. Polymorphisms in the CD14 and IL-6 genes associated with periodontal disease. J Clin Periodontol. 2007;34(5):377-83.
• 20. Soga Y, Nishimura F, Ohyama H, Maeda H, Takashiba S, Murayama Y. Tumor necrosis factor-alpha gene (TNF-alpha) -1031/-863, -857 single-nucleotide polymorphisms (SNPs) are associated with severe adult periodontitis in Japanese. J Clin Periodontol. 2003;30(6):524-31.
• 21. Erciyas K, Pehlivan S, Sever T, Igci M, Arslan A, Orbak R. Association between TNF-alpha, TGF-beta1, IL-10, IL-6 and IFN-gamma gene polymorphisms and generalized aggressive periodontitis. Clin Invest Med. 2010;33(2):E85.
• 22. Parkes M, Satsangi J, Jewell D. Contribution of the IL-2 and IL-10 genes to inflammatory bowel disease (IBD) susceptibility. Clin Exp Immunol. 1998;113(1):28-32.
• 23. Scarel-Caminaga RM, Trevilatto PC, Souza AP, Brito RB, Line SR. Investigation of an IL-2 polymorphism in patients with different levels of chronic periodontitis. J Clin Periodontol. 2002;29(7):587-91.
• 24. Hart PH, Vitti GF, Burgess DR, Whitty GA, Piccoli DS, Hamilton JA. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2. Proc Natl Acad Sci U S A. 1989;86(10):3803-7.
• 25. Holla LI, Fassmann A, Augustin P, Halabala T, Znojil V, Vanek J. The association of interleukin-4 haplotypes with chronic periodontitis in a Czech population. J Periodontol. 2008;79(10):1927-33.
• 26. Anovazzi G, Kim YJ, Viana AC et al:. Polymorphisms and haplotypes in the interleukin-4 gene are associated with chronic periodontitis in a Brazilian population. J Periodontol. 2010;81(3):392-402.
• 27. Donati M, Berglundh T, Hytonen AM, Hahn-Zoric M, Hanson LA, Padyukov L. Association of the -159 CD14 gene polymorphism and lack of association of the -308 TNFA and Q551R IL-4RA polymorphisms with severe chronic periodontitis in Swedish Caucasians. J Clin Periodontol. 2005;32(5):474-9.
• 28. Holla LI, Fassmann A, Stejskalova A, Znojil V, Vanek J, Vacha J. Analysis of the interleukin-6 gene promoter polymorphisms in Czech patients with chronic periodontitis. J Periodontol. 2004;75(1):30-6.
• 29. Kim YJ, Viana AC, Curtis KM et al:. Association of haplotypes in the IL8 gene with susceptibility to chronic periodontitis in a Brazilian population. Clinica chimica acta; international journal of clinical chemistry. 2010;411(17-18):1264-8.
• 30. Andia DC, de Oliveira NF, Letra AM, Nociti FH, Jr., Line SR, de Souza AP. Interleukin-8 gene promoter polymorphism (rs4073) may contribute to chronic periodontitis. J Periodontol. 2011;82(6):893-9.
• 31. Scarel-Caminaga RM, Kim YJ, Viana AC et al:. Haplotypes in the interleukin 8 gene and their association with chronic periodontitis susceptibility. Biochemical genetics. 2011;49(5-6):292-302.
• 32. Scarel-Caminaga RM, Curtis KM, Renzi R et al:. Variation in the CXCR1 gene (IL8RA) is not associated with susceptibility to chronic periodontitis. Journal of negative results in biomedicine. 2011;10:14.
• 33. Viana AC, Kim YJ, Curtis KM et al:. Association of haplotypes in the CXCR2 gene with periodontitis in a Brazilian population. DNA and cell biology. 2010;29(4):191-200.
• 34. Claudino M, Trombone AP, Cardoso CR et al:. The broad effects of the functional IL-10 promoter-592 polymorphism: modulation of IL-10, TIMP-3, and OPG expression and their association with periodontal disease outcome. J Leukoc Biol. 2008;84(6):1565-73.
• 35. Berglundh T, Donati M, Hahn-Zoric M, Hanson LA, Padyukov L. Association of the -1087 IL 10 gene polymorphism with severe chronic periodontitis in Swedish Caucasians. J Clin Periodontol. 2003;30(3):249-54.
• 36. Scarel-Caminaga RM, Trevilatto PC, Souza AP, Brito RB, Camargo LE, Line SR. Interleukin 10 gene promoter polymorphisms are associated with chronic periodontitis. J Clin Periodontol. 2004;31(6):443-8.
• 37. Yamazaki K, Tabeta K, Nakajima T et al:. Interleukin-10 gene promoter polymorphism in Japanese patients with adult and early-onset periodontitis. J Clin Periodontol. 2001;28(9):828-32.
• 38. Yamamoto K, Kobayashi T, Grossi S et al:. Association of Fcgamma receptor IIa genotype with chronic periodontitis in Caucasians. J Periodontol. 2004;75(4):517-22.
• 39. Sugita N, Kobayashi T, Ando Y et al:. Increased frequency of FcgammaRIIIb-NA1 allele in periodontitis-resistant subjects in an elderly Japanese population. J Dent Res. 2001;80(3):914-8.
• 40. Kobayashi T, Yamamoto K, Sugita N et al:. The Fc gamma receptor genotype as a severity factor for chronic periodontitis in Japanese patients. J Periodontol. 2001;72(10):1324-31.
• 41. Selvaraj P, Chandra G, Jawahar MS, Rani MV, Rajeshwari DN, Narayanan PR. Regulatory role of vitamin D receptor gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on macrophage phagocytosis and lymphoproliferative response to mycobacterium tuberculosis antigen in pulmonary tuberculosis. J Clin Immunol. 2004;24(5):523-32.
• 42. Gunes S, Sumer AP, Keles GC et al:. Analysis of vitamin D receptor gene polymorphisms in patients with chronic periodontitis. Indian J Med Res. 2008;127(1):58-64.
• 43. Nibali L, Parkar M, D'Aiuto F et al:. Vitamin D receptor polymorphism (-1056 Taq-I) interacts with smoking for the presence and progression of periodontitis. J Clin Periodontol. 2008;35(7):561-7.
• 44. Li S, Yang MH, Zeng CA et al:. Association of vitamin D receptor gene polymorphisms in Chinese patients with generalized aggressive periodontitis. J Periodontal Res. 2008;43(3):360-3.
• 45. Nosaka Y, Tachi Y, Shimpuku H, Kawamura T, Ohura K. Association of calcitonin receptor gene polymorphism with early marginal bone loss around endosseous implants. The International journal of oral & maxillofacial implants. 2002;17(1):38-43.
• 46. Suzuki A, Ji G, Numabe Y, Ishii K, Muramatsu M, Kamoi K. Large-scale investigation of genomic markers for severe periodontitis. Odontology / the Society of the Nippon Dental University. 2004;92(1):43-7.
• 47. Hart TC, Hart PS, Michalec MD et al:. Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation. J Med Genet. 2000;37(2):95-101.
• 48. Noack B, Gorgens H, Hoffmann T et al:. Novel mutations in the cathepsin C gene in patients with pre-pubertal aggressive periodontitis and Papillon-Lefevre syndrome. J Dent Res. 2004;83(5):368-70.
• 49. Yoshie H, Kobayashi T, Tai H, Galicia JC. The role of genetic polymorphisms in periodontitis. Periodontol 2000. 2007;43:102-32.
• 50. Itagaki M, Kubota T, Tai H, Shimada Y, Morozumi T, Yamazaki K. Matrix metalloproteinase-1 and -3 gene promoter polymorphisms in Japanese patients with periodontitis. J Clin Periodontol. 2004;31(9):764-9.
• 51. Ustun K, Alptekin NO, Hakki SS, Hakki EE. Investigation of matrix metalloproteinase-1--1607 1G/2G polymorphism in a Turkish population with periodontitis. J Clin Periodontol. 2008;35(12):1013-9.
• 52. Takashiba S, Noji S, Nishimura F et al:. Unique intronic variations of HLA-DQ beta gene in early-onset periodontitis. J Periodontol. 1994;65(5):379-86.
• 53. Ohyama H, Takashiba S, Oyaizu K et al:. HLA Class II genotypes associated with early-onset periodontitis: DQB1 molecule primarily confers susceptibility to the disease. J Periodontol. 1996;67(9):888-94.
• 54. Bonfil JJ, Dillier FL, Mercier P et al:. A "case control" study on the role of HLA DR4 in severe periodontitis and rapidly progressive periodontitis. Identification of types and subtypes using molecular biology (PCR.SSO). J Clin Periodontol. 1999;26(2):77-84.
• 55. Stein J, Reichert S, Gautsch A, Machulla HK. Are there HLA combinations typical supporting for or making resistant against aggressive and/or chronic periodontitis? J Periodontal Res. 2003;38(5):508-17.
• 56. LeVan TD, Bloom JW, Bailey TJ et al:. A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol. 2001;167(10):5838-44.
• 57. Yamazaki K, Ueki-Maruyama K, Oda T et al:. Single-nucleotide polymorphism in the CD14 promoter and periodontal disease expression in a Japanese population. J Dent Res. 2003;82(8):612-6.
• 58. James JA, Poulton KV, Haworth SE et al:. Polymorphisms of TLR4 but not CD14 are associated with a decreased risk of aggressive periodontitis. J Clin Periodontol. 2007;34(2):111-7.
• 59. Holla LI, Buckova D, Fassmann A, Halabala T, Vasku A, Vacha J. Promoter polymorphisms in the CD14 receptor gene and their potential association with the severity of chronic periodontitis. J Med Genet. 2002;39(11):844-8.
• 60. Gwinn MR, Sharma A, De Nardin E. Single nucleotide polymorphisms of the N-formyl peptide receptor in localized juvenile periodontitis. J Periodontol. 1999;70(10):1194-201.
• 61. Jones BE, Miettinen HM, Jesaitis AJ, Mills JS. Mutations of F110 and C126 of the formyl peptide receptor interfere with G-protein coupling and chemotaxis. J Periodontol. 2003;74(4):475-84.
• 62. Zhang Y, Syed R, Uygar C et al:. Evaluation of human leukocyte N-formylpeptide receptor (FPR1) SNPs in aggressive periodontitis patients. Genes Immun. 2003;4(1):22-9.
• 63. Atilla G, Emingil G, Kose T, Berdeli A. TGF-beta1 gene polymorphisms in periodontal diseases. Clin Biochem. 2006;39(9):929-34.
• 64. Babel N, Cherepnev G, Babel D et al:. Analysis of tumor necrosis factor-alpha, transforming growth factor-beta, interleukin-10, IL-6, and interferon-gamma gene polymorphisms in patients with chronic periodontitis. J Periodontol. 2006;77(12):1978-83.
• 65. Berdeli A, Gurkan A, Emingil G, Atilla G, Kose T. Endothelial nitric oxide synthase Glu298Asp gene polymorphism in periodontal diseases. J Periodontol. 2006;77(8):1348-54.
• 66. Concolino P, Cecchetti F, D'Autilia C et al:. Association of periodontitis with GSTM1/GSTT1-null variants--a pilot study. Clin Biochem. 2007;40(13-14):939-45.
• 67. Fassmann A, Holla LI, Buckova D, Vasku A, Znojil V, Vanek J. Polymorphisms in the +252(A/G) lymphotoxin-alpha and the -308(A/G) tumor necrosis factor-alpha genes and susceptibility to chronic periodontitis in a Czech population. J Periodontal Res. 2003;38(4):394-9.
• 68. Folwaczny M, Glas J, Torok HP, Mauermann D, Folwaczny C. The 3020insC mutation of the NOD2/CARD15 gene in patients with periodontal disease. European journal of oral sciences. 2004;112(4):316-9.
• 69. Folwaczny M, Glas J, Torok HP et al:. Polymorphisms of the interleukin-18 gene in periodontitis patients. J Clin Periodontol. 2005;32(5):530-4.
• 70. Folwaczny M, Glas J, Torok HP et al:. Prevalence of the -295 T-to-C promoter polymorphism of the interleukin (IL)-16 gene in periodontitis. Clin Exp Immunol. 2005;142(1):188-92.
• 71. Fraser DA, Loos BG, Boman U et al:. Polymorphisms in an interferon-gamma receptor-1 gene marker and susceptibility to periodontitis. Acta odontologica Scandinavica. 2003;61(5):297-302.
• 72. Glas J, Beynon V, Bachstein B et al:. Increased plasma concentration of surfactant protein D in chronic periodontitis independent of SFTPD genotype: potential role as a biomarker. Tissue antigens. 2008;72(1):21-8.
• 73. Gurkan A, Emingil G, Saygan BH et al:. Tissue plasminogen activator and plasminogen activator inhibitor-1 gene polymorphisms in patients with chronic periodontitis. J Periodontol. 2007;78(7):1256-63.
• 74. Ho YP, Lin YC, Yang YH, Ho KY, Wu YM, Tsai CC. Cyclooxygenase-2 Gene-765 single nucleotide polymorphism as a protective factor against periodontitis in Taiwanese. J Clin Periodontol. 2008;35(1):1-8.
• 75. Holla LI, Fassmann A, Vasku A, Znojil V, Vanek J, Vacha J. Interactions of lymphotoxin alpha (TNF-beta), angiotensin-converting enzyme (ACE), and endothelin-1 (ET-1) gene polymorphisms in adult periodontitis. J Periodontol. 2001;72(1):85-9.
• 76. Holla LI, Kankova K, Fassmann A et al:. Distribution of the receptor for advanced glycation end products gene polymorphisms in patients with chronic periodontitis: a preliminary study. J Periodontol. 2001;72(12):1742-6.
• 77. Hooshmand B, Hajilooi M, Rafiei A, Mani-Kashani KH, Ghasemi R. Interleukin-4 (C-590T) and interferon-gamma (G5644A) gene polymorphisms in patients with periodontitis. J Periodontal Res. 2008;43(1):111-5.
• 78. Houshmand B, Rafiei A, Hajilooi M, Mani-Kashani K, Gholami L. E-selectin and L-selectin polymorphisms in patients with periodontitis. J Periodontal Res. 2009;44(1):88-93.
• 79. Izakovicova Holla L, Buckova D, Fassmann A, Benes P, Znojil V. Plasminogen-activator-inhibitor-1 promoter polymorphism as a risk factor for adult periodontitis in non-smokers. Genes Immun. 2002;3(5):292-4.
• 80. Kocher T, Sawaf H, Fanghanel J, Timm R, Meisel P. Association between bone loss in periodontal disease and polymorphism of N-acetyltransferase (NAT2). J Clin Periodontol. 2002;29(1):21-7.
• 81. Laine ML, Murillo LS, Morre SA, Winkel EG, Pena AS, van Winkelhoff AJ. CARD15 gene mutations in periodontitis. J Clin Periodontol. 2004;31(10):890-3.
• 82. Li Q, Meng H, Zhang L et al:. Correlation between single nucleotide polymorphisms in a calprotectin subunit gene and risk of periodontitis in a Chinese population. Annals of human genetics. 2007;71(Pt 3):312-24.
• 83. Louropoulou A, van der Velden U, Schoenmaker T, Catsburg A, Savelkoul PH, Loos BG. Mannose-binding lectin gene polymorphisms in relation to periodontitis. J Clin Periodontol. 2008;35(11):923-30.
• 84. Meisel P, Krause T, Cascorbi I et al:. Gender and smoking-related risk reduction of periodontal disease with variant myeloperoxidase alleles. Genes Immun. 2002;3(2):102-6.
• 85. Meisel P, Timm R, Sawaf H, Fanghanel J, Siegmund W, Kocher T. Polymorphism of the N-acetyltransferase (NAT2), smoking and the potential risk of periodontal disease. Archives of toxicology. 2000;74(6):343-8.
• 86. Park OJ, Shin SY, Choi Y et al:. The association of osteoprotegerin gene polymorphisms with periodontitis. Oral diseases. 2008;14(5):440-4.
• 87. Reichert S, Machulla HK, Klapproth J et al:. Interferon-gamma and interleukin-12 gene polymorphisms and their relation to aggressive and chronic periodontitis and key periodontal pathogens. J Periodontol. 2008;79(8):1434-43.
• 88. Sahingur SE, Sharma A, Genco RJ, De Nardin E. Association of increased levels of fibrinogen and the -455G/A fibrinogen gene polymorphism with chronic periodontitis. J Periodontol. 2003;74(3):329-37.
• 89. Sakellari D, Katsares V, Georgiadou M, Kouvatsi A, Arsenakis M, Konstantinidis A. No correlation of five gene polymorphisms with periodontal conditions in a Greek population. J Clin Periodontol. 2006;33(11):765-70.
• 90. Savarrio L, Donati M, Carr C, Kinane DF, Berglundh T. Interleukin-24, RANTES and CCR5 gene polymorphisms are not associated with chronic adult periodontitis. J Periodontal Res. 2007;42(2):152-8.
• 91. Shimada Y, Tai H, Endo M, Kobayashi T, Akazawa K, Yamazaki K. Association of tumor necrosis factor receptor type 2 +587 gene polymorphism with severe chronic periodontitis. J Clin Periodontol. 2004;31(6):463-9.
• 92. Tsutsumi A, Kobayashi T, Ito S et al:. Mannose binding lectin gene polymorphism and the severity of chronic periodontitis. Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology. 2009;32(1):48-52.
• 93. Wohlfahrt JC, Wu T, Hodges JS, Hinrichs JE, Michalowicz BS. No association between selected candidate gene polymorphisms and severe chronic periodontitis. J Periodontol. 2006;77(3):426-36.
• 94. Wu YM, Juo SH, Ho YP, Ho KY, Yang YH, Tsai CC. Association between lactoferrin gene polymorphisms and aggressive periodontitis among Taiwanese patients. J Periodontal Res. 2009;44(3):418-24.
• 95. Xie CJ, Xiao LM, Fan WH, Xuan DY, Zhang JC. Common single nucleotide polymorphisms in cyclooxygenase-2 and risk of severe chronic periodontitis in a Chinese population. J Clin Periodontol. 2009;36(3):198-203.
• 96. Zhang L, Meng H, Zhao H et al:. Estrogen receptor-alpha gene polymorphisms in patients with periodontitis. J Periodontal Res. 2004;39(5):362-6.
• 97. Vijayalakshmi R, Geetha A, Ramakrishnan T, Emmadi P. Genetic polymorphisms in periodontal diseases: an overview. Indian journal of dental research : official publication of Indian Society for Dental Research. 2010;21(4):568-74.
• 98. Stephens JC, Schneider JA, Tanguay DA et al:. Haplotype variation and linkage disequilibrium in 313 human genes. Science. 2001;293(5529):489-93.
• 99. Caton J. International workshop for a classification of periodontal disease and conditions. Chicago, IL: American Academy of Periodontology, 1999
• 100.Hubacek JA, Rothe G, Pit'ha J et al:. C(-260)-->T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction. Circulation. 1999;99(25):3218-20.
• 101.Rothman KJ. Modern epidemiology. Boston, MA: Little Brown and Company, 1986