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RESEARCH REPORT |
2 Integrin +807 Polymorphism in Drug-induced Gingival Overgrowth
1 Divison of Gene Expression, Institute for Genome Research, The University of Tokushima, Kuramoto 3-18-15, Tokushima 770-8503, Japan;
2 Department of Periodontology and Endodontology, Institute of Health Bioscience, Graduate School, The University of Tokushima;
3 Department of Pathophysiology/Periodontal Science, Okayama University Graduate School of Medical and Dentistry;
4 Divison of Periodontology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; and
5 Faculty of Pharmaceutical Science, University of Tokushima, Japan;
* corresponding author, kataoka{at}genome.tokushima-u.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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2 integrin on fibroblasts is reported to play an important role in the induction of drug-induced gingival overgrowth, which is characterized by excessive accumulation of type I collagen in gingival connective tissue. Silent polymorphism 807 T/C within the 2 integrin gene is associated with high/low 2 integrin expression. The aim of this study was to test the hypothesis that expression of 2 integrin 807 T/C polymorphism correlates with drug-induced gingival overgrowth. A case-control study comparing 136 subjects taking calcium channel blockers (72 with vs. 64 without drug-induced gingival overgrowth) demonstrated that the frequency of the +807 C allele was significantly higher in the case group than in the controls (odds ratio, 3.61; 95% confidence interval, 2.14 – 6.10; P < 0.05). The present findings suggest that the 2 +807 C allele is one of the genetic risk factors for drug-induced gingival overgrowth.
KEY WORDS: drug-induced gingival overgrowth • 2 integrin • SNP • collagen phagocytosis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Integrins are the principle mediators of molecular dialogue between a cell and its extracellular matrix environment (Gumbiner, 1996). The unique combinations of integrin subunits determine which extracellular matrix molecules will be recognized by a cell. The function of the 2ß1 integrin on the platelet has been well-studied, and the availability of the 2ß1 integrin on the platelet surface plays an essential role in platelet adhesion to collagen in vessel walls (Saelman et al., 1994). Furthermore, an ’807 C to T single nucleotide’ exchange polymorphism in the gene encoding the 2 subunit of the 2ß1 integrin is known to be associated with an increase in the density of the 2ß1 integrin on the platelet surface, as well as with increased platelet adhesion to collagen (Jacquelin et al., 2001; Kunicki, 2002). The 2ß1 integrin serves as a specific receptor for type I collagen in fibroblasts (Dickeson et al., 1999), and the initial binding step of collagen phagocytosis relies on adhesive interaction between fibroblasts and collagen. The 2 integrin plays a critical role in the phagocytic regulation of collagen internalization (Chou et al., 1996; Lee et al., 1996; Lee and McCulloch, 1997), and drug-induced gingival overgrowth is caused by inhibition of collagen phagocytosis by a reduction of 2 integrin expression in fibroblasts, as demonstrated in a rat experimental model (Kataoka et al., 2003). Genetic polymorphism can cause unexpected outcomes, such as therapeutic failure, toxicity, and adverse effects in subjects undergoing medical treatment (Kim et al., 2004). These findings have led to the hypothesis that subjects with the 807 C genotype of the 2 integrin express less 2ß1 integrin on the gingival fibroblast surface, thus reducing the potential for fibroblast binding to type I collagen and collagen phagocytosis in response to drugs, and in turn increasing the risk of drug-induced gingival overgrowth. In this study, for early identification of individuals at risk for drug-induced gingival overgrowth, we investigated whether 2 integrin polymorphism is associated with calcium-channel-blocker-induced gingival overgrowth.
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MATERIALS & METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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2 integrin polymorphism is associated with the induction of drug-induced gingival overgrowth. We divided the subjects into two groups, those without gingival overgrowth (grade 1 or less) and those with gingival overgrowth (grade 2 or more): 64 subjects (29 men, 35 women; mean age, 68 yrs; range, 42–88 yrs) without (grade 1 or less) and 72 subjects (37 men, 35 women; mean age, 62 yrs; range, 8–83 yrs) with gingival overgrowth (grade 2 or more).
DNA Analysis
Genomic DNA was obtained from peripheral venous blood samples after standard venipuncture. All blood samples were collected in sterile tubes containing potassium EDTA. DNA was extracted by means of a DNA extraction kit (Takara Shuzo, Kyoto, Japan) according to the instruction manual. A DNA fragment containing the site of 2 integrin 807 T/C polymorphism was amplified by PCR with a specific primer set (5'-gtgtttaacttgaacacatataaaaccaa-3' and 5'-gaaggcagctgggaaagttaaatc-3') based on the sequence data (GenBank accession number AF035968). After the 310-bp DNA fragment had been purified by electrophoresis on 1.5% agarose gel, and the subsequent use of a DNA purification kit (QIAGEN GmbH, Hilden, Germany), nucleotide sequencing was performed by cycle sequencing coupled with primers designed for the amplification of DNA with Gene Rapid (Amersham, Arlington Heights, IL, USA).
Statistical Analysis
We used the 
2 test to compare differences between the case and control allele or genotype frequencies. Association between the allele and gingival overgrowth was assessed by calculation of the odds ratio and 95% confidence intervals (CI).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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). The enlarged fibrous gingival tissue covered the facial surfaces of the teeth, particularly in the interdental areas.
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2 Integrin in Subjects with or without Gingival Overgrowth2 integrin gene. The frequencies of the allele and genotypes of +807 polymorphism within the 2 integrin gene are shown in the Table. The CC and TC genotypes were present in 59.7% and 36.1% of the subjects with gingival overgrowth, respectively, whereas, in the control group, the corresponding frequencies were 29.7% and 39.1% (P = 2.17 x 10–5). Furthermore, a significant difference was observed between the case group (77.8%) and the control group (49.2%) in the frequency of the +807 C polymorphic allele (P = 9.20 x 10–7; odds ratio = 3.61, 95% CI = 2.14 – 6.10). These results indicated that the +807 polymorphism within the 2 integrin gene is a strong genetic factor involved in drug-induced gingival overgrowth.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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The 2 integrin is known to play an important role in the induction of drug-induced gingival overgrowth (Chou et al., 1996; Lee et al., 1996; Lee and McCulloch, 1997). Inhibition of collagen phagocytosis by reduction of 2 integrin expression in gingival fibroblasts induces excessive collagen accumulation in gingival connective tissue, which in turn leads to gingival overgrowth (Kataoka et al., 2003). Interestingly, 2 integrin expression on platelets is highly variable, even among normal individuals, and there is, on average, a five-fold range of platelet 2ß1 integrin density, associated with the inheritance of at least 3 2 gene alleles, that influences the degree of platelet adhesion to collagens (Kunicki et al., 1993, 1997; Kritzik et al., 1998; Roest et al., 2000; Jacquelin et al., 2001; Kunicki, 2002). The 2 gene 807 T is associated with a high density of platelet 2ß1, whereas allele 807 T/C and 807 C are associated with lower densities (Kunicki et al., 1993, 1997; Kritzik et al., 1998; Roest et al., 2000; Kunicki, 2002). Thus, it is conceivable that 2 gene alleles might directly affect changes in the density of 2ß1 integrin on gingival fibroblasts and collagen phagocytosis in gingival connective tissue. We therefore speculated that the 2 integrin 807 T/C polymorphism may be related to the induction of drug-induced gingival overgrowth, and that 2 integrin 807 C may predispose individuals to gingival overgrowth through low expression of the 2ß1 integrin on gingival fibroblasts. This would have more severe inhibitory effect on drug-induced collagen phagocytosis than that of 807 T, leading to excessive accumulation of collagen fibers in gingival connective tissues. With regard to the low density of the 2 integrin on fibroblasts resulting from 2 integrin 807 C, its expression level would be easily reduced to below the threshold of collagen phagocytosis for induction of gingival overgrowth by drugs. Recently, Di Paola et al.(2005) showed that the frequency of 807 T in a Japanese population is 0.41. The 807 T frequency of 0.508 in controls in this experiment is evidently higher than that of the other report. The reason for this frequency is unknown. However, if a control frequency of 0.41 were used, there would be 75 807 C and 53 807 T chromosomes, and the difference would still be statistically significant (P = 0.001). Likewise, the control genotypes would be 22 CC, 31 CT, and 11 TT, and the difference would still be significant (P = 0.003). The 2 integrin 807 T/C polymorphism does not affect the amino acid sequence of the 2 integrin protein. Although we did not examine 2 integrin expression on gingival fibroblasts in this study, linkage with other functionally relevant polymorphisms of the 2 integrin gene seems plausible. This is the first study to demonstrate an association between 2 integrin polymorphism and drug-induced gingival overgrowth.
In summary, analysis of our data provides evidence that the 2 integrin gene plays an etiologically important role in drug-induced gingival overgrowth, and that the frequency of the 2 integrin 807 C allele is significantly increased in subjects with drug-induced gingival overgrowth. Drug-induced gingival overgrowth may be reduced by the elimination (with dental plaque control and periodontal maintenance therapy) of exacerbating factors such as dental plaque and calculus, but not prevented in the susceptible patient. The most effective treatment of drug-induced gingival overgrowth is withdrawal or substitution of medication. The present findings will be useful for the early identification of individuals at risk for drug-induced gingival overgrowth, and may also provide a basis for the selection of medications to prevent it.
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ACKNOWLEDGMENTS |
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Received April 28, 2005; Last revision August 9, 2005; Accepted August 30, 2005
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