JADA Continuing Education
Clinical utility of a genetic susceptibility test for severe chronic periodontitis
A critical evaluation
GARY GREENSTEIN, D.D.S., M.S. and
THOMAS C. HART, D.D.S., Ph.D.
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ABSTRACT
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Background. A genetic susceptibility test for severe chronic periodontitis is now commercially available. It detects the simultaneous presence of a specific form of two interleukin genes—allele 2 at the IL1A+4845 and IL1B+3954 loci. Patients are referred to as being "genotype-positive" if both of these alleles are present. A fundamental premise of the test is that a combination of these alleles is responsible for increased secretion of IL-ß, which results in a hyperinflammatory response to a bacterial challenge, thereby predisposing a person to develop severe chronic periodontitis.
Types of Studies Reviewed. The authors reviewed controlled clinical trials that assessed the association between specific genotypes and the patient’s susceptibility to increased bleeding on probing, periodontitis and loss of teeth or dental implants.
Results. The relationship between specific IL-1 genotypes and the level of IL-1ß in the gingival crevicular fluid is unclear. Similarly, the ability of the genetic susceptibility test to forecast which patients will develop increased bleeding on probing, periodontitis, or loss of teeth or dental implants is ambiguous.
Clinical Implications. Additional prospective clinical trials are needed to determine the risk of developing periodontitis or peri-implantitis when allele 2 at the IL1A+4845 and IL1B+3954 loci is present. Therefore, it is unclear how results of the genetic susceptibility test can be used to alter patients’ periodontal maintenance schedules or to change treatment regimens in periodontally symptomatic or asymptomatic patients.
It is conceptually possible for measures to be initiated to prevent or mitigate destruction of the periodontium if people predisposed to developing chronic periodontitis could be identified. In this regard, a relatively new genetic susceptibility test (Periodontal Susceptibility Test, Interleukin Genetics Inc., Waltham, Mass.) has become commercially available to assess a patient’s risk of developing severe chronic periodontitis. However, important issues need to be resolved before this test can be integrated into the daily management of patients.
The ability of the genetic susceptibility test to forecast which patients will develop increased bleeding on probing, periodontitis, or loss of teeth or dental implants is ambiguous.
In this article, we review the biological basis for this genetic susceptibility test and evaluate data concerning its ability to predict which patients are predisposed to developing periodontal disease. The U.S. Food and Drug Administration has confirmed that a test can detect targeted genetic polymorphisms; however, it has not concluded that the test can be used to identify patients at risk of developing periodontitis.
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PATHOGENESIS OF CHRONIC PERIODONTITIS
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Bacterial pathogens are the primary etiologic factors in the initiation of periodontitis.1 However, the simple presence of pathogens is not enough to cause periodontitis. To induce destruction of the periodontium, bacteria must exceed a critical threshold and overcome antagonistic bacteria and the host response.2 In addition, the disease process appears to be modified by genetic factors, environmental factors (for example, smoking) and acquired conditions (for example, systemic diseases).3,4
Researchers and clinicians also recognize that the host response can be both protective and destructive. If neutrophils and other cells cannot control the microbial challenge, the host response results in a cascade of events that induce connective-tissue and alveolar bone loss.5 Lipopolysaccharides from the cell walls of gram-negative bacteria cause certain host cells, such as monocytes and macrophages, to release cytokines (that is, proinflammatory mediators) such as interleukin-1, or IL-1, and tumor necrosis factor alpha, or TNF-
. These mediators then recruit other cells (for example, fibroblasts and epithelial cells) to produce prostaglandins (that is, PGE2) that are associated with bone resorption and matrix metalloproteinases, which destroy connective tissue. Accordingly, genes that control the host response may play a major role in modulating the severity of periodontal diseases.6 Furthermore, data suggest that specific genes may determine the extent to which a person’s immune response is protective or destructive.7,8
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GENES AND GENETIC MODELS OF DISEASE
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The human genome refers to all the DNA genetic information in a cell’s nucleus. Genes are composed of nucleotides and are organized in the chromosomes within the cell’s nucleus.9 The sequence of nucleotides determines the expression of the gene, (that is, what type of protein is made). There may be multiple (poly) forms (morphism) of a gene, and the altered forms of a gene’s structure are referred to as "genetic polymorphisms." Different configurations of nucleotides making up a gene that occupy a particular locus in a chromosome are referred to as "alleles." Allele 1 usually denotes the most common form of the gene and allele 2 the second most common form. To delineate the specific site on a gene where the nucleotide alteration has occurred, scientists use a numbering system from a designated point to localize polymorphisms. For example, the genetic nomenclature "allele 2 at IL1B+3954 locus" means that this genetic polymorphism occurred at the 3,954th nucleotide and is the second most common form of gene IL1B at that locus.
Detection of a genetic polymorphism should not be interpreted to mean that it will have a functional effect. While some nucleotide changes have functional consequences, most do not, and the correlation between a base pair sequence and a specific phenotype often is unclear.10 In this respect, researchers have estimated that every person has 6 billion nucleotides and 0.1 percent (6 million) are polymorphic.11 Only a small fraction of these genetic variations are translated into alterations in amino acid sequence that are phenotypically important.
When the transfer of disease susceptibility is based on inheritance of a specific gene, it is referred to as a mendelian disorder. However, single mutant genes or pairs of mutant genes cause relatively few diseases (for example, Tay-Sachs disease).3 These illnesses often manifest themselves in childhood and usually occur independently of common environmental factors. In contrast, chronic diseases such as periodontitis and cardiovascular disease are considered to be multifactorial diseases and are thought to be caused by the action of multiple genes with subtle genetic alterations that interact over prolonged periods with environmental factors.10
Recent investigations have suggested that 50 percent of the clinical variability in chronic periodontitis might be attributed to genetic factors.12,13 Furthermore, genetic studies have shown that periodontitis is a complex disease in which multiple genes contribute a small part to susceptibility, while environmental factors appear to be critically important in the disease process.3 However, the clinical course of multifactorial diseases is hard to predict, and we do not know how many genetic polymorphisms are present and what gene-gene and gene-environmental interactions need to occur to affect the pathogenesis of periodontitis. Thus, while it is likely that polymorphisms of genes that control the immune response may affect the host response to a bacterial challenge, we should not presume that knowledge of a single nucleotide polymorphism will predict disease susceptibility.
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THE ROLE OF INTERLEUKINS AND GENES THAT CONTROL INTERLEUKIN-1
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Interleukins are a family of mediators closely associated with the pathogenesis of periodontitis. Offenbacher5 noted that the levels of several interleukins, including IL-1, were increased dramatically in the gingival crevicular fluid of patients with chronic periodontitis. There are two forms of IL-1, which are referred to as IL-1 and IL-1ß. Researchers have determined that IL-1ß plays a pivotal role in chronic inflammation and has many functions.5,14 IL-1ß is a potent stimulator of connective-tissue catabolism, activates immunocytes and induces other nucleated cells to produce prostaglandins and matrix metalloproteinases.5,14
Nicklin and colleagues15 determined that three genes control the production of IL-1: IL1A, IL1B and IL-receptor antagonist, or ILRN. Gene IL1A controls the production of proinflammatory protein IL-1 and gene IL1B regulates the production of proinflammatory protein IL-1ß. ILRN controls the synthesis of an antagonistic protein that impedes IL-1 and IL-1ß. Other genes also interact with these genes in controlling interleukin production.
The prevalence of specific genotypes may vary among different ethnic groups, and information derived from one group should not be extrapolated to another without verification of its accuracy.
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COMMERCIALLY AVAILABLE GENETIC SUSCEPTIBILITY TEST
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The genetic susceptibility test for severe periodontitis became commercially available after publication of a study by Kornman and colleagues.16 They reported that patients who were nonsmokers and positive for allele 2 at IL1A–899 and IL1B+3953 loci (when both of these alleles were present, the authors referred to the patients as being "genotype-positive," and we use this nomenclature in this report) had a 6.8 times greater chance of having severe periodontitis (that is, seven or more sites with 50 percent or more bone loss, and a mean bone loss of more than 34 percent) than patients who did not possess these alleles (referred to as being "genotype-negative").
However, in patients who were smokers, the genetic test results were inconclusive because smoking is a risk factor that confounds the risk assessment. Furthermore, if a patient had only a single allele 2 at one of the assessed loci, no relationship was found between the genetic test results and the presence of severe periodontitis. Kornman and colleagues16 also found no correlation between the test results and mild or moderate forms of periodontitis. Consequently, the test is specific for a relationship between genotype and severe periodontitis among nonsmokers. In addition, we should note that the study was composed of only 18 nonsmokers with severe disease.16
A basic premise of the genetic susceptibility test is that in the presence of allele 2 of the IL1B gene, an increased production of IL-1ß would occur and thus an increased predilection to develop periodontal disease. This assumption is based on in vitro work by Pociot and colleagues,17 who challenged human monocytes from diabetic patients with Escherichia coli lipopolysaccharide to determine how much IL-1ß was produced. They reported that monocytes homozygous for allele 1 of the IL1B+3953 gene produced 5.2 nanograms per milliliter of IL-1ß. However, if the monocytes had one allele 1 and one allele 2 of the IL1B+3953 gene, the interleukin level was 12 ng/mL. If two copies of allele 2 were present at the IL1B+3953 locus, the amount of IL-1ß produced was 19 ng/mL. Kornman and colleagues16 interpreted these data to indicate that patients with allele 2 at the IL1B+3953 locus might produce a greater amount of IL-1ß than patients with allele 1, and this could result in increased destruction of the periodontium.
Currently, allele 2 at the IL1A+4845 locus is assessed when using the commercially available genetic susceptibility test as opposed to IL1A–889, because they are concordant (if one is present, the other usually is present), and it is easier to test for IL1A+4845.18 In addition, the nomenclature has been changed, so that polymorphism at the IL1B+3953 locus is now referred to as IL1B+3954.18 These changes in terminology need to be noted so that data published before these revisions were made can be interpreted properly.
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GENOTYPE PREVALENCE IN THE POPULATION
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The frequency of genetic polymorphisms often varies among different ethnic groups. Therefore, it is necessary to determine the occurrence of specific alleles in ethnic categories to determine if information derived from one group can be extrapolated to another.
Several studies have indicated that 28 to 38 percent of whites possess the simultaneous genetic polymorphism of allele 2 at the IL1A+4845 and IL1B+3954 loci (that is, are genotype-positive).16,19–21 In contrast, Armitage and colleagues18 noted that only 2.3 percent of subjects in a Chinese population were genotype-positive. Furthermore, Walker and colleagues22 reported that less than 15 percent of African-Americans in their study population were genotype-positive. In addition, studies that addressed aggressive periodontitis in blacks found that allele 1, not allele 2, was associated with aggressive periodontitis.22,23 Clearly, the prevalence of allele 2 at both the IL1A+4845 and IL1B+3954 loci is different in different populations. Thus, we conclude that the prevalence of specific genotypes may vary among different ethnic groups, and information derived from one group should not be extrapolated to another without verification of its accuracy.
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CORRELATION BETWEEN INTERLEUKIN-1 GENOTYPES AND CLINICAL CONDITIONS
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Bleeding on probing.
Lang and colleagues19 assessed the relationship between IL-1 polymorphisms and bleeding tendencies. After undergoing periodontal surgery, patients receiving maintenance therapy were tested to determine if a correlation existed between the incidence of bleeding on probing and the presence of allele 2 at both the IL1A+4845 and IL1B+3954 loci (genotype positivity). When smokers were included in the statistical assessment, the authors found no relationship between bleeding tendency and the assessed genotypes. However, they reported significantly more bleeding among nonsmokers who were genotype-positive. This finding may be due to the fact that smoking is a risk factor for periodontitis, and it is not possible to determine if genetic assessments reveal patients who are predisposed to develop a more pronounced host response to a microbial challenge.24 Goodson and colleagues25 also noted an increased amount of bleeding on probing among genotype-positive patients in a gingivitis study.
In contrast, several other investigators found that among untreated16,26 and treated patients,20,27 there was no correlation between the genetic susceptibility test results and the amount of bleeding on probing (Table 1
).28 Furthermore, different levels of oral hygiene, professional maintenance therapy and small study populations could account in part for these conflicting results. Thus, we conclude that the relationship between bleeding on probing and the patient’s genotype is ambiguous, and studies have not verified that genotype-positive people are predisposed to develop increased bleeding on probing (Table 1).
Bone and clinical attachment loss.
Several studies have evaluated the correlation between bone loss and genotype status and reported an association between genotype positivity and the development of severe periodontitis. Kornman and colleagues16 determined that nonsmokers who were genotype-positive were 6.8 times more likely (6.8 odds ratio) to manifest severe periodontitis than genotype-negative patients. However, 14 (38 percent) of 37 patients with moderate disease and 10 (23 percent) of 44 healthy patients in their study also were genotype-positive (that is, false-positive findings). McDevitt and colleagues29 also reported that genotype-positive patients were 3.75 times more likely to have moderate-to-advanced periodontitis than were genotype-negative patients. On the other hand, Mark and colleagues,30 similar to Kornman and colleagues,16 found no relationship between genotype status and the presence of mild-to-moderate periodontitis.
Researchers have noted different genetic polymorphisms associated with chronic periodontitis and aggressive periodontitis.22,23,31 The finding that the prevalence of allele 1 and not allele 2 of the IL1B+3953 locus was higher among people with aggressive periodontitis has been interpreted by several authors22,23,31 to indicate there may be genetic differences related to different types of periodontal diseases. Other explanations for these results include the possibility that other genes closely linked to the tested IL-1 polymorphisms may be etiologic for periodontal disease susceptibility.32
Conflicting data preclude our deducing that genotype assessments could help predict which patients are predisposed to losing teeth as a result of periodontitis.
Tooth loss.
Ultimately, the sine qua non of performing dental procedures is to maintain teeth in a state of health and comfort for the life of the patient. Thus, it would be beneficial to be able to predict which people are at increased risk of losing teeth, so this information could be incorporated into a patient’s risk profile. To test this concept, McGuire and Nunn21 performed a retrospective study, genotyping 42 patients they had followed up over 13 years. They reported that genotype-positive patients were associated with a 2.7 times greater chance of losing teeth as a result of periodontal problems. The odds ratio might have been even higher in a group of patients who did not comply with maintenance recall appointments.
On the other hand, the study results were unclear in regard to how many teeth were lost among smokers and nonsmokers and how many teeth were lost per patient. It is interesting that 26 (62 percent) of 42 patients with periodontal disease in this investigation were genotype-negative (that is, false-negative findings using the genetic test), which is the opposite of what would be expected in a group of patients in a periodontal practice.
In contrast, several other investigators genotyped patients who had been monitored during maintenance therapy for 10 or more years after periodontal treatment and did not find an increased incidence of tooth loss among those who were genotype positive.33–35 Thus, conflicting data preclude our deducing that genotype assessments could help predict which patients are predisposed to losing teeth as a result of periodontitis.
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RELATIONSHIP BETWEEN GENOTYPE AND MAINTENANCE OF CLINICAL ATTACHMENT AFTER PERIODONTAL THERAPY
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One study suggested that genotype-positive patients were more prone to develop additional clinical attachment loss after treatment than were genotype-negative patients.20 However, several other clinical trials that monitored patients after periodontal therapy did not find a greater predilection for attachment loss among genotype-positive patients treated nonsurgically34,35 or surgically.34 Therefore, we cannot conclude that genotype-positive patients are more susceptible to develop additional attachment loss after periodontal therapy.
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IMPLANT LOSS
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If genotyping could predict the survivability of teeth, it might be able to do the same for implants. To investigate this possibility, Wilson and Nunn36 assessed the relationship between IL-1 genotype and implant loss. They found no increased loss of implants among patients who were genotype-positive.36 Siervo and colleagues37 confirmed this finding. Thus, similar to tooth loss, the data do not support the contention that dental implants are at greater risk of being lost among genotype-positive people.
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RELATIONSHIP BETWEEN INTERLEUKIN-1 BETA LEVEL AND GENOTYPE STATUS
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The biological premise of the commercially available genetic susceptibility test is that the level of IL-1ß is related to genetic polymorphisms that are detected by the test—specifically, that allele 2 of IL1B is associated with an increased propensity to secrete IL-1ß on microbial lipopolysaccharide stimulation. As indicated above, this assumption is based on the in vitro work of Pociot and colleagues,17 who reported that people with allele 2 at the IL1B+3953 locus produced increased amounts of IL-1ß. However, other studies have reported conflicting information (Table 2).27,28,38–41
For example, Engebretson and colleagues38 found that genotype-positive patients had an elevated level of IL-1ß in the gingival crevicular fluid from shallow pockets (
4 millimeters), but this relationship was not significant in deeper probing depths (> 4 mm). Mark and colleagues30 also noted that the level of IL-1ß was not related to genotype status. Other investigators who examined the levels of IL-1ß and a single polymorphism at allele 2 of the IL1B+3953 locus also reported no significant relationship with regard to the level of IL-1ß.39,40
Therefore, we conclude that the relationship between genotype status and the level of IL-1ß is not completely understood, and that polymorphisms detected by the genetic susceptibility test cannot be used to reliably predict which patients will manifest elevated levels of IL-1ß (Table 2
). Furthermore, the finding of great variation among patients with respect to the level of IL-1ß also suggests that other genetic loci may be involved that influence the quantitative and qualitative aspects of the periodontal inflammatory response.
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ODDS RATIOS
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In retrospective studies, investigators frequently use odds ratios to delineate the risk of negative events, such as the development of periodontitis. Odds ratios are calculated to characterize the strength of a relationship between a risk factor and the chance of developing a disease. Odds ratios, however, are not good forecasters of disease emergence.42 In other words, if the risk of developing a disease is 6.8 times greater when a risk factor is present (for example, genotype positivity) than when it is absent, a question left unanswered is this: 6.8 times greater than what? We do not know what percentage of genotype-positive or genotype-negative patients will develop severe periodontitis.
Prospective studies (for example, controlled clinical trials) are needed to calculate the probability of an adverse event occurring. For example, if 50 of 100 patients who are genotype-positive developed periodontitis, then the absolute risk of developing the disease could be calculated (50 of 100, or 50 percent chance of developing the disease). This type of calculation can be done only in prospective studies; it cannot be done in retrospective investigations in which patients are selected after they already have the disease.42 Thus, additional prospective studies that enroll a sufficient number of subjects are needed to derive valid predictive rates of chronic periodontitis associated with a genotype-positive test result.
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TREATMENT DECISIONS INFLUENCED BY GENETIC TESTING
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The finding that a dental patient is genotype- positive does not indicate that the patient will develop severe periodontitis. For instance, Papapanou and colleagues43 recently reported that among healthy patients (n = 73) and patients with periodontitis (n = 132), the percentage of genotype-positive patients was 41.7 percent and 45.2 percent, respectively. These findings cast doubt on the ability of genotyping to screen for susceptibility to develop periodontitis. Furthermore, in the study by Kornman and colleagues,16 23 percent of the healthy patients and 38 percent of the patients with moderate periodontitis were genotype-positive. In addition, 33 percent of their patients with severe periodontitis were genotype-negative.
Thus, detection of a positive genotype is not sufficient to initiate therapy, and the finding of a negative genotype is inadequate to conclude that the patient will not develop severe periodontitis. In this vein, we should point out that periodontitis is an infectious disease and may not follow the same clinical course as that of inflammatory diseases. In other words, even if the presence of specific genetic polymorphisms associated with an increased risk of developing periodontitis is identified, periodontitis will not develop if the bacterial pathogens do not overwhelm the host response.
With respect to use of this genetic test to facilitate screening of patients, several issues need to be explored. If a genetic test is used to identify people at increased risk of developing a disease, clinicians must be aware that the age of the patient, the part of the dentition to become affected and the percentage of genotype-positive patients who will manifest severe periodontitis all are unknown. Thus, for asymptomatic genotype-positive patients, it is unclear how their maintenance schedules should be changed to avoid development of periodontitis. Furthermore, since these patients may never develop any periodontal problems, altering their maintenance schedules could result in excessive monitoring and unnecessary treatment.
In regard to the management of periodontal patients, no intervention studies have been performed based on genotype determinations. Thus, we do not know the extent to which treatment needs to be altered among patients identified at risk in order to reduce the incidence of periodontitis. In addition, no data exist to suggest that genotype-negative patients can be treated more conservatively or that genotype-positive patients should be treated more aggressively. Ultimately, when additional data are available, the utility of genetic testing needs to be evaluated based on its ability to improve intervention strategies.
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UPDATE: ADDITIONAL STUDIES
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Since this article was accepted for publication, several studies have been published regarding the utility of IL-1 genotyping. Meisel and colleagues44 reported that genotype-positive nonsmokers were not at increased risk of developing periodontitis. In another prospective study conducted over five years, Cullinan and colleagues45 evaluated the relationship between periodontitis and the IL-1 genotype. They concluded that IL-1 polymorphisms may be a contributing risk factor for periodontal disease progression, but are not essential for it to occur, and by themselves may have only a small effect. Rogers and colleagues46 performed IL-1 genotyping on 119 white subjects and 60 white healthy control subjects. The investigators concluded that the simultaneous presence of allele 2 at the IL1A–889 and IL1B+3953 loci was not found more often among subjects with early-onset or adult periodontitis or among subjects with failed implants.
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CONCLUSION
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If additional longitudinal studies confirm the ability of the genetic susceptibility test to predict which patients are at greater risk of developing periodontitis, it may be appropriate for clinicians to incorporate this information into a patient risk profile. However, clinicians must carefully consider how the results of this test will aid treatment decisions. Additional research is needed before assessment of specific polymorphisms associated with the commercially available genetic susceptibility test can be integrated reliably into the daily management of patients.
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Dr. Greenstein is a clinical professor, Department of Periodontology, University of Medicine and Dentistry of New Jersey, Newark. He also maintains a private practice in periodontics, 900 W. Main St., Freehold, N.J. 07728, e-mail "ggperio@aol.com". Address reprint requests to Dr. Greenstein.
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FOOTNOTES
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Dr. Hart is an associate professor, Department of Oral Medicine and Genetics, University of Pittsburgh, School of Dental Medicine.
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REFERENCES
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- Haffajee AD, Socransky SS. Microbial etiological agents of destructive periodontal diseases. Periodontol 2000 1994;5:78–111.
- Darveau RP, Tanner A, Page RC. The microbial challenge in periodontitis. Periodontol 2000 1997;14:12–32.
- Hart TC, Kornman KS. Genetic factors in the pathogenesis of periodontitis. Periodontol 2000 1997;14:202–15.
- Salvi GE, Lawrence HP, Offenbacher S, Beck JD. Influence of risk factors on the pathogenesis of periodontitis. Periodontol 2000 1997;14: 173–201.
- Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol 1996;1:821–78.[Medline]
- Woo P. Cytokine polymorphisms and inflammation. Clin Exp Rheumatol 2000;18:767–71.[Medline]
- Le Souef PN, Goldblatt J, Lynch NR. Evolutionary adaptation of inflammatory immune responses in human beings. Lancet 2000;356: 242–4.[Medline]
- Malo D, Skamene E. Genetic control of host resistance to infection. Trends Genet 1994;10:365–71.[Medline]
- DNA structure and function. In: Strachan T, Read AP, eds. Human molecular genetics 2. Oxford, England: BIOS Scientific; 1996:1–31.
- Terwilliger JD, Goring HH. Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design. Hum Biol 2000;72(1):63–132.[Medline]
- Hubbard R, Lewontin RC. Pitfalls of genetic testing. N Engl J Med 1996;18:1192–4.
- Michalowicz BS, Diehl SR, Gunsolley JC, et al. Evidence of a substantial genetic basis for risk of adult periodontitis. J Periodontol 2000; 71:1699–707.[Medline]
- Michalowicz BS, Aeppli D, Virag JG, et al. Periodontal findings in adult twins. J Periodontol 1991;62:293–9.[Medline]
- Birkedal-Hansen H. Role of cytokine and inflammatory mediators in tissue destruction. J Periodontal Res 1993;28:500–10.[Medline]
- Nicklin MJ, Weith A, Duff GW. A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes. Genomics 1994;19:382–4.[Medline]
- 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.[Medline]
- Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 b) gene correlates with secretions in vitro. Eur J Clin Invest 1992;22:396–402.[Medline]
- Armitage GC, Wu Y, Wang HY, et al. Low prevalence of a periodontitis-associated interleukin-1 composite genotype in individuals of Chinese heritage. J Periodontol 2000;71(2):164–71.[Medline]
- Lang NP, Tonetti MS, Suter J, et al. Effect of interleukin-1 gene polymorphisms on gingival inflammation assessed by bleeding on probing in a periodontal maintenance population. J Periodontal Res 2000;35(2):102–7.[Medline]
- De Sanctis M, Zucchelli G. Interleukin-1 gene polymorphisms and long-term stability following guided tissue regeneration therapy. J Periodontol 2000;71:606–13.[Medline]
- McGuire MK, Nunn ME. Prognosis versus actual outcome, IV: the effectiveness of clinical parameters and IL-1 genotype in accurately predicting prognoses and tooth survival. J Periodontol 1999;70(1): 49–56.[Medline]
- Walker SJ, Van Dyke T, Rich S, et al. Genetic polymorphisms of the IL-1alpha and IL-1beta genes in African-American LJP patients and an African-American control population. J Periodontol 2000;71: 723–8.[Medline]
- Diehl SR, Wang Y, Brooks CN, et al. Linkage disequilibrium of interleukin-1 genetic polymorphisms with early-onset periodontitis. J Periodontol 1999;70:418–30.[Medline]
- Tomar SL, Asma S. Smoking-attributable periodontitis in the United States: findings from NHANES III. National Health and Nutrition Examination Survey. J Periodontol 2000;71:743–51.[Medline]
- Goodson JM, Palys MD, Socransky S. Gingival bleeding accentuated by plaque in healthy IL-1 (+) genotype subjects (abstract 221). J Dent Res 2000;79:171.
- Jespen S, Lohnert S, Acil Y, et al. The interleukin-1 genotype and experimental gingivitis (abstract 14). J Clin Periodontol 2000;27(special issue):21.
- Cutler CW, Stanford TW, Abraham C, Cederberg RA, Boardman TJ, Ross C. Clinical benefits of oral irrigation for periodontitis are related to reduction of pro-inflammatory cytokine levels and plaque. J Clin Periodontol 2000;27(2):134–43.[Medline]
- Greenstein G, Hart T. A critical assessment of IL-1 genotyping when used in a genetic susceptibility test for severe chronic periodontitis. J Periodontol 2002;73:231–47.[Medline]
- McDevitt MJ, Wang HY, Knobelman C, et al. Interleukin-1 genetic association with periodontitis in clinical practice. J Periodontol 2000;71(2):156–63.[Medline]
- Mark LL, Haffajee AD, Socransky SS, et al. Effect of the interleukin-1 genotype on monocyte IL-1beta expression in subjects with adult periodontitis. J Periodontal Res 2000;35:172–7.[Medline]
- Parkhill JM, Hennig BJ, Chapple IL, Heasman PA, Taylor JJ. Association of interleukin-1 gene polymorphisms with early-onset periodontitis. J Clin Periodontol 2000;27:682–9.[Medline]
- Hodge PJ, Riggio MP, Kinane DF. Failure to detect an association with IL-1 genotypes in European Caucasians with generalised early onset periodontitis. J Clin Periodontol 2001;28:43–6.
- Cattabriga M, Rotundo R, Muzzi L, et al. Retrospective evaluation of the influence of the interleukin-1 genotype on radiographic bone levels in treated periodontal patients over 10 years. J Periodontol 2001; 72:767–73.[Medline]
- Caffesse RG, de La Rosa RM, de La Rosa GM. The role of the IL-1 genotype on periodontal maintenance needs (abstract 263). J Clin Periodontol 2000;27(special issue):84.
- Ehmke B, Kress W, Karch H, Grimm T, Klaiber B, Flemmig TF. Interleukin-1 haplotype and periodontal disease progression following therapy. J Clin Periodontol 1999;26:810–3.[Medline]
- Wilson TG Jr, Nunn M. The relationship between interleukin-1 periodontal genotype and implant loss: initial data. J Periodontol 1999; 70:724–9.[Medline]
- Siervo S, Wirz J, Schmidli F, Coraini C, Siervo P. Late implant failures and genetic susceptibility: links and hints (abstract 240). J Clin Periodontol 2000;27(special issue):78.
- Engebretson SP, Lamster IB, Herrera-Abreu M, et al. The influence of interleukin gene polymorphism on expression of interleukin-1ß and tumor necrosis factor- in periodontal tissue and gingival crevicular fluid. J Periodontol 1999;70:567–73.[Medline]
- Gore EA, Sanders JJ, Pandey JP, Palesch Y, Galbraith GM. lnterleukin-1 beta +3953 allele 2: association with disease status in adult periodontitis. J Clin Periodontol 1998;25:781–5.[Medline]
- Galbraith GM, Hagan C, Steed RB, Sanders JJ, Javed T. Cytokine production by oral and peripheral blood neutrophils in adult periodontitis. J Periodontol 1997;68:832–8.[Medline]
- Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL1-IRN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol 1998;47:195–8.[Medline]
- Greenstein G, Lamster I. Understanding diagnostic testing for periodontal diseases. J Periodontol 1995;66:659–66.[Medline]
- Papapanou PN, Neiderud AM, Sandros J, Dahlen G. Interleukin-1 gene polymorphism and periodontal status: a case-control study. J Clin Periodontol 2001;28:389–96.[Medline]
- Meisel P, Siegmund A, Dombrowa S, et al. Smoking and polymorphisms of the interleukin-1 gene cluster (IL-1, IL-1ß and IL-RN) in patients with periodontal disease. J Periodontol 2001;734:27–32.
- Cullinan MP, Westerman B, Hamlet SM, et al. A longitudinal study of interleukin-1 gene polymorphisms and periodontal disease in a general adult population. J Clin Periodontol 2001;28:1137–44.[Medline]
- Rogers MA, Figliomeni L, Baluchova K, et al. Do interleukin-1 polymorphisms predict the development of periodontitis or the success of dental implants? J Periodontal Res 2002;37:37–41.[Medline]
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J Dent Educ.,
February 1, 2008;
72(2_suppl):
86 - 94.
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ABSTRACT
PATHOGENESIS OF CHRONIC...
