Results of segregation analyses support the possibility that risk of Early Onset Periodontitis (EOP) may be due to a single major gene. Alternatively, several genes of moderate effect may contribute significantly to increasing risk of the disease. We conducted linkage analyses spanning the entire human genome to evaluate these hypotheses. Families with two or more close relatives affected by EOP were ascertained in the state of Virginia, and the country of Chile. DNA was extracted from blood and highly polymorphic markers distributed throughout the human genome were typed using the polymerase chain reaction. Linkage analyses were performed using a dominant model of disease transmission which is most strongly supported by the segregation analysis studies, as well as additional analyses based on assumptions of alternative modes of disease gene transmission. We also applied nonparametric methods of inferring linkage and/or linkage disequilibrium which do not require assumptions about the diseases genetic architecture. We evaluated African-American families and Caucasian families, both separately and combined, and also evaluated LJP and G-EOP subtypes of EOP both separately and combined for all analyses. Dr. David Duffy of Queensland Institute of Medical Research in Australia contributed substantially to these statistical analyses. For our genome scan for EOP susceptibility we used the non-parametric SIBPAL program to assess evidence of linkage. We performed LOD score analyses using dominant, recessive and intermediate modes of transmission using the FASTLINK program. We obtained six regions with LOD scores above 2.0. We recognize that as a consequence of performing so many multiple comparisons in a genome search we expect to obtain several such LOD scores by chance alone. In fact, current analyses suggest that one would expect to obtain a LOD score of 3.3 about 5% of the time in a genome scan of a complex disease even in the absence of any true susceptibility loci. Thus this threshold constitutes the standard type I error criterion. In our study, we also performed multiple analyses based on different disease definitions, modes of inheritance and racial groups, so additional adjustments need to be made. However, we often found results to be highly correlated among these alternative analyses, so a simple Bonferroni method would be overly conservative. Our strongest finding is on chromosome 19 with a multipoint LOD score of 3.72 (Figure 1). Our second highest multipoint LOD score is 2.90 is for a region of chromosome 8 implicated for both LJP and G-EOP susceptibility. Future work will focus on follow-up of our finding of a strong association of IL-1 polymorphisms with generalized EOP, and on a new initiative aimed at identifying genetic and environmental factors underlying risk of adult periodontitis. Clinical subject recruitment will continue to be through long-standing collaborations with periodontists in Virginia and Chile. An additional collaborative study, relevant to periodontal diseases, is the study of smoking cessation carried out at the Jerry L. Pettis Memorial Veterans Administration (VA) Medical Center in Loma Linda, California. As a supplement to an ongoing VA protocol, ambulatory veterans from the VA Preventive Medicine Clinic and the VA Stop Smoking Classes are being recruited to participate in this two-pronged study to test whether immunoglobulin levels change after smoking cessation and to evaluate possible hereditary influences on smoking behaviors. Questionnaires regarding past smoking and success in smoking cessation, as well as blood from each subject are being delivered to our laboratory for molecular analyses. We are evaluating differences in IgG2levels between subjects that do versus those that do not succeed in quitting smoking. This information isrelevant toperiodontaldisease, since it has been found that smoking tends to decrease IgG2 levels and also increases risk ofperiodontal disease. We are also planning to study genetic markers of the dopamine pathways that have been suggested by previous studies to influence addiction including smoking behaviors. The study population will ultimately consist of approximately 300 (male and female) ambulatory veterans who are enrolled in the ongoing Smoking Cessation Program. We plan to complete recruitment of our target study population and to characterize both serum related markers such as IgG2 and genetic markers potentially associated with smoking addiction such as polymorphisms in the dopamine and serotonin pathways.
| Michalowicz, B S; Diehl, S R; Gunsolley, J C et al. (2000) Evidence of a substantial genetic basis for risk of adult periodontitis. J Periodontol 71:1699-707 |
