Cytokine gene polymorphism and immunoregulation in periodontal disease.

Abstract

Summary and future prospects The genetic element for periodontal disease, a central pathogenic role for cytokines, as well as the principle of individual variation in disease experience are tenets of periodontal research. However, a role for cytokine gene polymorphism in immunoregulation in periodontal disease remains suggestive rather than being firmly established. The problems (and some potential solutions) relating to association analyses and experimental studies of cytokine gene polymorphisms at the molecular genetic level are outlined in the preceding sections. Our response to these challenges will be aided by the recent and rapidly developing fields of genomics, proteomics and bioinformatics. Developments in genomics are providing fundamental structural information about the human genome and genomic variation, e.g. dbSNP (Table 1)(155, 163). Analysis of the entire genomic complement of individual human SNPs in population studies of genetic association remains beyond our technical and economic resources. However, the increasing availability of high throughput technologies should make analysis of SNPs across multiple gene loci a fairly routine matter and association studies incorporating the analysis of several thousand gene polymorphisms are beginning to be done (18). Characterization of the physical relationship between individual SNPs in the genome and development of a genome-wide haplotype map will facilitate more detailed studies of genetic basis for human disease (61). For example, genotyping studies within individual loci have revealed that haplotypes within particular genetic regions contain informative SNPs and redundant SNPs; determination of the genotype of informative SNPs identifies the haplotype in that gene or region of the genome and these have been termed ‘haplotype tag SNPs’ (htSNPs) (97). Genotyping htSNPs promises to reduce the genotyping effort required and to aid investigations of the role of polymorphism and linkage disequilibrium across wide regions of the genome. Developments in technologies able to provide mRNA profiles (transcriptomics) and protein profiles (proteomics) at the cellular level are providing comprehensive phenotypic information with a wide range of applications in immunologic and pathologic studies of human disease. Cellular immune responses can now be mapped to changes in regulatory networks, rather than individual mediators, in response to defined stimuli (161). These technologies promise to facilitate comprehensive studies of genotype/phenotype relationships and will provide more sophisticated models for analyzing complex elements of human diseases (25). There is an increasing appreciation that biological research relies on efficient and imaginative information processing, especially in the post-genomic era. Bioinformatic approaches have evolved from demands of handling nucleic acid and protein sequences in molecular biological research and have now expanded to other areas such as immunologic research, where analysis of complex regulatory networks is critical to understanding immune responses in health and disease (2). There is no doubt that we now have the technologic basis to generate and analyze large volumes of information in the pursuit of understanding complex diseases such as periodontal disease at the molecular genetic level. However, in order to successfully exploit these developments there needs to be a move away from the reductionist view, which supports a central role for individual gene variants and loci in genetic susceptibility to complex diseases. Periodontal disease should be viewed as a polygenic disease in which many interacting gene variants contribute to disease susceptibility. Also, sophisticated models need to be developed which integrate modern perspectives on genetic variation at the genomic level, the dynamic nature of host immune responses and the relationship between immune parameters and disease activity (25, 147). These models must also consider the multifactorial nature of periodontal disease and in particular the contribution of environmental factors such as smoking. However, given the critical role of cytokines in immune responses, the limited information concerning the role of cytokine polymorphisms outside the IL-1 cluster, and our restricted understanding of cytokine regulation, cytokine genes and immune regulation are likely to remain an important field of investigation in periodontal research.