Promoter polymorphisms in the CD14 receptor gene and their potential association with the severity of chronic periodontitis.

Periodontitis, a chronic inflammation of the tissues surrounding the teeth, is a common disease affecting all populations. The main aetiology remains a bacterial infection that leads to gingival inflammation, loss of alveolar bone, and tooth loss. Although the presence of pathogenic micro-organisms is required to trigger this process, the amplification and progression of the disease is believed to rely heavily on the production of host mediators in response to bacteria and/or their metabolic products. The CD14 molecule, described as the major endotoxin receptor, is one of the receptors which act on the recognition of lipopolysaccharides (LPS, endotoxin) and gram positive or mycobacterial cell wall components and thus can initiate the innate immune response to bacterial invasion. It is constitutively expressed primarily on the surface of monocytes, macrophages, neutrophils, and gingival fibroblasts (mCD14). In addition, a soluble form of CD14 (sCD14) is abundant in serum and is apparently derived both from the secretion of CD14 and from enzymatically cleaved glycosyl-phosphatidylinositol anchored mCD14. Besides the role of CD14 in the host defence, several other biological functions have been found. CD14 is involved in the phagocytosis of gram negative bacteria, LPS mediated bone resorption, and monocyte-endothelial cell interactions. Furthermore, changes in CD14 expression and serum sCD14 levels seem to be associated with a number of pathological states including periodontal diseases. CD14 production is genetically regulated. The gene for the CD14 receptor is on chromosome 5 (region q23-21), consists of ≈3900 bp organised in two exons, and encodes a protein of 375 amino acids. In the promoter region of the CD14 gene, a C to T transition was identified at position –159 upstream from the major transcription site, which is near to an SP1 binding site that has a major influence on the monocyte specific expression of CD14, and near a CCAAT/enhancer binding protein site that may play an important role in the promoter activation of the CD14 gene during monocyte development. 13 Recent observations suggest that the TT homozygotes for this gene have a significantly increased density of CD14 in blood monocytes and increased serum levels of CD14 (sCD14) when compared with those involving the CT or the CC genotype. 15 More recently, four additional SNPs within 2 kb of the CD14 transcription start sites, at positions –1619, –1359, –1145, and –809, have been identified. Carriers of the –1359GG/– 1145AG/–159CT and –1359GT/–1145AG/–159CT haplotypes had a higher sCD14 than any other groups and the group with haplotypes –1359TT/–1145AA/–159CC had the lowest concentrations of sCD14. These findings suggest that the individual CD14 genotypes may be relevant in conditions where CD14 levels are increased, as in periodontitis. Considering the previously reported data, selected functional CD14 promoter polymorphisms were analysed in periodontitis patients compared to healthy controls in order to explore if CD14 genetic variances may be involved in the susceptibility and/or severity of chronic periodontitis. METHODS Study subjects All subjects were Europid of exclusively Czech ethnicity, free of all systemic diseases (especially cardiovascular disorders, such as coronary heart disease (CHD) and hypertension, diabetes mellitus, or allergy) and were not taking any medication. Phenotype status was assigned without knowledge of the genotypes by two independent investigators. One hundred and thirty-five Czech patients with chronic periodontitis (69 Key points