Periodontitis, Aggressive, 1

A number sign (#) is used with this entry because of evidence that aggressive periodontitis-1 is caused by homozygous mutation in the CTSC gene (602365) on chromosome 11q14.

Description

Aggressive periodontitis, which may be generalized or localized, is characterized by severe and protracted gingival infections, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting (American Academy of Periodontology, 2000). The term 'aggressive periodontitis' replaced the terms 'early-onset,' 'prepubertal,' or 'juvenile periodontitis' at a 1999 International workshop for a classification of periodontal disease and conditions, where it was decided that the classification terminology should not be age dependent or require knowledge of rates of progression (Armitage, 1999).

Genetic Heterogeneity of Aggressive Periodontitis

Aggressive periodontitis-2 (608526) has been mapped to chromosome 1q25.

Clinical Features

Jorgenson et al. (1975) described periodontitis in 3 (1 male) of 7 sibs in a black family. They found 12 reports of families with more than 1 affected child and unaffected parents. In 3 of the families the parents were first cousins. In 1 family, a first cousin was affected. Three pairs of like-sex twins were concordant for the trait. Rao et al. (1979) could detect no evidence of significant heritability.

Saxen and Nevanlinna (1984) studied 30 families. None of the 60 parents had any sign of the disorder. Of the 52 sibs, 9 (in 7 families) were affected. The findings were considered compatible with autosomal recessive inheritance.

Long et al. (1987) studied 37 kindreds with 2 rare types of familial periodontitis: a localized form usually diagnosed in late adolescence and a more generalized form with a later mean age of diagnosis. They found several families in which both forms occurred, making it unlikely that these 2 varieties have unrelated genetic causes.

Shapira et al. (1997) described a family with prepubertal periodontitis in several members in 3 generations. Localized and generalized forms were found in sibs. Variability in disease expression was further indicated by the fact that a pair of monozygotic twins were similarly but not identically affected.

Inheritance

Beaty et al. (1987) performed segregation analysis of data from 28 families ascertained through a proband with juvenile periodontitis. There was strong evidence of familial aggregation. The best fitting model was an autosomal recessive one. Long et al. (1987) favored autosomal recessive inheritance for early-onset periodontitis.

Melnick et al. (1976) concluded that juvenile periodontitis is probably inherited as an X-linked, dominant trait with decreased penetrance but relatively consistent gene expressivity, They stated that no male-to-male transmission had been reported and cited a female:male ratio of affected persons of about 2:1. However, Hart et al. (1991, 1992) noted that more complete family data document father-to-son transmission and that when the proportions of affected males and females are examined, rather than total numbers of affected individuals, the proportion of affected males and females is similar. They found no female preponderance after correction for ascertainment bias.

Biochemical Features

Exposure of polymorphonuclear leukocytes (PMNs) to N-formyl peptides stimulates these cells to migrate in a directed fashion (i.e., respond chemotactically) as well as release selectively a portion of their lysosomal contents (i.e., degranulate) and generate highly reactive oxygen-derived free radicals such as superoxide anion. These processes are initiated by the binding of formyl peptides to specific receptors on the PMN membrane. Van Dyke et al. (1980) demonstrated that PMNs from some patients with JP exhibit abnormal chemotactic responses when challenged with the synthetic chemotactic peptide FMLP. Furthermore, Van Dyke et al. (1981) reported that the PMNs from some JP patients show a diminution in their ability to bind radiolabeled FMLP indicating a decrease in receptor number. Perez et al. (1991) found a patient with JP in whom abnormal PMN chemotactic responsiveness to formyl peptide was associated with a defective population of formyl peptide receptors (FPRs). The PMNs failed to respond chemotactically when challenged with FMLP, but exhibited normal chemotactic responses upon exposure to purified human C5a (120900). Furthermore, the patient's PMNs were capable of degranulating and generating superoxide anion radicals as well as normal PMNs upon exposure to FMLP. Binding studies showed that the patient's PMNs had a reduction in the number of high-affinity FPRs.

Mapping

Hart et al. (2000) reported a consanguineous Jordanian family in which 4 members had prepubertal periodontitis. All 4 had gingival inflammation and radiographic evidence of alveolar bone loss. Hart et al. (2000) localized a gene of major effect for PPP in this kindred to a 14-cM genetic interval on chromosome 11q14 flanked by D11S916 and D11S1367 (maximum lod = 3.55 for D11S901). This interval overlapped the region of chromosome 11q14 containing the CTSC gene (602365), mutations in which can cause Papillon-Lefevre (245000) and Haim-Munk (245010) syndromes.

Genetic Heterogeneity

Roulston et al. (1985) studied dentinogenesis imperfecta (DGI; 125490) in the triracial population of Brandywine, Maryland, and found that a localized form of juvenile periodontitis (JP) was cosegregating. Discovery of 2 recombinant offspring supported linkage, not pleiotropism. In the full data, reported by Boughman et al. (1986), the maximum lod score for JP and group-specific complement (GC; 139200) was 3.1 at theta 0.05 and that for DGI and GC was 2.0 at theta 0.12. The lod score of 0.9 at theta 0.20 for linkage of DGI and JP suggested that GC is located between the 2 dental disease loci on chromosome 4q. The study suggested that types II and III DGI are allelic or perhaps the same disorder. (According to the classification of Shields et al. (1973), type I DGI is the form that occurs with osteogenesis imperfecta. Type II DGI (125490) is the form first shown to be linked to GC; confusion is possible because the official gene symbol for this form is DGI1. Shields type III DGI is the Brandywine form (125500) which was originally studied by Witkop and his colleagues (Hursey et al., 1956).)

Since the linkage of early-onset or juvenile periodontitis to GC was based on linkage studies in 1 large kindred, Hart et al. (1993) evaluated the generality of the finding by studying 19 unrelated families with 2 or more affected individuals. Twelve genetic models that varied in diagnostic classification, penetrance, and mode of inheritance were evaluated. Results for all models strongly excluded linkage between a periodontitis susceptibility gene and the proximal region of 4q, assuming locus homogeneity. The data statistically excluded the possibility that more than 40% of the families were linked to this candidate region for one model tested. Linkage under heterogeneity was excluded less strongly for other models, but no significant evidence in support of linkage was obtained for any model. Hart et al. (1993) concluded, therefore, that either the previous report of linkage was a false positive or that there are 2 or more unlinked forms of JPD, with the form located at 4q12-q13 being less common.

Association Pending Confirmation

In 159 German patients with generalized aggressive periodontitis, Schaefer et al. (2009) analyzed 3 SNPs on chromosome 9p21.3, rs2891168, rs1333042, and rs1333048, known to be in linkage disequilibrium with SNPs previously associated with coronary heart disease (see CHDS8, 611139), and found that the 3 SNPs tested were all associated with periodontitis (adjusted p = 0.0036 to 0.0077). The association was replicated in an independent population of 146 German patients with less severe localized aggressive periodontitis (adjusted p = 0.021 to 0.071). The region of association maps to the sequence of a large antisense noncoding RNA, ANRIL (CDKN2BAS; 613149), which partly overlaps regulatory and coding sequences of the CDKN2A (600160) and CDKN2B (600431) genes. A closely located type 2 diabetes-associated variant (see 125853) was independent of the CHD and periodontitis risk haplotypes. Schaefer et al. (2009) concluded that CHD and periodontitis are genetically related by at least 1 susceptibility locus.

Schaefer et al. (2010) conducted a genomewide association study in German patients with aggressive periodontitis. The phenotype was strongly associated with the intronic SNP rs1537415 in the GLT6D1 gene (613699). In a combined analysis with the addition of a Dutch cohort (n = 1758), rs1537415 reached a genomewide significance level of P = 5.51 x 10(9), OR = 1.59 (95% CI 1.36-1.86). The associated rare G allele of rs1537415 showed an enrichment of 10% in periodontitis cases (48% in comparison with 39% in controls). Fine-mapping and haplotype analysis indicated that rs1537415 showed the strongest association signal; sequencing identified no further associated variant. Tissue-specific expression analysis of GLT6D1 indicated high transcript levels in testis, leukocytes, and gingiva. Analysis of potential transcription factor binding sites at the locus predicted a significant reduction of GATA3 (131320) binding affinity, and EMSA analysis indicated a T cell-specific reduction of protein binding for the G allele. Overexpression of GATA3 in HEK293 cells resulted in allele-specific binding of GATA3, indicating the identity of GATA3 as the binding protein. Schaefer et al. (2010) concluded that GLT6D1 is an important susceptibility factor for aggressive periodontitis and suggested that GATA3 may be a potential signaling component in the pathophysiology of periodontitis.

Molecular Genetics

By sequence analysis of the CTSC gene in a family segregating prepubertal periodontitis, Hart et al. (2000) found that all affected members were homozygous for a missense mutation (602365.0013). None of those affected had palmoplantar keratoderma.

Hewitt et al. (2004) identified a mutation in the CTSC gene (602365.0012) in only 1 of 2 families with juvenile periodontitis. They suggested that the disorder is genetically heterogeneous and that one form represents a partially penetrant Papillon-Lefevre syndrome.

Association Studies

Amer et al. (1988) reported evidence for an association between HLA alleles and susceptibility to periodontitis. They studied 49 patients with severe periodontal disease, an elderly group with minimal disease, and a young group with minimal disease. The HLA-A9 antigen was present in 36.7% of the patients with severe disease and only 2.5% of the elderly patients with minimal disease, whereas the HLA-A10 antigen was present in 30% of the resistant group and was absent from the patient group. The authors concluded that A10 may play a role in resistance to periodontal disease, whereas A9 may confer additional susceptibility.

Nomenclature

Periodontosis was at one time considered to be an idiopathic destruction of alveolar bone distinct from periodontitis. Periodontosis and periodontitis were later found to be the same disorder (Boughman, 1987).