|Year : 2013 | Volume
| Issue : 5 | Page : 645
|Clinical and genetic aspects of generalized aggressive periodontitis in families of Tumkur district of Karnataka, India
Vaibhavi Joshipura1, Shobha Krishna Subbaiah2, Ravi Prakash Bdurga Saiprakash3, Netravathi Thumbigere Dasakariyappa3, BV Smitha3, Mahantesha4
1 Department of Periodontics, The Oxford Dental College and Hospital, Bangalore, India
2 The Oxford Dental College and Hospital, Bangalore, India
3 Department of Periodontics, Sri Siddhartha Dental College and Hospital, Tumkur, India
4 Department of Periodontics, Sharavathi Dental College and Hospital, Shivamoga, Karnataka, India
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|Date of Submission||28-Apr-2013|
|Date of Decision||04-Apr-2013|
|Date of Acceptance||10-Sep-2013|
|Date of Web Publication||21-Dec-2013|
| Abstract|| |
Background: Aggressive periodontitis (AP) is a complex disease whose phenotype is determined by genetic and environmental influences on the affected individuals. About 45% of the adult population in India has periodontitis. In Tumkur district of Karnataka, India, consanguineous first cousin and uncle-niece marriages are common, with a high incidence of AP. These discrepancies in the expression of periodontal disease directed us to find genetic etiology with respect to the Tumkur population. The clinical and genetic aspects of AP from this area have been presented in this paper.
Materials and Methods: A total of nine families were ascertained at the Department of Periodontics, Sri Siddhartha Dental College and Hospital (Sri Siddhartha University), Tumkur. The clinical and radiographic data were gathered according to 1999 Consensus Classification of Periodontal Diseases. Peripheral blood samples were collected for total genomic DNA isolation using a Wizard TM Genomic Purification Kit (Promega, USA). The homozygosity mapping was carried out in a large consanguineous family to map a novel locus using autosomal markers from the CHLC/Weber Human Screening Set 10 (Research Genetics Inc., USA) at Indian Institute of Sciences, Bangalore.
Results: The pedigree analysis suggested that the disorder is segregating as an autosomal trait. The homozygosity mapping failed to identify a locus for generalized AP in the family.
Conclusion: The disorder may not be segregating as an autosomal recessive trait and we could have been misled by consanguinity in the family. It could be a multifactorial trait, or it could be still segregating as an autosomal recessive trait, but the region of homozygosity could be small and we failed to detect it using microsatellite markers. Therefore, SNP-marker-based analysis is warranted in future.
Keywords: Aggressive periodontitis, autosomal dominant, autosomal recessive, complex diseases, consanguinity, gene mapping
|How to cite this article:|
Joshipura V, Subbaiah SK, Saiprakash RB, Dasakariyappa NT, Smitha B V, Mahantesha. Clinical and genetic aspects of generalized aggressive periodontitis in families of Tumkur district of Karnataka, India. Indian J Dent Res 2013;24:645
Aggressive periodontitis (AP) is an inflammatory disease of the periodontal tissues caused by infection with highly virulent periodontal pathogens in susceptible individuals. Generalized and localized forms of AP are rare types of periodontal diseases that appear at young age, with rapid attachment and bone loss, and strong familial aggregation. 
|How to cite this URL:|
Joshipura V, Subbaiah SK, Saiprakash RB, Dasakariyappa NT, Smitha B V, Mahantesha. Clinical and genetic aspects of generalized aggressive periodontitis in families of Tumkur district of Karnataka, India. Indian J Dent Res [serial online] 2013 [cited 2019 Dec 10];24:645. Available from: http://www.ijdr.in/text.asp?2013/24/5/645/123422
The etiology, although unclear, includes the sum of environmental and genetic factors. The pathogenesis of periodontal diseases suggests that they occur as a result of complex interactions between periodontopathic microorganisms and immune responses that follow. For these reasons, periodontitis is considered as a complex disease whose phenotype is determined by both the genetic factors as well as the environmental influences on the affected individuals. 
A recent review states that not much is known regarding the patients at risk and how initiation of periodontal disease can be prevented. The focus of periodontal epidemiology has been on identifying populations that have disparities in disease prevalence. 
There are many reports in the literature describing families with multiple AP-affected individuals, suggesting familial aggregation. ,, The patterns of disease in these families have led investigators to postulate both dominant and recessive modes of Mendelian inheritance for AP. ,,
It is proved by the research that identifying genes that contribute to the pathogenesis of periodontitis can have significant public health, therapeutic and scientific repercussions. Loss of teeth induced by periodontitis has a considerable effect on homeostasis of the craniofacial and oral tissues, and consequently on the general wellbeing of the individuals. 
In Tumkur district of Karnataka (India), consanguineous first cousin and uncle-niece marriages are common, with a high incidence of AP. However, there are no reports about clinical and genetic analyses in these families with AP. We report here the clinical and genetic aspects of AP in nine families evaluated from this area.
| Materials and Methods|| |
A total of nine families with generalized aggressive periodontitis (GAP) were ascertained at the Department of Periodontics, Sri Siddhartha Dental College and Hospital (SSDCH), Sri Siddhartha University, Tumkur, Karnataka, India, following approval from the institutional ethics committee. Further, five out of nine families were consanguineous.
Diagnosis of aggressive periodontitis was based on the 1999 Consensus Classification of Periodontal Diseases. Our diagnostic criteria took into consideration family history, clinical findings, and radiologic evidence. We classified patients as having AP when we had evidence of the following characteristics. 
- Healthy status, except for the presence of periodontitis: All patients with possible contributory medical history, such as specific recognized genetic disease with periodontal manifestations (i.e. Papillon-Lefever syndrome), diabetes, cardiovascular disease or prolonged use of corticosteroids or immunosuppressive medications were excluded.
- Rapid attachment loss and bone destruction, proven by radiographs obtained a few years apart. In the absence of sequential radiographs, young age was considered as a sign of rapid progression, in patients aged more than 35 years at the time of the initial diagnosis.
- Familial aggregation: We tried to ascertain the familial aggregation.
- Clinical and radiographic diagnosis: All the patients with a suspected diagnosis of AP were examined by a single experienced clinician. Full-mouth measurements were obtained using UNC-15 probe (University of North Carolina) for probing pocket depth, recession (measured as distance from the cement-enamel junction, CEJ, to the gingival margin) and lifetime cumulative attachment levels (LCAL, measured either as a direct measurement of CEJ to the base of the pocket, or as a calculation of probing pocket depth and recession). Six sites were measured for each natural tooth, each at the mesiobuccal, midbuccal, distobuccal, distolingual, midlingual, and mesiolingual sites encircling the tooth. Appropriate radiographic examinations were completed on each patient.
We classified patients as having GAP when we had evidence of the following characteristics. 
- Rapid attachment and bone loss in otherwise healthy patients
- Generalized interproximal attachment loss affecting at least three teeth other than first molars and incisors
- LCAL ≥ 4 mm on the affected site.
All probands were diagnosed with GAP in our department from February 2010 to February 2011. The suspected genetic background of their condition was explained to them. In this context, the importance of examining their first-degree blood relatives was highlighted. All available first-degree relatives were invited for a specific assessment at SSDCH, Tumkur.
For genetic analysis, 3-5 ml of peripheral blood sample was collected in a Na-EDTA Vacuitainer TM tube (Beckton-Dickinson, Gurgaon, India) from each individual. This study was performed in compliance with the Declaration of Helsinki principles and after approval from the ethics committee of the Sri Siddhartha University, Tumkur. Peripheral blood samples were subsequently used for total genomic DNA isolation using a Wizard TM Genomic Purification Kit (Promega, USA). In order to map a novel locus for GAP, homozygosity mapping  was carried out using autosomal markers from the CHLC/Weber Human Screening Set 10 (Research Genetics Inc., USA) as described by Kumar et al.  Genetic analyses were carried out at the Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore.
| Results|| |
The patients diagnosed as having AP were in the age group of 15-35 years. They were asymptomatic except mobility in some teeth as well as the loss of a few teeth due to periodontitis. The patients were unaware about the cause of mobility and the loss of teeth. Most of them had never gone to the dentist and the reason for reporting to the institution was primarily for the extraction of mobile teeth as well as for the replacement of missing teeth.
The clinical examination of the patients showed minimal local factors.
The gingiva appeared normal, without any visible signs of inflammation. Periodontal examination revealed pocket depths ranging from 5-11 mm [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]. In the family AGP-3 [Figure 7], individual III-1 had only 3-4 teeth left when she visited our clinic at the age of 30 years [Figure 8]. The youngest patient (individual IV-1) was 17 years of age [Figure 1]. In the family AGP-1, three out of six siblings were affected in third generation, whereas in the family AGP-3, five out of six siblings were affected in third generation. In the family AGP-9, seven out of eight siblings were affected in second generation; the disease had passed on to third generation also. Five of nine families exhibited consanguinity. Most of the older individuals (a total 14 people) in these families had lost several of their teeth to chronic periodontitis.
|Figure 4: 6 mm pocket mesial to 34, partially edentulous patient due to aggressive periodontitis|
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|Figure 7: Pedigrees of aggressive periodontitis. Square and round symbols represent males and females respectively. Shaded symbols represent affected individuals|
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The radiologic examination showed angular and vertical bony defects in most of the patients. Some defects had become periodontal-endodontic lesions [Figure 9]. All the patients and their family members were educated about AP and treated for periodontal problems followed by restoration of lost teeth, and are on regular follow up since then.
|Figure 9: Orthopentomograph showing angular defects and periodontal-endodontic lesion|
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The visual examination of pedigrees [Figure 7] suggested that GAP segregates as an autosomal recessive trait in seven of nine families (AGP-1, AGP-2, AGP-3, AGP-5, AGP-6, AGP-7 and AGP-9). The mode of the inheritance seemed to be autosomal dominant in the remaining two families, AGP-4 and AGP-8 [Figure 7].
We selected this large consanguineous family AGP-3 and subjected it to a whole-genome linkage scan using 231 autosomal PCR-based microsatellite markers.  The initial genotyping was carried out using DNA from individuals II-2, II-3, III-1, III-2, and IV-1 [Figure 7]. Homozygosity mapping  was carried out using autosomal markers from the CHLC/Weber Human Screening Set 10 (Research Genetics Inc., USA) as described by Kumar et al.  Once the homozygosity for microsatellite markers was identified in affected individuals, the entire family was genotyped with the marker. The analysis failed to identify a locus of AP in this family.
| Discussion|| |
In India, with many geographic, ethnic, cast, and economic variations, a variety of studies on periodontal health have been performed on population subgroups.  In these studies, periodontitis has been shown to be associated with age, poor oral hygiene, fluorosis, chewing of betel nuts, and no access to regular dental care, which predisposes rural population to periodontal diseases. However, there are not many studies focusing on region specific incidence of AP.
India's population is composed of approximately 50,000 to 60,000 endogamous subpopulations or caste groups.  Several authors have reported substantial variation and differentiation among populations at all levels: among regional populations and among broad caste groups as well as tribal populations. 
A recent review about the prevalence of periodontitis in India suggested different prevalence rates among different states of India varying to a wide range. These discrepancies in the prevalence of periodontitis in different ethnic groups in different parts of the country in the study done by WHO could have been due to different etiological and risk factors. 
Thus, it became very important to find risk factors for the rural population of Tumkur showing high incidence of AP. In this study, patients and their relatives were ruled out for all the other contributing factors for severe forms of periodontitis, before inclusion of patients in the study, except microbial etiology.
The concept of high risk group has been evaluated by some authors, where the entire population not having access to dental care does not show similar presence and severity of disease. , This was evident in our study group that showed variability in disease expression.
The presence of minimal local factors in all the patients was in contrast to a positive association being found by some authors between amount of plaque and generalized forms of AP. ,
It was reported that offspring of subjects with chronic periodontitis exhibit a relatively high prevalence of periodontal breakdown when under the age of 15, suggesting a strong familial influence on the prevalence of both chronic and AP.  In our study 14 people in the older generation of patients exhibited chronic periodontitis [Table 1].
Taking all these observations into account, it directed us to the genetic etiology in this population. Recently, periodontal research is growing in the area of genetic etiology in periodontal disease. With an increased understanding of the genome, functional interrelationships of gene products with each other and with environmental agents are better understood. This knowledge has proved that there is a geneticbasis for most diseases, including periodontitis. 
Based on both family and twin studies, it is found that the basis for periodontitis appears not to be bacterial, environmental or behavioral in nature, but genetics seems to form basis for susceptibility to periodontitis 
The pedigree analysis in our study group showed both recessive and dominant pattern in different families. In a family study of young patients with severe periodontitis the mode of inheritance was suggested to be as autosomal dominant in African-American and Caucasian kindred with 70% penetration. 
In a study, it was concluded that India has more human genetic diversity than any other comparable global region in the world, with the exception of Africa. , Variation and differentiation among populations, including variation influencing infection and disease, could arise due to both demographic history such as consanguinity and evolutionary genetic forces, such as selection, mutation, and recombination. However, while demographic processes affect the entire genome, region-specific effects of selection affect specific loci.  Tumkur district presents distinctive qualities of region-specific rural population; hence, this study was carried out with specific loci hypothesis on this population.
Among Indians, consanguinity and marriages within caste groups as well as within the family are well known, and these factors may have important clinical consequences and thus, impact on community genetics. A number of complex genetic disorders, such as coronary heart disease, cancer, psychiatric disorders and asthma, have been found to be associated with consanguinity in several human populations. 
In Tumkur district of Karnataka (India), consanguineous first cousin and uncle-niece marriages are common, with a high incidence of AP. There have not been any genetic analyses done for periodontal diseases of this population till date. The patients coming predominantly from rural areas have other factors to be taken into consideration, such as awareness about periodontal diseases and oral hygiene maintenance. Most of the participants were either illiterate or barely literate.
In a reviewon the socioeconomic status and periodontal disease, Luisa et al.  concluded that persons who are socioeconomically disadvantaged consistently have poor periodontal outcomes. In this part of country, people stay in large joint families, which make them vulnerable to horizontal and vertical transmission of the periodontopathic microorganisms, predisposing them to periodontal diseases. However, no microbiological evaluation was done in this study, restricting it to clinical and genetic analysis.
The identification of a locus for GAP was done by homozygosity mapping, because five out of nine families were consanguineous. In homozygosity mapping, linkage of the disorder in a consanguineous family to a locus is based on the observation of the same homozygous haplotype by descent in all affected individuals. In our study, members of the four generation consanguineous family AGP-3 [Figure 7] were subjected to homozygosity mapping as described earlier to identify a locus for GAP, but the study failed to identify the locus in this family with an autosomal recessive mode of inheritance. Views as to whether the transmission of AP is X-linked dominant, autosomal recessive or autosomal-dominant have been the subject of much debate in the literature. Family linkage studies and segregation analyses of families with AP support a major locus hypothesis and potential inheritance models include autosomal dominantautosomal recessive) and X-linked dominant). Despite the familial aggregation of AP, the mode of inheritance is still unclear. 
Genetic influences on the inflammatory component of complexdisease expression may manifest themselves in multiple ways. Different persons have different expressions of inflammatory processes and over a periodof time, this different expression pattern is sufficient to change the disease severity. The genetic factors act as disease modifiers. The susceptibility condition by itself is insufficient for the disease, but the onset and progression of disease may be earlier and faster in susceptible persons than in others. 
In most early reports, the increased prevalence among families, and transmission of the disorders through generations in pedigrees, has been used to support the hypothesis of X-linked dominant inheritance. By segregation analysis (especially complex segregation analysis), earlier support for X-linked dominant transmission has been refuted, and an autosomal-recessive model was preferred. However, some instances of intergenerational transmission suggest the possibility of a dominant inheritance. 
Previously, only three family linkage studies have been performed on families with AP. The first two studies suggested that a locus responsible for AP was located on chromosome 4, while the last study reported evidence of linkage on chromosome 1q25. In addition, mutations were described in the cathepsin C gene, which is also defective in the allelic syndromes, Papillon-Lefevre syndrome, Haim-Munk syndrome, in and some AP families. 
Since the pedigrees in our study showed autosomal recessive pattern, further evaluation was carried out by mapping with linkage analysis in order to find specific locus for AP in this population. The particular result of our study could be due to the following reasons. (1) The disorder may not be segregating as an autosomal recessive trait in the family and we could have been misled by consanguinity in the family. In this scenario, it could be a multifactorial trait. (2) It could be still segregating as an autosomal recessive trait, but the region of homozygosity could be small which we failed to detect by whole-genome linkage scan using 231 autosomal PCR-based microsatellite markers. Therefore, SNP marker-based analysis is warranted in future. Future studies also warrant analysis of plaque microorganisms including viruses in these patients.
The studies directed towards finding the etiological significance of genes reflect the heterogeneity and complexity in genetic etiology among different families, which is consistent with the fact that human disease and syndromes with a similar clinical appearance are known to result from different mechanisms. 
| Summary and Conclusion|| |
Looking at the incidence of AP in families from the Tumkur district in Karnataka (India), the genetic etiology was considered as a significant factor in the expression of disease in this population. Based on this hypothesis, the genetic analysis using homozygosity mapping was carried out to find a locus for AP in a large consanguineous family. The pedigree analysis suggested an autosomal recessive mode of Mendelian inheritance in this and most of the families. The homozygosity mapping using autosomal markers, failed to identify a locus. The result of this study showed that the disorder may not be segregating as an autosomal recessive trait in the family and we could have been misled by consanguinity in the family. In this scenario, it could be a multifactorial trait, or it could be still segregating as an autosomal recessive trait, but the region of homozygosity could be small and we failed to detect using microsatellite markers. Therefore, single nucleotide polymorphism (SNP) marker based analysis is warranted in future.
In conclusion, AP is a multifactorial, genetically complex disease. It can occur as a result of many accumulative susceptibility factors. Although many factors, including a variable onset of the trait, racial and ethnic variables, microbiologic and other epigenetic factors or the problems of clinical diagnosis ruling out other forms of periodontal disease like chronic periodontitis, may influence genetic studies of AP and identifying possible causal mechanisms and sources of heterogeneity. 
| Acknowledgment|| |
The authors would like to acknowledge the help, support and encouragement given at every level by Professor Arun Kumar and M.H. Shah of MRDG department, Indian Institute of Sciences, Bangalore.
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Shobha Krishna Subbaiah
The Oxford Dental College and Hospital, Bangalore
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
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