Interleukin polymorphisms in aggressive periodontitis: A literature review.

Aggressive periodontitis (AgP), occurs in a younger age group (≤35 years) and is associated with the rapid destruction of periodontal attachment and supporting bone. Genetic polymorphisms are allelic variants that occur in at least 1% of the population that could potentially alter the function of the proteins that they encode. Interleukins are a group of cytokines that have complex immunological functions including proliferation, migration, growth and differentiation of cells and play a key role in the immunopathogenesis of periodontal disease. The aim of this review was to summarize the findings of studies that reported associations or potential associations of polymorphisms in the interleukin family of cytokines, specifically with AgP.

INTRODUCTION

Periodontitis is a complex, multifactorial disease that may be classified as two main types, chronic periodontitis (CP) and aggressive periodontitis (AgP), among other subclasses in the 1999 world workshop classification of periodontal diseases and conditions.[1] The destruction of periodontal tissues occurs by a complex interaction of the bacterial biofilm and host response and is also influenced by genetic, systemic and environmental factors. AgP, previously known as juvenile periodontitis (JP) or early onset periodontitis (EOP) occurs in a younger age group (≤35 years) and is associated with the rapid destruction of periodontal attachment and supporting bone. AgP can be either generalized (GAgP) or localized to the first molars and incisors localized (LAgP).[2] The terms AgP, LAgP and GAgP have been used throughout this manuscript to refer to this disease.

Genetic polymorphisms are allelic variants that occur in at least 1% of the population. Single nucleotide polymorphisms (SNPs) are the most commonly found type of genetic polymorphisms. Such changes in genes could potentially alter the function of the proteins that they encode. In complex diseases like periodontitis, interaction of several different alleles may lead to an increased susceptibility to the disease. AgP is associated with familial aggregation, suggesting a strong genetic influence in this form of periodontitis.[3] Associations of several genetic polymorphisms in various genes with AgP have been previously reported, including the FcGammaR2, Vitamin D receptor and neutrophil formyl peptide receptor.[4]

Interleukins (ILs) are a group of cytokines that have complex immunological functions including proliferation, migration, growth and differentiation of cells. They can be pro- or anti-inflammatory, and some interleukins also function as chemokines or chemoattractants for other cells.[5] Various interleukins are involved at different levels in the inflammatory pathway that ultimately leads to tissue destruction and the clinical presentation of AgP. Due to these key roles that interleukins play in inflammation and periodontal disease pathogenesis, they make important potential therapeutic targets.[5] A large number of studies have been conducted in different populations groups reporting genetic polymorphisms in various interleukins and their associations with both CP and AgP. The aim of this review was to summarize the findings of studies that reported associations or potential associations of polymorphisms in the interleukin family of cytokines, specifically with AgP.

METHODS

A PubMed search was conducted using the keywords “interleukin”, “polymorphisms”; “aggressive” and “periodontitis” to identify articles published until September 30th, 2013. The focused question during the search was “what polymorphisms, specifically in the interleukin cytokine family of genes, are associated with AgP?” Studies were included that reported on specific interleukin polymorphisms and had a patient population of either AgP or AgP and CP. All reviews and meta-analyses were excluded from this review. Studies were also excluded if they did not specifically identify a patient population with AgP or were not available in the English language. Although some studies examined other genetic polymorphisms, only interleukins polymorphisms of are reported in this review.

RESULTS

The electronic PubMed search identified 79 articles that were further evaluated. After review, fifteen were excluded for being a review of other publications, not having clear information as to which results were specifically with AgP patients, and not having an English translation. Sixty four articles were included; Tables 1, 2 and 3 summarize the findings of studies that examined various interleukin cytokines and their associated polymorphisms in different population groups in their respective geographic locations.

Table 1

IL-1 polymorphisms in AgP

Table 2

ILs 2, 4, 6 and 8 polymorphisms in AgP

Table 3

ILs 10, 12, 13, 17, 18 and 23 polymorphisms in AgP

Interleukin-1 gene cluster polymorphisms

Interleukin-1 is a pro-inflammatory cytokine with several functions that contribute to the microbial immune response cascade, including guiding inflammatory cells into infection sites, promoting bone resorption, stimulating monocyte and fibroblast eicosanoid release and stimulating release of matrix metalloproteinases that degrade collagen.[6] The IL-1 family consists of IL-1α, IL-1β and IL-1 receptor antagonist (IL-1 Ra, the gene encoding it is designated IL-1RN). The IL-1 gene cluster is located within 430 kb region on chromosome 2q13. IL-1 has been extensively studied, since it is one of the key cytokines involved in the pathogenesis of periodontal disease. Kornman et al. reported that individuals carrying allele 2 of the IL-1β +3953 and IL-1α − 889 loci either in the homozygous or heterozygous forms are at a significantly greater risk for severe CP, in a population of Northern European heritage.[7] This publication has since spawned several reports on IL-1 polymorphisms in CP as well as AgP in various population groups.

Diehl et al.[8] analyzed localized and generalized forms of AgP in Caucasians and African Americans in the US. They reported a significant association of a polymorphic site in the IL-1β gene (allele 1) and GAgP, with a similar trend in LAgP, which was not significant. This was opposite to the findings of Kornman et al.[7] A subsequent study investigating African Americans with localized JP reported a high prevalence of IL-1B + 3953 allele 1 in both cases and controls and was not significantly associated with disease.[9] A study conducted in Central Americans from El Salvador reported no association with IL-1 genotypes with AgP.[10]

In South America, IL-1 polymorphisms in AgP have been investigated among Brazilians and Chileans. IL-1 polymorphisms did not appear to play a role in periodontitis susceptibility in a Brazilian family with siblings diagnosed with AgP.[11] Another study reported that the T allele of IL-1B + 3954 was more prevalent in CP than AgP in a population group from the south-eastern region of Brazil.[12] This study reported not stratifying their study group by ethnicity due to the high miscegenation in Brazilians. The same authors reported a correlation of IL-1A − 889 polymorphism with Brazilians with CP, but not AgP.[13] Consistent with this, another study revealed that there was no association of the same polymorphism in Brazilian Caucasians with GAgP.[14] Among Chileans, a population in Santiago that stems from Amerindians and Spanish, IL-1B + 3954 allele 2 polymorphism has been positively associated with AgP.[15]

Several studies conducted in Europe investigated the association of IL-1 polymorphisms with AgP. Studies conducted in the UK have shown conflicting results. One study involving LAgP reported a significant association of IL-1β +3954 homozygosity for allele 1 combined with smoking as well as a combination of IL-1β +3954 allele 1 and IL-IRN allele 1 to be significantly increased in AgP cases,[16] while another study in GAgP failed to find any association of the IL-1α and IL-1β polymorphisms with this disease.[17] A more recent study, however reported a statistically significant genotype frequency of IL-1β +3954 in patients with AgP, compared to controls.[18] Studies are investigating the association of IL-1 polymorphisms in German,[10192021] Dutch[19] and Danish[22] Caucasians with AgP have mostly demonstrated negative results. In an Italian Caucasian population, some weak evidence of the association of IL-1B + 3953 as well as significantly different distribution of IL-1RN variable number tandem repeat (VNTR) genotype distribution between GAgP and controls was reported.[23] However, subsequent reports by the same authors failed to find any association in of IL-1 polymorphisms in a similar population.[2425] A study conducted in a Greek population failed to detect any association of IL-Iα +3954, IL-1β +4845 or IL-1RN VNTR polymorphisms with AgP and CP.[26] Another study In Polish subjects also failed to demonstrate any association of IL-1 polymorphism IL-1β +3954 with AgP.[27] A study conducted in Czech Republic suggested that IL-1 genotype may be associated with progressive forms of EOP.[28]

In an Australian Caucasian population, no associations of IL-1 polymorphisms were found with AgP, but an association of IL-1β +3953 was found with adult periodontitis.[29]

A number of studies conducted in Asia have focused on IL-1 polymorphisms in AgP. In the Indian subcontinent population, Masamatti et al. reported an association of IL-1β +3954 polymorphism with CP, but not with AgP.[30] All subjects in this study belonged to the state of Karnataka in the South of India. Similar results were reported by another group who reported the association of allele C of the IL-1β +3954 polymorphism with CP, but not with AgP, in a Dravidian population group from the state of Kerala, also in the South of India.[31] Studies conducted in China concluded that IL-1α +4845 and 1 L-1β − 511 polymorphisms may be associated with an increased susceptibility of AgP in Chinese males.[3233] In a Thai population, however, there was no association of IL-1α − 889 and IL-1β +3954 with AgP.[34] A study in a Japanese population with GAgP found no association with IL-1α and 1 L-1β genotypes with AgP, but suggested that IL-1RN VNTR polymorphic alleles were significantly higher in these patients.[35] In a Jordanian population, SNPs IL-1α − 889, IL-1β − 511, − 35, +3953 and IL-1RN + 8006, +9589 and + 11100 were not associated with AgP, but some SNPs were associated with CP.[36] Among Iranians, one study reported a positive association of IL-1β polymorphism and GAgP,[37] but another study in North-Eastern Iranians reported no association of IL-1β +3954 polymorphism and the risk of AgP.[38] Another study reported that IL-1RN genotype AIA2 and allele A2 were significantly increased in Iranian Khorasanian subjects with GAgP.[39] Conflicting results have been reported in the Turkish population as well. One study reported that heterozygosity for allele 1 of IL-1α +4845 or homozygosity for allele 1 of IL-1β +3954 was related to increased susceptibility for LAgP,[40] whereas a more recent study reported no association of IL-1β +3954 with AgP.[41] Furthermore, GAgP in Turkish subjects has been associated with IL-1RN2 allele positivity.[42]

Findings show that the classic IL-1 positive genotype reported to be associated with CP does not appear to be associated with AgP. The association of IL-1 + 3954 allele 2 has shown some consistency between studies, especially in Caucasians [Table 1].

Interleukin-2 polymorphisms

Interleukin-2 is a cytokine produced by CD4 + cells and has a direct effect on the activation, growth and differentiation of T and B lymphocytes and natural killer cells. The gene encoding IL-2 is located on chromosome 4q26-q27. Reichert et al.[43] reported an association of two previously reported polymorphisms - 330 TàG and 166 Gà T with CP, but not AgP in German Caucasians. Another study did not find an independent association of IL-2 polymorphism (−330) with AgP in Italian Caucasians, but reported significant gene-gene interactions associated with AgP involving this polymorphism.[25] There are insufficient studies on IL-2 polymorphisms in different population groups. IL-2 polymorphisms in AgP may not be significant individually. However, evidence shows that they may affect the host response in combination with other gene polymorphisms, when inherited as specific haplotypes. This concept may be true for other polymorphisms as well [Table 2].

Interleukin-4 polymorphisms

Interleukin-4 is a cytokine generally involved in humoral immunity and important in down-regulating macrophage function. Selected IL-4 polymorphisms have been identified and associated with an increase in gene function, and have been linked to asthma, atopy, Crohn's disease and rheumatoid arthritis. The polymorphisms IL-4 − 590C→T and a 70 bp repeat in intron 2 were initially studied for a relationship to EOP in a German population, mostly Caucasian, where the two polymorphisms were found in 27.8% of the AgP group and in none of the healthy controls.[44] These same polymorphisms were then tested in both a Caucasian and Japanese population with the conclusion that although there was a significantly greater frequency of these polymorphisms in all Japanese subjects, there was only slight, but nonsignificant association for Caucasians and no association with the Japanese population for GAgP.[45] Further studies of a German Caucasian population for different variants (−590C→T, −34C→T) showed that although the allelic distribution was not significantly different between the groups, there was a significantly greater frequency of the − 590TT and − 34TT genotypes in the GAgP population.[46] In another European cohort looking at multiple polymorphisms, it was reported that IL-4 (−590), (−33) and an IL-4 short tandem repeat (STR) were not individually associated with AgP, although the IL-4 STR was found to be significantly associated through gene-gene interaction.[25] Looking at a polymorphism in the IL-4 receptor (IL-4RA) in a German Caucasian population, the author concluded that there was no significant relationship with AgP, although a signification association was seen with CP + AgP.[47]

Interleukin-4 has been studied in other regions of the world with mixed results. The − 590 SNP and 70 bp repeat in intron 2 were examined in a Brazilian population of African heritage and found to not be significantly associated with AgP.[48] Another study on the IL-4 (C − 590T) SNP in an Iranian population showed no difference for either allele frequency or genotype distribution.[49] Jain et al. examined the IL-4 + 33C/T SNP in a Dravidian population from South India and found a significantly greater association of the C allele and CC genotype in AgP + CP when compared to controls, but analyzing the AgP group alone found there was only a significant association for the C allele and an insignificant difference in the genotype distribution.[50]

There appears to be no significant trend overall in the association of IL-4 polymorphisms with AgP, but some association might be seen when looking at just GAgP in specific patient populations. There may be an association of IL-4 + 33 CC genotype and C allele with AgP in the Indian subcontinent population. Further research is needed to verify these trends [Table 2].

Interleukin-6 polymorphisms

Interleukin-6 is a pro-inflammatory cytokine that is also an important regulator of the immune response and has been associated with periodontal disease. IL-6 has been examined in several patient populations with varying results. Brett et al.[18] examined 10 SNPs in 7 candidate genes from Caucasians living in the UK, including alleles of IL-1, IL-6, and IL-10 as well as other non-IL genes. The IL-6 (−174) genotype was found to be not significantly related to AgP, although there was a significant association between AgP + CP, as well as a significant finding involving CP when compared to controls.[18] Other studies have looked at multiple SNPs in the IL-6 promoter region of subjects with Caucasians, African, Asian and other heritage in the UK and were able to find several significant results, including: An association with IL-16 − 1363 and AgP when looking at all ethnicities, an association with IL-6 − 1480 and LAgP in all ethnicities, an association of IL-6 174, − 1363, and − 1480 SNPs in Caucasian subjects with LAgP, and haplotypes involving IL-6 − 1363 and − 1480 had the strongest significant association with LAgP in Caucasians.[51] The same group also evaluated, in a similar multi-cultural UK population base, the presence of IL-6 SNPs and compared it to known periodontal pathogens, finding that AgP subjects with the IL-6–174GG genotype had a significantly greater rate of detection of Aggregatibacter. actinomycetemcomitans[52] as did those with IL-6 − 1480.[53] Another analysis of this same patient base involved subjects diagnosed with AgP and their first-degree relatives, finding that AgP subjects that were homozygous for IL-6 − 174 and − 1480 had a higher percentage of relatives with AgP, and that of the relatives diagnosed with AgP, there was an increased tendency for homozygosity at − 174 (GG), −1363 (GG), −1480 (CC) compared to healthy relatives.[54] When looking at a larger sample of a similar population with the same five IL-6 SNPs, further associations were made at the allelic (IL-6 − 1363), genotype (IL-6 − 1480 and − 6106), and haplotype (IL-6 − 1363 with − 1480 P = 0.001 and all five SNPs P = 0.01) level for Caucasian subjects diagnosed with LAgP.[55] In other areas of Europe, a study looking at multiple genotypes in multiple genes showed a strongly significant association for a polymorphism of IL-6 (−572) in Caucasian Italians with AgP at both allelic and genotype level, as well as significant associations for IL-6 variants (IL-6 − 1480, IL-6 − 6106) in combination with other tested SNPs. However, several SNPs of IL-6 that were found to be significant in the UK Caucasian population, did not show an association with AgP.[25]

In other regions of the world, IL-6 − 172 has been examined in a Turkish population and found to have no significant differences in the allele frequency or genotype distribution between subjects with GAgP and healthy controls.[56] Polymorphisms in the IL-6 receptor gene were studied in a Japanese population, with associations in both the AgP and CP group seen with the genotype frequency of IL6R + 48892.[57]

Overall, IL-6 promoter polymorphisms show a trend for association with AgP, especially in combination with each other in specific haplotypes. Moreover, there is evidence that IL-6 polymorphisms may be associated with specific microbial profiles. More extensive studies in different population groups is warranted, especially correlating genotypes with microbial profiles [Table 2].

Interleukin-8 polymorphisms

Interleukin-8 is a CXC chemokine and the most potent chemoattractant for the directed migration of neutrophils which are the first line of defense against periodontotpathic bacteria. The gene encoding IL-8 is located on chromosome 4q12-q13. A study in Iranians with AgP and CP, showed no association of individual polymorphisms with AgP, but reported a possible protective effect of 251 AàT, 396GàT and 1633 CàT, due to significantly increased genotype frequencies among healthy controls compared to periodontitis patients.[58] More recent studies showed no association of IL-8 polymorphisms with AgP in Brazilian[59] and Czech population.[60]

Insufficient studies exist that correlate IL-8 polymorphisms with AgP. Existing studies show that there is no significant trend in association of IL-8 polymorphisms with AgP [Table 2].

Interleukin-10 polymorphisms

Interleukin-10 is a regulatory IL which is strongly involved in the downregulation of the inflammatory response. Multiple studies, most of which were published looking at a European population, have examined a possible relationship between different IL-10 polymorphisms and AgP, but showedmostly insignificant associations. A 1999 study on patients in Glasgow with diagnosed GAgP showed no significant association for two microsatellites (known polymorphisms) at IL-10. G or IL-10.R.[61] IL-10 (−627 and − 1082) were examined in a UK Caucasian population, and no significant association was found with AgP.[18] In a German Caucasian population, one study showed no association with SNPs of IL-10 − 824 and − 597,[62] whereas another study looking at IL-10 (−1082, −819, and − 590) did conclude that certain alleles of IL-10 − 819 and IL-10 − 590 occurred more frequently in AgP (not significant) and that the haplotype ATA/ATA was significantly associated with GAgP,[63] although after adjusting for age and presence of Aa and Pg, this was also found to be not significantly different. Scapoli et al. examined polymorphisms of IL-10 (−819, −592, −1082) as three of the 28 SNPs studied in 14 candidate genes in an Italian Caucasian population, and found no significant association with AgP.[25]

Outside of Europe, there have also been multiple studies of the IL-10 gene polymorphisms that show differing results, based on region and ethnicity. In a Turkish population diagnosed with GAgP, there was no significant association with SNPs of IL-10 (−1082, −819, −592).[56] In Jordanian subjects diagnosed with LAgP, there were no significant differences noted either at the allelic or genotype level when looking at SNPs of IL-10 (−1087, −597).[64] A polymorphism of IL-10 (−1082) was examined in an Iranian population diagnosed with GAgP, and no association was seen with either allele or genotype frequency.[65] SNPs of IL-10 (−592, −819, and − 1082) were evaluated in a Taiwanese (Han Chinese ethnicity) population in which individual genotype frequencies were not significantly associated with GAgP (although the distribution of IL-10 (−592) was statistically different between CP, AgP and controls) and haplotype analysis showed the composite ATA/ATA to be significantly associated with GAgP.[66]

Existing data shows no significant associations of IL-10 polymorphisms with AgP. However, certain IL-10 polymorphisms in haplotype combinations with each other may play a role in altering the host response in AgP. Further research is needed to confirm these associations [Table 3].

Interleukin-12 polymorphisms

Interleukin-12 is an important cytokine involved in the immune response that promotes Th1 response and IFN-γ (interferon-gamma) production. IL-12 binds to the IL-12 receptor (consists of IL-12R-β1 and IL-12R-β2) found on activated T cells. IL-12 and IFN-γ polymorphisms do not seem to be associated with AgP in a German Caucasian population.[67] However, in a Japanese population IL-12R-β2 5’ flanking region polymorphisms were reported to be associated with AgP.[68]

A polymorphism in the 3’-untranslated region of IL-12B (+16974) was evaluated in a Taiwanese (Han Chinese ethnicity) population and found to show no difference in genotype distribution when comparing AgP and controls, although a difference was noted for CP.[66]

Insufficient studies exist that correlate IL-12 polymorphisms with AgP. Existing studies show that there is no significant trend in association of IL-12 polymorphisms with AgP, but, IL-12R-β2 5’ flanking region polymorphisms may be associated with AgP [Table 3].

Interleukin-13 polymorphisms

Interleukin-13 shares many of the same functions as IL-4, and is also suspected of acting indirectly on fibroblasts by activating transforming growth factor-β production in macrophages. It has been previously associated with CP, and specific polymorphisms have been associated with asthma and Graves’ disease.[69] IL-13 SNPs and their relationship to AgP have only been studied in limited patient populations with mixed results. Analysis of two SNPs, IL-13 − 1112 CàT and-1512 AàC in a German Caucasian population showed that there was no significant difference in the distribution of genotypes or in allelic frequencies between AgP and controls.[46] Looking at IL-13 − 1112C/T in a Taiwanese (Chinese) population of Han-ethnicity, researchers found a significantly higher frequency of the CC genotype and the C allele in the AgP population, with a higher odds ratio noted after adjustment for age, gender, smoking and betel nut chewing.[70] However, when stratifying groups by smoking status and adjusting for the other mentioned factors, regression analysis showed that the CC genotype was only significantly associated with AgP in the nonsmoking group.

Insufficient studies exist that correlate IL-13 polymorphisms with AgP. There may be an association of polymorphism IL-13 − 1112 C with AgP, but conflicting results exist in different patient populations. Further studies with a more diverse patient population are needed to substantiate this association [Table 3].

Interleukin-17 polymorphisms

Interleukin-17 is a pro-inflammatory cytokine that has six known ligands (IL-17 A-F). In addition to inducing tissue inflammation, it has also been found to activate cells such as osteoclasts and has been suggested to be a possible candidate gene for rheumatoid arthritis, a chronic inflammatory condition that has similarities to CP. Although studies have been done looking at IL-17 and CP, there is more limited information on its association with AgP. SNPs of IL-17 (IL-17 A and IL-17 F) have been analyzed in a Brazilian population, in which a significantly higher frequency of the G allele and GG genotype of IL-17A was seen in AgP group, and no significant difference was seen with IL-17 F.[71] Interestingly, Saraiva et al. concluded that for IL-17 A, both the A allele and AA genotype are higher in the control group which might confer protection against periodontal disease. In a study utilizing a Dravidian population from South India, analysis of IL-17 F found no significant differences among allelic frequency or genotype distribution for SNPs IL-17 F 7383A/G and 7488A/G.[50]

Insufficient studies exist evaluating the relationship between IL-17 polymorphisms and AgP. From the published studies, it appears that polymorphisms of IL-17F do not appear to be associated with AgP, and that there might be a significant association between IL-17A polymorphisms and AgP. Further research is needed in a more diverse patient population [Table 3].

Interleukin-18 polymorphisms

Interleukin-18 is a pro-inflammatory cytokine and a member of the IL-1 family that has the capacity to induce either Th1 or Th2 cells in response to gram-negative infections. It has only been examined in a small number of studies to date, looking at different loci. In a study looking at IL-18 − 838 C > A and − 368 G > C as well as SNPs of Toll-like receptor 4 (TLR4) in a German Caucasian population, there were no significant differences noted in any of the alleles or genotypes between AgP patients and controls. Another study evaluating multiple alleles including IL-18 (−607) in an Italian Caucasian population showed no significant association for either the genotype or allele in patients with AgP.[25] They did show, however, that the IL-18 (−607) was significantly associated in combination with other SNPs.

Insufficient studies exist that correlate IL-18 polymorphisms with AgP. Existing studies show that there is no significant trend in association of IL-18 polymorphisms with AgP alone, but may show significant associations in combination with polymorphisms in other genes [Table 3].

Interlekin-23 polymorphisms

Interlekin-23 is a pro-inflammatory cytokine produced by activated antigen presenting cells and is involved in stimulating IL-1β and tumor necrosis factor-α, as well as inducing the secretion of IL-17. It has previously been positively correlated with CP. A polymorphism of IL-23 (IL-23R rs11209026) was evaluated along with SNPs of IL-17 in a Brazilian population, in which there was no significant association seen between AgP and healthy controls for IL-23.[71]

Insufficient studies exist that correlate IL-23 polymorphisms with AgP. Existing studies show that there is no significant trend in association of IL-23 polymorphisms with AgP [Table 3].

CONCLUSIONS

Aggressive periodontitis is known to have a familial component, and it is widely accepted that the host response is altered in this patient population. ILs are a vital component of this host response, and polymorphisms within these cytokines could be a reason for this host alteration, and therefore a target of future therapies to treat this destructive disease. Overall, IL polymorphisms that are correlated to AgP seem to differ from those associated with CP, supporting a different mechanism of pathogenesis for both entities. IL polymorphisms appear to vary widely by population group and geographic location in AgP patients, making it difficult to determine any definitive conclusions from the published data Some IL polymorphisms (for example, IL-1 gand IL-6) have received a lot more attention than others, and have been studied in a diverse patient population looking at multiple polymorphisms. Others (such as IL-13 and 23) have only been examined in one or two patient populations, looking at only one or two polymorphisms. It is difficult to draw conclusions about trends in associations when such a narrow field of study exists. Furthermore, several of these studies only examined specific polymorphisms that had been identified from other areas of research, but did not evaluate the entire genetic profile of an individual IL. This means that IL polymorphisms could exist that are related to AgP, but have not yet been identified. Most studies included in this review were limited by sample size and had variations in case inclusion criteria. Genetic studies can also be limited by geographic differences seen between population groups and the heterogeneity of polymorphisms even within a particular population due to possible differences in ethnicities. Further studies, preferably multicenter studies, that are well controlled and in well-defined population groups with large sample sizes and consistent inclusion criteria are warranted to confirm the associations of specific IL polymorphisms with AgP. In addition, future studies looking at combinations of polymorphisms within specific haplotypes and also correlating host genotype with microbial profiles can provide important information regarding the pathogenesis of this complex disease.