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Folwaczny M, Tengler B, Glas J. Variants of the human NR1I2 (PXR) locus in chronic periodontitis. J Periodont Res 2012; 47: 174-179. © 2011 John Wiley & Sons A/S Background and Objective: Recent studies on genetic variants of the pregnane X receptor (PXR) revealed associations with the mucosal immune response. This study aimed to investigate the potential association of functional polymorphisms of the NR1I2 ( PXR)-encoding gene (rs12721602, rs3814055, rs1523128, rs1523127, rs45610735, rs6785049, rs2276707 and rs3814057) with chronic periodontitis. Material and Methods: At total of 402 periodontitis patients and 793 healthy individuals were genotyped using PCR and melting-curve analysis. Results: Frequency distribution of genotypes for the eight single nucleotide polymorphisms showed no significant difference between patients with periodontitis and controls. Among the eight tested polymorphisms, two blocks were defined showing complete or almost complete linkage disequilibrium (linkage disequilibrium block 1: rs3814055 and rs1523127; and linkage disequilibrium block 2: rs6785049, rs2276707 and rs3814057). For one haplotype (GTGAG) composed of rs12721602, rs3814055, rs1523128, rs12721607 and rs6785049, a significant association with periodontitis was found [ p-value after permutation with 100,000 iterations ( ppermut.) = 0.011, odds ratio = 0.46, 95% confidence interval: 0.25-0.84) following adjustment for age, gender and smoking. Conclusion: A rare haplotype of the NR1I2 ( PXR) locus was associated with the individual susceptibility for chronic periodontitis in a German cohort. As a result of the borderline significance and the small effect size the present results need further confirmation. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex class I chain-related gene A (MICA)-TM exon 5 trinucleotide polymorphism, the MICB-C1_2_A intron 1 dinucleotide polymorphism and the tetranucleotide polymorphism C1_4_1 located in the major histocompatibility complex class I region on chromosome 6 were shown to influence various chronic inflammatory conditions. We investigated the association of these microsatellite polymorphisms with chronic periodontitis, a highly prevalent oral inflammatory disease in 389 periodontitis patients and 771 healthy controls with South German genetic background. Genotyping of the MICA-TM, MICB-C1_2_A and C1_4_1 microsatellite polymorphisms was performed by PCR amplification and fragment analysis. Global frequency distribution of MICB-C1_2_A ( P = 0.006) and C1_4_1 ( P = 0.028) alleles was significantly different between both study groups. Allele-specific analysis revealed that the MICA-TM allele A5 was more prevalent among male periodontitis patients [ P = 0.0001; odds ratio (OR) 2.17, 95% confidence interval (CI) 1.55-3.03]. In C1_4_1 allele, three was significantly higher in healthy controls ( P = 0.006; OR 0.74, 95% CI 0.60-0.91). Two haplotypes (MICA:A5-C1_4_1:5; P = 0.002; OR 2.63, 95% CI 1.46-4.74 and MICB:CA16-C1_4_1:3; P = 0.014; OR 0.68, 95% CI 0.50-0.92) showed significant differences between periodontitis patients and controls. The MICA-TM, MICB-C1_2_A and C1_4_1 microsatellite polymorphism seem to influence the individual susceptibility to chronic periodontitis in patients with German genetic background. [ABSTRACT FROM AUTHOR]

Periodontal diseases are complex inflammatory diseases and affect up to 20% of the worldwide population. An unbalanced reaction of the immune system toward microbial pathogens is considered as the key factor in the development of periodontitis. Defensins have a strong antimicrobial function and are important contributors of the immune system toward maintaining health. Here, we present the first systematic association study of DEFB1. Using a haplotype-tagging single nucleotide polymorphism (SNP) approach, including described promoter SNPs of DEFB1, we investigated the associations of the selected variants in a large population (N=1337 cases and 2887 ethnically matched controls). The 3′ untranslated region SNP, rs1047031, showed the most significant association signal for homozygous carriers of the rare A allele (P=0.002) with an increased genetic risk of 1.3 (95% confidence interval: 1.11–1.57). The association was consistent with the specific periodontitis forms: chronic periodontitis (odds ratio=2.2 (95% confidence interval: 1.16–4.35), P=0.02), and aggressive periodontitis (odds ratio=1.3 (95% confidence interval 1.04–1.68), P=0.02). Sequencing of regulatory and exonic regions of DEFB1 identified no other associated variant, pointing toward rs1047031 as likely being the causative variant. Prediction of microRNA targets identified a potential microRNA-binding site at the position of rs1047031. [ABSTRACT FROM AUTHOR]

Surfactant protein (SP) D belongs to the family of collectins, which are humoral molecules of the innate immune system. Collectins belong to pattern recognition receptors and are present in plasma and on mucosal surfaces and recognize several microbial components, the pathogen-associated molecular patterns (PAMPs). While SP-A is primarily expressed in the lung, expression of SP-D is more widely detected including different mucosal surfaces and in serum. Therefore, SP-D is considered a functional candidate in chronic periodontitis. The present study sought to investigate whether plasma concentration of SP-D is altered in chronic periodontitis and whether polymorphisms within the SFTPD gene (Met11Thr, Ala160Thr and Ser270Thr) are associated with chronic periodontitis. The study population comprised 105 patients with chronic periodontitis and 122 healthy, unrelated control individuals. SP-D Plasma concentrations were determined using enzyme-linked immunosorbent assay test. Genotyping of SFTPD polymorphisms was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. Plasma concentrations were significantly increased in patients with chronic periodontitis compared with the controls. The median plasma concentrations were 81.6 ng/ml in the patients and 52.6 ng/ml in the controls ( P = 0.00051). In contrast, the three SFTPD polymorphisms displayed no significant association with chronic periodontitis; thus, the increased plasma concentrations were independent on the genotype. The study showed significantly increased SP-D plasma concentrations in patients with chronic periodontitis compared with healthy controls. Thus, SP-D can potentially be used as a biomarker for chronic periodontitis. As no significant associations of SFTPD gene polymorphisms could be detected, other mechanisms influencing SP-D serum/plasma expression might exist. [ABSTRACT FROM AUTHOR]

Bactericidal/permeability-increasing protein (BPI) is a member of the pattern recognition receptors of the innate immune system and recognizes lipopolysaccharides (LPS), a bacterial component belonging to the pathogen-associated molecular patterns (PAMPs). BPI mediates the neutralization of LPS and increases the phagocytosis and cytotoxicity against bacteria. Recently, the functionally effective polymorphism A645G resulting in the amino acid alteration Lys216Glu has been described. The aim of the study was to investigate the association of the A645G polymorphism with chronic periodontal disease. The study population comprised 123 patients with periodontal disease (36 with mild, 52 with moderate and 35 with severe periodontitis) and 122 healthy, unrelated control individuals. Genotyping of the BPI gene polymorphism A645G (Lys216Glu) was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. Statistical analysis was carried out employing the χ2 test with Yates correction. Genotype and allele frequencies of the polymorphism tested herein showed no significant differences between periodontal disease as compared to the control group. The frequencies of the G allele were 52.4% in patients with periodontal disease and 49.2% in the control individuals ( P = 0.528). Moreover, no significant associations could be detected after stratification for disease severity and according to gender. The present study does not give evidence for the contribution of the BPI gene to the genetic background of chronic periodontal disease. [ABSTRACT FROM AUTHOR]

Background and aims: Recent data suggest identification of causal genetic variants for inflammatory bowel disease in the DLG5 gene and in the organic cation transporter (OCTN) cluster, both situated in previously described linkage regions. Patients and methods: The polymorphisms in DLG5 (113 G→A, 4136 C→A, and DLG5•e26), SLC22A4 (1672 C→T), and SLC2245(-207 G→C) were assessed in 625 patients with Crohn's disease (CD), 363 patients with ulcerative colitis (UC), and 1012 healthy controls. Association with disease susceptibility, clinical phenotypes, and possible genetic interactions of these polymorphisms with disease associated CARD 15/NOD2 mutations was analysed. Results: No significant association of DLG5 polymorphisms with CD or UC was observed. Homozygosity for the OCTN-TC haplotype was associated with an increased CD risk (OR =1.65), which was even greater in the presence of CARD 15 mutations. Genotype-phenotype analysis revealed that this association was particularly strong in patients with colonic disease. The TC haplotype was associated with non- fistulising non-fibrostenotic disease, an earlier age of disease onset, and reduced need for surgery. Conclusion: Our observations argue against a role of DLG5 polymorphisms in the susceptibility for inflammatory bowel disease, whereas the OCTN polymorphisms are associated with CD. However, due to the comparable weak association observed herein, extended linkage disequilibrium analyses of these variants with the IBD5 haplotype tagged single nucleotide polymorphims might be advisable before definitive conclusions about their causative role in CD can be drawn. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-16 is involved in the regulation of the expression of several proinflammatory cytokines, i.e. tumour necrosis factor (TNF)α and interleukin (IL)-1β. The present study aimed to determine the prevalence of the −295 promoter polymorphism of the interleukin (IL)-16 gene in periodontal disease. A total of 123 patients with periodontal disease and 122 healthy controls were genotyped for the −295 IL-16 promoter polymorphism. Genotyping has been performed by PCR and restriction fragment length polymorphism (RFLP) analysis. The frequencies of alleles and genotypes as well of haplotypes within both study groups were compared using the Pearson χ2 test at a level of significance of 5% ( P < 0·05). The distribution of genotypes for the −295 IL-16 gene polymorphism showed no significant difference between periodontitis patients and healthy control subjects ( P = 0·886). Also stratification analysis according to the disease severity revealed no significant difference regarding the genotype distribution among both study groups. Herein the IL-16 −295 gene polymorphism was not associated with chronic periodontitis. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLR) are signal molecules essential for the cellular response to bacterial cell wall components. Different functional effective polymorphisms for the TLR 4 gene (Asp299Gly; Thr399Ile) and for the TLR 2 gene (Arg677Trp, Arg753Gln) have recently been described that are associated with impaired lipopolysaccharide signal transduction. A total of 122 patients with chronic periodontal disease and 122 healthy unrelated controls were genotyped for the Asp299Gly and Thr399Ile polymorphism of the TLR 4 gene and the Arg677Trp and Arg753Gln mutation of the TLR 2 gene. The mutations were identified with polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis. The prevalence of the Asp299Gly and the Thr399Ile mutant allele was 4·1% (10/244) and 4·5% (11/244) among periodontitis patients. For the healthy controls the prevalence was 3·3% (8/244) for the Asp299Gly ( P = 0·810) and 3·7% (9/244) for the Thr399Ile mutant allele ( P = 0·819). The Arg753Gln mutant allele was found in 2·9% (7/244) of the periodontitis subjects as compared to 4·1% (10/244) in the control group ( P = 0·622). The Arg677Trp mutant allele was not found in any of the study subjects. Unlike in ulcerative colitis there was not observed an association between chronic periodontitis and the various mutations of the TLR 2 and 4 gene. [ABSTRACT FROM AUTHOR]

Background: Tumor necrosis factor-α (TNF-α) is involved in the pathogenesis of chronic active hepatitis C. Polymorphisms in the promoter region of the TNF-α gene can alter the TNF-α expression and modify the host immune response. The present study aimed at the correlation of the G308A TNF-α polymorphism with the response to antiviral combination therapy in chronic hepatitis C. Patients and Methods: 62 patients with HCV and 119 healthy unrelated controls were genotyped for the G308A TNF-α promoter polymorphism. The patients received 3 × 3 million units of interferon alfa-2a and 1,000–1,200 mg ribavirin daily according to their body weight. A response was defined as absence of HCV-RNA and normalization of S-ALT after 6 months of combination therapy. Results: With respect to the allele and genotype frequency, a significant difference was not observed between controls and patients with chronic hepatitis C. Furthermore, such a difference was also not observed if responders and non-responders to antiviral therapy were compared. Conclusions: The promoter polymorphism of the TNF-α gene investigated herein is equally distributed in healthy individuals and patients with hepatitis C and does not seem to predict the response to therapy with interferon alfa-2a and ribavirin. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The new allele MICA*055 contains eight GCT repeats within the exon 5 MICA-TM microsatellite polymorphism. [ABSTRACT FROM AUTHOR]