A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis

Abstract

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 ¼ 1337 cases and 2887 ethnically matched controls). The 3 0 untranslated region SNP, rs1047031, showed the most significant association signal for homozygous carriers of the rare A allele (P ¼ 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 ¼ 2.2 (95% confidence interval: 1.16-4.35), P ¼ 0.02), and aggressive periodontitis (odds ratio ¼ 1.3 (95% confidence interval 1.04-1.68), P ¼ 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.

What is the Contribution of Genetics to Periodontal Risk?

“…A suggestive association was found between the DEFB1 SNP rs1047031 and AgP. This association was not replicated in another Dutch-German AgP study population, but positively in a German-Dutch CP cohort (805 cases versus 1415 controls) (70).…”

“…Currently, only a fraction of susceptibility genes is robustly identified, namely GLT6D1, ANRIL and COX2, IL1 and IL10 have repeatedly been associated with periodontitis (49,57,58,61,67,(71)(72)(73) AgP and CP (61,70). Probably, the identified SNPs are "genetic markers" and are not the true causative variants for both AgP and CP.…”

“…The gene DEFB1 was proposed as candidate gene for periodontitis and again firstly investigated in AgP in a cohort of 532 patients and 1472 controls of German-Dutch origin (70). A suggestive association was found between the DEFB1 SNP rs1047031 and AgP.…”

Defensins and their role in the maintenance of the oral cavity homeostasis – a literature review

“…In keratinocytes of psoriatic patients also the expression of HBD-1 rises [18,19]. While the HBD 1 expression in the human body occurs constantly, the transcription of the HBD 2 gene becomes induced in the presence of cytokines like IL-1β and TNF-α, bacterial lypopolysaccharides and fungi [4,24]. HBD-2 concentration therefore elevates in various inflammatory conditions.…”

Human Defensins: Potential Tools for Clinical Applications

“…As human defensins are involved in chronic periodontal inflammation as well as the carcinogenesis of oral tumors, it is an interesting new hypothesis that they might act as key-molecules in the inflammation-tumorsequence [7,8,16,[83][84][85][86]. On the one hand DEFB1 encoding for hBD-1 has been identified as a major periodontitis-associated gene [87] with important functions in local host defense. On the other, hBD-1 was found to be an important factor in proliferation control of oral cancers [7,8,16,83,85].…”