Case‐only design identifies interactions of genetic risk variants at SIGLEC5 and PLG with the lncRNA CTD‐2353F22.1 implying the importance of periodontal wound healing for disease aetiology

Abstract

Aim: The basis of phenotypic variation of periodontitis is genetic variability. Disease relevant effects of individual risk alleles are considered to result from genetic interactions. We investigated gene  gene (GÂG) interactions of suggestive periodontitis susceptibility alleles.Materials and Methods: We used the case-only design and investigated singlenucleotide polymorphism (SNPs) that showed associations in our recent genomewide association study (GWAS) and GWAS meta-analysis with p < 5  10 À6 . CRISPR-dCas9 gene activation followed by RNA-sequencing and gene-set enrichment analyses elucidated differentially expressed genes and gene networks. With the databases of SNPInspector and Transfac professional, luciferase reporter gene assays and antibody electrophoretic mobility shift experiments, we analysed allele-specific effects on transcription factor binding.Results: SNPs at the genes sialic acid binding Ig-like lectin 5 (SIGLEC5) and plasminogen (PLG) showed GÂG interactions with rs1122900 at the long non-coding RNA (lncRNA) CTD-2353F22. Associated chromatin cis-activated CTD-2353F22.1 6.5-fold (p = .003), indicating CTD-2353F22.1 as target gene of this interaction. CTD-2353F22.1 regulated GADD45A (p adj < 4.9  10 À11 , log 2 fold change (FC) = À0.55), THBS1, SERPINE1 and Tissue Factor F3 (p adj < 5  10 À7 , log 2 FC ≥ À0.35) and the gene set "angiogenesis" (area under the curve = 0.71, p adj = 8.2  10 À5 ). rs1122900 effect C-allele decreased reporter gene activity (5.5-fold, p = .0003) and PRDM14 binding (76%).Ricarda Müller and Sandra Freitag-Wolf contributed equally.

Novel Protein Biomarkers and Therapeutic Targets for Type 1 Diabetes and Its Complications: Insights from Summary-Data-Based Mendelian Randomization and Colocalization Analysis

“…At present, investigations into SIGLEC5 and T1D remain relatively limited, emphasizing the significant untapped potential for the development of targeted medications. However, a number of studies have highlighted a substantial association between SIGLEC5 and the risk of periodontitis [ 29 , 30 , 31 , 32 ]. Consequently, similarly to MANSC4, SIGLEC5 might offer novel insights into the intricate interplay between T1D and periodontitis.…”

Stroke and the risk of gastrointestinal disorders: A Mendelian randomization study

“…This was done in light of the small number of SNPs ( P < 5 × 10 −8 ) that reached genome-wide significance. This strategy has been applied extensively in earlier MR investigations ( 33 , 34 ). Second, the results of MR analysis are believed to be unaffected by weak instrumental bias if there is an F-statistic larger than 10.…”

Plasmin-Mediated Fibrinolysis in Periodontitis Pathogenesis

“…A correlated variant (rs1740430, R 2 = 0.96) has been reported as an eQTL for lipoprotein a ( LPA ) expression in esophageal mucosa. Recently, Müller et al (2023) reported evidence of interactions between variants rs1247559 in PLG and rs4284742 in SIGLEC5 (the only genome-wide significant locus of periodontitis in consortium meta-analysis reported by Shungin et al 2019) with the functional variant rs1122900 (a predicted transcription factor PRDM14 binding site) of the long noncoding RNA (lncRNA) CTD-2353F22.1, also known as SLC1A3 antisense RNA 1 ( SLC1A3-AS1 ). This case-only investigation among ~900 European adults found gene–gene interactions (odds ratio due to interaction = 1.6) of PLG and SIGLEC5 with SLC1A3-AS1 that are linked to the expression of SLC1A3-AS1 (mostly expressed in mast cells, B cells, and dendritic cells) and with downstream regulatory effects on the coagulation cascade and on pathways involved in response to wounding and revascularization.…”