Validation of reported genetic risk factors for periodontitis in a large‐scale replication study

Schäefer, Arne S.; Bochenek, Gregor; Manke, Thomas; Nothnagel, Michael; Graetz, Christian; Thien, Anneke; Jockel‐Schneider, Yvonne; Harks, Inga; Staufenbiel, Ingmar; Wijmenga, Cisca; Eberhard, Jörg; Güzeldemir-Akçakanat, Esra; Çine, Naci; Folwaczny, Mathias; Noack, Barbara; Meyle, Joerg; Eickholz, Peter; Trombelli, Leonardo; Scapoli, Chiara; Nohutçu, Rahime M.; Bruckmann, Corinna; Doerfer, Christof; Jepsen, Søren; Loos, Bruno G.; Schreiber, Stefan

doi:10.1111/jcpe.12092

Cited by 78 publications

(113 citation statements)

References 37 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…The associations between AgP and SNPs in the CDKN2B antisense RNA 1 (ANRIL) locus can be considered as the best replicated genetic associations in periodontitis to date (Table 1) (61,(71)(72)(73). The interest for the ANRIL locus is based on pleitropy, since this locus was first the best replicated gene locus for cardiovascular diseases, in particular coronary artery disease in Caucasians (71).…”

Section: Anril On Chromosomementioning

confidence: 99%

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What is the Contribution of Genetics to Periodontal Risk?

Loos

Papantonopoulos

Jepsen

et al. 2015

Dental Clinics of North America

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This review addresses the multi-causal etiology of periodontitis, in which genetic factors play a role. The various proposed causes for periodontitis always play a role simultaneously, but the relative contribution of each of these, varies from case to case. In young individuals often with aggressive periodontitis (AgP) a stronger contribution from genetic factors is apparent, while in older individuals often with chronic periodontitis (CP), the relative contribution of the established subgingival biofilms (environmental factors) and life style factors (e.g. smoking, stress, diet), play a more dominant role in the phenotype of the disease.Nevertheless always some genetic susceptibility is present, for CP estimated at 25%.Periodontitis is therefore a complex disease, i.e. it behaves in a nonlinear fashion. Actually the disease progression rate fluctuates, where the disease sometimes moves into an aberrant state of host response and then swings back into a resolving state; in between, a settlement zone is present where essentially no differences are found for immunological parameters between cases with periodontitis and healthy controls. The genotype determines part of this fluctuation and the extent of it. The disease is polygenic, i.e. multiple genetic variants in multiple genes determine the phenotype, but there are individual and ethnic differences in the genes involved. We are still at the early stage to have identified the involved genes, in comparisons to other chronic diseases, we need to count on it that at least 100 causative genes across various global populations exist in AgP and CP. To date, the genetic variations firmly and repeatedly associated with periodontitis in some populations are found within the following genes: ANRIL, COX2, IL1, IL10, DEFB1, while many proposed periodontitis candidate genes have not been firmly proven or replicated. 3 KeypointsPeriodontitis is a multi-causal disease, with each of the causal factors playing a role but the relative contribution of these vary form case to case.The disease behaves in a nonlinear fashion, with periods of aberrant host response to periods within an active disease resolving state.To date only a few of the multitude of possible genetic factors for periodontitis are identified. Outline

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Section: Discussionmentioning

confidence: 99%

Section: Anril On Chromosomementioning

confidence: 99%

What is the Contribution of Genetics to Periodontal Risk?

Loos

Papantonopoulos

Jepsen

et al. 2015

Dental Clinics of North America

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“…37 A recent large-scale replication study also suggested that only IL-10SNP(rs 61815643) was associated with Dutch and German/Austrian AgP samples. 38 Claudino et al 39 studied the effect of IL-10(-592) gene polymorphism on cytokine expression in 116 CP patients and 173 control subjects. In CP, a significantly lower IL-10 mRNA expression was verified in both CA and AA genotypes when compared to CC genotype carriers.…”

Section: Discussionmentioning

confidence: 99%

IL-6 and IL-10 gene polymorphisms in patients with aggressive periodontitis: effects on GCF, serum and clinic parameters

et al. 2017

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“…15 See Tables IV and V in the Data Supplement for gene names, SNPs, genotypes, and association statistics of the associated genetic regions. Potential associations that were observed for genotype data of the immunochip were validated in silico in an independent case-control panel of 159 Dutch AgP cases and 679 population representative Dutch controls as described in 16 . Potential associations that were observed for genotype data of the 500K array genome-wide association study (GWAS) data were replicated using a panel of 424 German AgP cases and 3628 German controls and validated using 159 Dutch AgP cases and 352 periodontal healthy Dutch controls, as described in Table 1.…”

Section: Analysis Of Candidate Genesmentioning

confidence: 99%

Genetic Evidence for PLASMINOGEN as a Shared Genetic Risk Factor of Coronary Artery Disease and Periodontitis

Schäefer¹,

Bochenek²,

Jochens³

et al. 2015

Circ Cardiovasc Genet

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Background— Genetic studies demonstrated the presence of risk alleles in the genes ANRIL and CAMTA1/VAMP3 that are shared between coronary artery disease (CAD) and periodontitis. We aimed to identify further shared genetic risk factors to better understand conjoint disease mechanisms. Methods and Results— In-depth genotyping of 46 published CAD risk loci of genome-wide significance in the worldwide largest case–control sample of the severe early-onset phenotype aggressive periodontitis (AgP) with the Illumina Immunochip (600 German AgP cases, 1448 controls) and the Affymetrix 500K array set (283 German AgP cases and 972 controls) highlighted ANRIL as the major risk gene and revealed further associations with AgP for the gene PLASMINOGEN ( PLG ; rs4252120: P =5.9×10 −5 ; odds ratio, 1.27; 95% confidence interval, 1.3–1.4 [adjusted for smoking and sex]; 818 cases; 5309 controls). Subsequent combined analyses of several genome-wide data sets of CAD and AgP suggested TGFBRAP1 to be associated with AgP (rs2679895: P =0.0016; odds ratio, 1.27 [95% confidence interval, 1.1–1.5]; 703 cases; 2.143 controls) and CAD ( P =0.0003; odds ratio, 0.84 [95% confidence interval, 0.8–0.9]; n=4117 cases; 5824 controls). The study further provides evidence that in addition to PLG , the currently known shared susceptibility loci of CAD and periodontitis, ANRIL and CAMTA1/VAMP3 , are subjected to transforming growth factor-β regulation. Conclusions— PLG is the third replicated shared genetic risk factor of atherosclerosis and periodontitis. All known shared risk genes of CAD and periodontitis are members of transforming growth factor-β signaling.

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Validation of reported genetic risk factors for periodontitis in a large‐scale replication study

Abstract: Previous candidate genes carry no susceptibility factors for AgP. Association of IL-10 rs61815643 with AgP is suggested. ANRIL is associated with periodontitis across different populations.

Cited by 78 publications

References 37 publications

What is the Contribution of Genetics to Periodontal Risk?

What is the Contribution of Genetics to Periodontal Risk?

IL-6 and IL-10 gene polymorphisms in patients with aggressive periodontitis: effects on GCF, serum and clinic parameters

Genetic Evidence for PLASMINOGEN as a Shared Genetic Risk Factor of Coronary Artery Disease and Periodontitis

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