Mendelian randomization studies of periodontitis:Understanding benefits and natural limitations in an applied context

Mendelian randomization (MR) is a flexible analytical tool that has been widely applied to strengthen causal inference in observational epidemiology and is now gaining attention in many areas including periodontal research. The interpretation of results drawn from MR is based on a series of assumptions, which can be unrealistic or difficult to meet faithfully in some settings. However, we argue that with care, this does not necessarily prevent valuable deployment of the approach. We argue that clarity of presentation as well as careful assessment of specific analytical conditions is a fundamental part of all MR analyses. To that end, awareness of its limitations should also guide the design of MR investigations and the presentation of results rather than rule out its use altogether. Notably, considerations similar to those known to be important in conventional epidemiological settings apply to MR. While MR studies are valuable in their contrast to other study limitations, the application of this technique must be carefully cross-examined. Specific considerations include possible confounders, recruitment strategy and phenotypic measurement and differential analysis properties across studies. In the case of periodontal research, current MR applications are limited by the available evidence base for genetic contributions to periodontitis; however, this sets a specific scene for the strategic use of MR and shines light on a need for greater research emphasis on the genetics of the condition and intermediaries. This article provides a perspective on the uses and inherent limitations of MR studies and the importance of adhering to basic epidemiological principles when designing them

Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium

Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI).Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis.Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data.Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals

Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health

Consortium-based genome-wide meta-analysis for childhood dental caries traits

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5–18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure

Hip Fractures Before and During the COVID-19 Pandemic: Comparative Demographics and Outcomes

Introduction: During the height of the COVID-19 pandemic in New York, hip fractures requiring operative management continued to present to Stony Brook University Hospital. Given the novelty of SARS-CoV-2, there is recent interest in the pandemic and its relationship to orthopedic operative outcomes. This retrospective cohort study compared outcomes for operative hip fractures in patients prior to and during the COVID-19 pandemic at a level 1 academic center. Materials and Methods: Data was collected on patients age 18 years or older who underwent operative management for hip fractures performed from January 21, 2019 to July 1, 2019 (pre-pandemic) or from January 21, 2020 to July 1, 2020 (pandemic). COVID-19 status, demographics and outcomes were analyzed. Results: Overall, 159 patients with hip fractures were included in this study, 103 in the 2019 group and 56 in the 2020 group. Within the 2019 group, there was a significantly greater proportion of female patients compared to 2020 (p = 0.0128). The length of hospital stay was shorter for the 2020 group by 1.84 days (p = 0.0138). COVID-19 testing was positive in 4 (7.1%) patients in the 2020 group, negative for 22 patients (39.3%), and the remaining 30 patients in the 2020 group (53.7%) were not tested during their admission. There were no other significant differences in demographics or outcomes between the 2019 and 2020 groups. Discussion: The COVID-19 pandemic did not significantly alter most aspects of care for hip fracture patients at our institution. Interestingly, postoperative pulmonary outcomes were not affected by the pandemic. Conclusions: In this study, a significantly higher proportion of males presented with hip fractures in the pandemic group. In addition, the average length of hospital stay was shorter during the COVID-19 pandemic. Further research is needed to understand the nuances that may lead to improved care for patients with hip fractures during a pandemic. </jats:sec

Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data

AbstractDental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.</jats:p