Causal Association Between Periodontitis and Type 2 Diabetes: A Bidirectional Two-Sample Mendelian Randomization Analysis

Background: Previous observational studies have reported a bidirectional association between periodontitis and type 2 diabetes, but the causality of these relationships remains unestablished. We clarified the bidirectional causal association through two-sample Mendelian randomization (MR).Methods: We obtained summary-level data for periodontitis and type 2 diabetes from several published large-scale genome-wide association studies (GWAS) of individuals of European ancestry. For the casual effect of periodontitis on type 2 diabetes, we used five independent single-nucleotide polymorphisms (SNPs) specific to periodontitis from three GWAS. The summary statistics for the associations of exposure-related SNPs with type 2 diabetes were drawn from the GWAS in the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium and the FinnGen consortium R5 release, respectively. For the reversed causal inference, 132 and 49 SNPs associated with type 2 diabetes from the DIAGRAM consortium and the FinnGen consortium R5 release were included, and the summary-level statistics were obtained from the Gene-Lifestyle Interactions in Dental Endpoints consortium. Multiple approaches of MR were carried out.Results: Periodontitis was not causally related with the risk of type 2 diabetes (all p > 0.05). No causal effect of type 2 diabetes on periodontitis was found (all p > 0.05). Estimates were consistent across multiple MR analyses.Conclusion: This study based on genetic data does not support a bidirectional causal association between periodontitis and type 2 diabetes.

Mendelian randomization study updates the effect of 25-hydroxyvitamin D levels on the risk of multiple sclerosis

Background Observational studies and previous Mendelian randomization (MR) studies have shown that genetically low 25-hydroxyvitamin D (25OHD) levels are associated with a high susceptibility to multiple sclerosis (MS). The present MR study aims to update the causal estimates for the effects of 25OHD levels on MS risk. Methods To date, the largest genome-wide association study (GWAS) for serum 25OHD (n = 401,460) and MS (14,498 MS cases and 24,091 controls) was used to assess the effect of serum 25OHD levels on MS. All participants were of European ancestry. The MR-egger_intercept test and Cochran’s Q statistic were used to determine the pleiotropy and the heterogeneity, respectively. MR-egger, weighted median, inverse variance weighted (multiplicative random effects), simple mode, and weighted mode methods were used to evaluate the causal association of serum 25OHD levels with MS. Finally, the effect of a single 25OHD SNP (single nucleotide polymorphism) on MS was used to test the SNP bias. Results One hundred and fifteen newly identified serum 25OHD genetic variants were extracted from a large-scale serum 25OHD GWAS dataset. The 20 most effective and independent 25OHD genetic instrumental variables were extracted from the MS GWAS summary statistics. Pleiotropy analysis suggested no significant pleiotropic variant among the 20 selected 25OHD genetic instrument variants in MS GWAS datasets. As serum levels of 25OHD based on genetic changes increased, the risk of MS decreased using MR-egger (Beta = − 0.940, p = 0.001; OR = 0.391), weighted median (Beta = − 0.835, p = 0.000; OR = 0.434), IVW (Beta = − 0.781, p = 0.000; OR = 0.458), simple mode (Beta = − 1.484, p = 0.016; OR = 0.227), and weighted mode (Beta = − 0.913, p = 0.000; OR = 0.401). Our results were robust, with no obvious bias based on investigating the single 25OHD SNP on MS. Conclusions Our analysis suggested a causal association between genetically increased serum 25OHD levels and reduced MS in the European population.

Network Mendelian randomization study: exploring the causal pathway from insomnia to type 2 diabetes

IntroductionInsomnia is a novel pathogen for type 2 diabetes mellitus (T2DM). However, mechanisms linking insomnia and T2DM are poorly understood. In this study, we apply a network Mendelian randomization (MR) framework to determine the causal association between insomnia and T2DM and identify the potential mediators, including overweight (body mass index (BMI), waist-to-hip ratio, and body fat percentage) and glycometabolism (HbA1c, fasting blood glucose, and fasting blood insulin).Research design and methodsWe use the MR framework to detect effect estimates of the insomnia–T2DM, insomnia–mediator, and mediator–T2DM associations. A mediator between insomnia and T2DM is established if MR studies in all 3 steps prove causal associations.ResultsIn the Inverse variance weighted method, the results show that insomnia will increase the T2DM risk (OR 1.142; 95% CI 1.072 to 1.216; p=0.000), without heterogeneity nor horizontal pleiotropy, strongly suggesting that genetically predicted insomnia has a causal association with T2DM. Besides, our MR analysis provides strong evidence that insomnia is causally associated with BMI and body fat percentage. There is also suggestive evidence of an association between insomnia and the waist-to-hip ratio. At the same time, our results indicate that insomnia is not causally associated with glycometabolism. Higher BMI, waist-to-hip ratio, and body fat percentage levels are strongly associated with increased risk of T2DM.ConclusionsGenetically predicted insomnia has a causal association with T2DM. Being overweight (especially BMI and body fat percentage) mediates the causal pathway from insomnia to T2DM.

Leukocytoclastic Vasculitis Following COVID-19 Vaccination: A Case Report

Background: Hypersensitivity or Leukocytoclastic vasculitis (LCV) following the COVID-19 vaccination has been reported rarely all over the world. LCV can be induced by certain factors such as infections, autoimmune disorders, malignancy, or some classes of drugs. Case presentation: A 32-year-old man, who was a known case of seizure disorder from his childhood presented to the department of dermatology with itchy red lesions on extremities and abdomen for the past 1 month. He explains a history of COVID-19 vaccination 1-month back and experienced itching on his lower limbs on the same day at night. A gradual worsening of the condition was observed day by day. He was hospitalized and diagnosed as LCV through clinical and laboratory findings. Conclusion: This case highlights a temporal association with the event of vaccination. The causality assessment showed an indeterminate causal association to LCV with COVID-19 Vaccination.

Nexus between Foreign Direct Investment and Poverty Reduction: A case of Pakistan

The key objective of this paper is to examine the direct and causal association between foreign direct investment (FDI) and the reduction of poverty in Pakistan. Poverty reduction is the fundamental task and issue for developing economies like Pakistan. This study uses annual data set from 1987 to 2018 and implies the ARDL method for data analysis. The data has been taken from economic surveys of the Federal statistics house (FSH) of Pakistan. The finding shows the bidirectional causality between poverty and FDI. The outcome of this study also reveals that the causal effects of FDI on reducing poverty are stronger than poverty reduction effects on FDI.

A lineage-specific Exo70 is required for receptor kinase-mediated immunity in barley

In the evolution of land plants, the plant immune system has experienced expansion in immune receptor and signaling pathways. Lineage-specific expansions have been observed in diverse gene families that are potentially involved in immunity, but lack causal association. Here, we show that Rps8-mediated resistance in barley to the fungal pathogen Puccinia striiformis f. sp. tritici (wheat stripe rust) is conferred by a genetic module: LRR-RK and Exo70FX12, which are together necessary and sufficient. The Rps8 LRR-RK is the ortholog of rice extracellular immune receptor Xa21 and Exo70FX12 is a member of the Poales-specific Exo70FX clade. The Exo70FX clade emerged after the divergence of the Bromeliaceae and Poaceae, and comprises from 2 to 75 members in sequenced grasses. These results demonstrate the requirement of a lineage-specific Exo70FX12 in Rps8 LRR-RK immunity and suggest that the Exo70FX clade may have evolved a specialized role in receptor kinase signaling.

Carfilzomib-induced thrombotic microangiopathy. A case report

Introduction Drug-induced thrombotic microangiopathy (DITMA) is an acquired condition resulting from exposure to a drug that induces the formation of platelet-rich thrombi in small arterioles or capillaries secondary to drug-dependent antibodies or direct tissue toxicity. Carfilzomib is a selective proteasome inhibitor approved to treat selected patients with Multiple Myeloma (MM). It is one of the drugs with the strongest evidence for a causal association with non-antibody-mediated DITMA. Case Report A 75-year-old man presented to the emergency department for the outbreak of vomit, asthenia, oliguria and dark stool emission. He was recently diagnosed with multiple myeloma, treated with lenalidomide, dexamethasone and carfilzomib. Laboratory exams were significant for microangiopathic haemolytic anaemia, thrombocytopenia and new-onset renal failure. ADAMTS-13 levels were in range, and no infectious signs were found both in blood nor in stool test. Management & Outcome A carfilzomib induced thrombotic microangiopathy was soon suspected. Thus, since daily haemodialysis and supportive care did not seem to get a fast enough recovery, the patient was treated with eculizumab with a good general outcome. Discussion Drug-induced thrombotic microangiopathy is a rare and often life-threatening acquired condition whose diagnosis can be challenging and whose therapy is not always limited to supportive treatment and drug avoidance. Carfilzomib, along with other proteasome inhibitors, is one of the described potential drugs which can trigger such a manifestation.

The Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome: a Multi-Cohort Non-Targeted Metabolomics Observational and Mendelian Randomization Study

Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity with circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data was generated by non-targeted ultra-performance liquid-chromatography coupled to time-of-flight mass-spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N=1,135), PIVUS (N=970), and TwinGene (N=2,059). We assessed associations between general adiposity measured as body mass index (BMI) and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We employed MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N=7,373), the CHARGE consortium (N=8,631), the Framingham Heart Study (N=2,076) and the DIRECT consortium (N=3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (<i>p</i>-value <0.05) of increased general adiposity and reduced levels of arachidonic acid, dodecanedioic acid and lysophosphatidylcholine (<i>P-</i>16:0) as well as with increased creatine levels. The replication effort provided support for a causal association of adiposity on reduced levels of arachidonic acid (<i>p</i>-value 0.03). Adiposity is associated with variation of large parts of the circulating metabolome, however causality needs further investigation in well-powered cohorts.

Association of Thyroid Function with Blood Pressure and Cardiovascular Disease: A Mendelian Randomization

Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper- or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study. Single nucleotide polymorphisms (SNPs) associated with thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), hyper- and hypothyroidism, and anti-thyroid peroxidase antibodies (TPOAb), from genome-wide association studies (GWAS), were selected as MR instrumental variables. SNPs–outcome (BP, CVD) associations were evaluated in a large-scale cohort, the Malmö Diet and Cancer Study (n = 29,298). Causal estimates were computed by inverse-variance weighted (IVW), weighted median, and MR-Egger approaches. Genetically increased levels of TSH were associated with decreased systolic BP and with a lower risk of atrial fibrillation. Hyperthyroidism and TPOAb were associated with a lower risk of atrial fibrillation. Our data support a causal association between genetically decreased levels of TSH and both atrial fibrillation and systolic BP. The lack of significance after Bonferroni correction and the sensitivity analyses suggesting pleiotropy, should prompt us to be cautious in their interpretation. Nevertheless, these findings offer mechanistic insight into the etiology of CVD. Further work into the genes involved in thyroid functions and their relation to cardiovascular outcomes may highlight pathways for targeted intervention.