Complement C3 as a potential drug target in periodontitis: Evidence from the cis-Mendelian randomization approach.

AIM: Evidence from a Phase IIa trial showed that a complement C3-targeted drug reduced gingival inflammation in patients with gingivitis. Using drug-target Mendelian randomization (MR), we investigated whether genetically proxied C3 inhibition alters the risk of periodontitis. MATERIALS AND METHODS: We used multiple 'cis' instruments from the vicinity of the encoding loci of C3. Instrument selection was restricted to the drug target encoding loci (chromosome 19; 6,677,715-6,730,573 (GRCh37/hg19)). We selected three uncorrelated single-nucleotide polymorphisms (rs141552034, rs145406915, rs11569479) that were associated with serum C3 levels (p value <1 × 10-4 ) from a genome-wide association study (GWAS) of 5368 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis to estimate the odds ratio (OR) of the genetically proxied inhibition of C3 in relation to periodontitis. RESULTS: MR analysis revealed that the inhibition of C3 reduces the odds of periodontitis (OR 0.91 per 1 standard deviation reduction in C3; 95% confidence interval 0.87-0.96, p value = .0003). CONCLUSIONS: Findings from our MR analysis suggest a potential protective effect of C3 blockade against periodontitis.

Targeted therapies in patients with newly diagnosed glioblastoma-A systematic meta-analysis of randomized clinical trials.

Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor-treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta-analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled in a random-effects meta-analysis. Twelve RCTs (n = 3941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti-angiogenic approaches and poly (ADP-ribose) polymerase (PARP) inhibitors were included in the meta-analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR = 0.98 [95% confidence interval (CI) 0.86-1.11, P = .7731]). By comparison, targeted therapy showed a benefit for PFS (HR = 0.83 [95% CI 0.74-0.94, P = .0037]), especially for patients with an unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter (0.75 [95% CI 0.56-0.99, P = .0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR = 0.70 [95% CI 0.61-0.80, P = .0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared to standard care. However, no improvement in OS was observed with any of the targeted agents.

Body shape phenotypes of multiple anthropometric traits and cancer risk: a multi-national cohort study.

BACKGROUND: Classical anthropometric traits may fail to fully represent the relationship of weight, adiposity, and height with cancer risk. We investigated the associations of body shape phenotypes with the risk of overall and site-specific cancers. METHODS: We derived four distinct body shape phenotypes from principal component (PC) analysis on height, weight, body mass index (BMI), waist (WC) and hip circumferences (HC), and waist-to-hip ratio (WHR). The study included 340,152 men and women from 9 European countries, aged mostly 35-65 years at recruitment (1990-2000) in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: After a median follow-up of 15.3 years, 47,110 incident cancer cases were recorded. PC1 (overall adiposity) was positively associated with the risk of overall cancer, with a HR per 1 standard deviation (SD) increment equal to 1.07 (95% confidence interval 1.05 to 1.08). Positive associations were observed with 10 cancer types, with HRs (per 1 SD) ranging from 1.36 (1.30-1.42) for endometrial cancer to 1.08 (1.03-1.13) for rectal cancer. PC2 (tall stature with low WHR) was positively associated with the risk of overall cancer (1.03; 1.02-1.04) and five cancer types which were not associated with PC1. PC3 (tall stature with high WHR) was positively associated with the risk of overall cancer (1.04; 1.03-1.05) and 12 cancer types. PC4 (high BMI and weight with low WC and HC) was not associated with overall risk of cancer (1.00; 0.99-1.01). CONCLUSIONS: In this multi-national study, distinct body shape phenotypes were positively associated with the incidence of 17 different cancers and overall cancer.

Effect of 25-hydroxyvitamin D levels on the internalising dimension as a transdiagnostic risk factor: Mendelian randomisation study.

BACKGROUND: Observational studies indicate a relationship between vitamin D (25-hydroxyvitamin D; 25OHD) deficiency and the development of internalising disorders, especially depression. However, causal inference approaches (e.g. Mendelian randomisation) did not confirm this relationship. Findings from biobehavioural research suggests that new insights are revealed when focusing on psychopathological dimensions rather than on clinical diagnoses. This study provides further evidence on the relationship between 25OHD and the internalising dimension. AIMS: This investigation aimed at examining the causality between 25OHD and internalising disorders including a common internalising factor. METHOD: We performed a two-sample Mendelian randomisation using genome-wide association study (GWAS) summary data for 25OHD (417 580 participants), major depressive disorder (45 591 cases; 97 674 controls), anxiety (5580 cases; 11 730 controls), post-traumatic stress disorder (12 080 cases; 33 446 controls), panic disorder (2248 cases; 7992 controls), obsessive-compulsive disorder (2688 cases; 7037 controls) and anorexia nervosa (16 992 cases; 55 525 controls). GWAS results of the internalising phenotypes were combined to a common factor representing the internalising dimension. We performed several complementary analyses to reduce the risk of pleiotropy and used a second 25OHD GWAS for replication. RESULTS: We found no causal relationship between 25OHD and any of the internalising phenotypes studied, nor with the common internalising factor. Several pleiotropy-robust methods corroborated the null association. CONCLUSIONS: Following current transdiagnostic approaches to investigate mental disorders, our results focused on the shared genetic basis between different internalising phenotypes and provide no evidence for an effect of 25OHD on the internalising dimension.

Calcium intake in vegan and vegetarian diets: A systematic review and Meta-analysis.

In recent years, plant-based diets have experienced increasing popularity. However, plant-based diets may not always ensure an adequate supply of micronutrients, in particular calcium. We performed a systematic review and meta-analysis of calcium intake in vegan and vegetarian diets as compared to omnivorous diets. We searched PubMed and Web of Science and identified 2,009 potentially relevant articles. Mean calcium intake values were pooled and standardized mean differences (SMD) and 95% confidence intervals (CI) were computed.We analyzed 74 studies, including 7,356 vegan, 51,940 vegetarian, and 107,581 omnivorous participants. Of these, dietary calcium intake was examined in 23 studies of vegans, 60 studies of vegetarians and 74 studies of omnivores. Vegans showed a substantially lower calcium intake than vegetarians (SMD = -0.57; 95%CI = -0.83 to -0.32; p = <0.0001) and omnivores (SMD = -0.70; 95%CI = -0.95 to -0.59; p < 0.0001), whereas no statistically significant difference in calcium intake was noted between vegetarians and omnivores (SMD = 0.07; 95%CI = -0.04 to 0.19; p = 0.1976). In conclusion, vegans show a lower calcium intake than vegetarians and omnivores. This finding emphasizes the need for vegans to monitor their calcium status.

Association between circadian physical activity patterns and mortality in the UK Biobank.

BACKGROUND: The benefit of physical activity (PA) for increasing longevity is well-established, however, the impact of diurnal timing of PA on mortality remains poorly understood. We aimed to derive circadian PA patterns and investigate their associations with all-cause mortality. METHODS: We used 24 h PA time series from 96,351 UK Biobank participants aged between 42 and 79 years at accelerometry in 2013-2015. Functional principal component analysis (fPCA) was applied to obtain circadian PA patterns. Using multivariable Cox proportional hazard models, we related the loading scores of these fPCs to estimate risk of mortality. RESULTS: During 6.9 years of follow-up, 2,850 deaths occurred. Four distinct fPCs accounted for 96% of the variation of the accelerometry data. Using a loading score of zero (i.e., average overall PA during the day) as the reference, a fPC1 score of + 2 (high overall PA) was inversely associated with mortality (Hazard ratio, HR = 0.91; 95% CI: 0.84-0.99), whereas a score of -2 (low overall PA) was associated with higher mortality (1.69; 95% CI: 1.57-1.81; p for non-linearity < 0.001). Significant inverse linear associations with mortality were observed for engaging in midday PA instead of early and late PA (fPC3) (HR for a 1-unit increase 0.88; 95% CI: 0.83-0.93). In contrast, midday and nocturnal PA instead of early and evening PA (fPC4) were positively associated with mortality (HR for a 1-unit increase 1.16; 95% CI: 1.08-1.25). CONCLUSION: Our results suggest that it is less important during which daytime hours one is active but rather, to engage in some level of elevated PA for longevity.

Genotype-driven NPC1L1 and PCSK9 inhibition and reduced risk of periodontitis.

AIM: Epidemiological and pre-clinical studies suggest a chemoprotective role of lipid-lowering agents in periodontitis. We tested the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) with periodontitis. MATERIALS AND METHODS: Genetic variants in HMGCR, NCP1L1 and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N = 188,578) were used to proxy therapeutic inhibition of HMGCR, NPC1L1 and PCSK9. For these genetic variants, associations with periodontitis were obtained from GWAS of 17,353 cases and 28,210 controls in the GeneLifestyle Interactions in Dental Endpoints consortium. Generalized weighted least squares analysis accounted for linkage disequilibrium of genotypes to derive pooled estimates. RESULTS: While genetically proxied HMGCR inhibition equivalent to 1 mmol/L reduction in LDL was not associated with odds of periodontitis (odds ratio [OR] = 0.92 [95% confidence interval [CI]: 0.73; 1.16]; p = .4905; false discovery rate [FDR] = 0.4905), genetically proxied NPC1L1 (OR = 0.53 [95% CI: 0.35; 0.81]; p = .0038; FDR = 0.0077) and PCSK9 (OR = 0.84 [95% CI: 0.74; 0.95]; p = .0051; FDR = 0.0077) inhibition lowered the odds of periodontitis. CONCLUSIONS: Genetically proxied inhibition of NCP1L1 and PCSK9 was associated with lower odds of periodontitis.

Relationship between genetically proxied vitamin D and psoriasis risk: a Mendelian randomization study.

BACKGROUND: Observational research suggests that vitamin D levels affect psoriasis. However, observational studies are prone to potential confounding or reverse causation, which complicates interpreting the data and drawing causal conclusions. AIM: To apply Mendelian randomization (MR) methods to comprehensively assess a potential association between vitamin D and psoriasis. METHODS: Genetic variants strongly associated with 25-hydroxyvitamin D (25OHD) in genome-wide association study (GWAS) data from 417 580 and 79 366 individuals from two independent studies served as instrumental variables (used as the discovery and replication datasets, respectively). As the outcome variable, we used GWAS data of psoriasis (13 229 people in the case group, 21 543 in the control group). We used (i) biologically validated genetic instruments, and (ii) polygenic genetic instruments to assess the relationship between genetically proxied vitamin D and psoriasis. We carried out inverse-variance weighted (IVW) MR analyses for the primary analysis. In sensitivity analyses, we used robust MR approaches. RESULTS: MR analyses of both the discovery and replication datasets did not show an effect of 25OHD on psoriasis. Neither the IVW MR analysis of the biologically validated instruments [discovery dataset: odds ratio (OR) 0.99; 95% confidence interval (CI) 0.88-1.12, P = 0.873; replication dataset: OR 0.98, 95% CI 0.66-1.46, P = 0.930] nor that of the polygenic genetic instruments (discovery dataset: OR 1.00, 95% CI 0.81-1.22, P = 0.973; replication dataset: OR 0.94, 95% CI 0.64-1.38, P = 0.737) revealed an impact of 25OHD on psoriasis. CONCLUSION: The present MR study did not support the hypothesis that vitamin D levels, measured by 25OHD, affect psoriasis. This study was conducted on Europeans, so the conclusions may not be applicable to all ethnicities.

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

Physical activity and the risk of periodontitis: an instrumental variable study.

OBJECTIVES: Observational studies suggested an inverse association between physical activity and periodontitis. However, observational studies might be subject to unobserved confounding and reverse causation bias. We conducted an instrumental variable study to strengthen the evidence on the relationship between physical activity and periodontitis. MATERIALS AND METHODS: We used genetic variants associated with self-reported and accelerometer-assessed physical activity in 377,234 and 91,084 UK Biobank participants, respectively, as instruments. For these instruments, genetic associations with periodontitis were obtained from 17,353 cases and 28,210 controls in the GeneLifestyle Interactions in Dental Endpoints consortium. RESULTS: We found no evidence for effects of self-reported moderate-to-vigorous physical activity, self-reported vigorous physical activity, accelerometry "average accelerations," and "fraction of accelerations > 425 milli-gravities" on periodontitis. For example, the odds ratio for self-reported moderate-to-vigorous physical activity was 1.07 (95% credible interval: 0.87; 1.34) in Causal Analysis using Summary Effect Estimates. We conducted sensitivity analyses to rule out weak instrument bias and correlated horizontal pleiotropy. CONCLUSIONS: The study does not support an effect of physical activity on the risk of periodontitis. CLINICAL RELEVANCE: This study provides little evidence that recommending physical activity would help prevent periodontitis.

Sedentary behavior and cancer-an umbrella review and meta-analysis.

Several systematic reviews and meta-analyses have summarized the association between sedentary behavior (SB) and cancer. However, the level of evidence and the potential for risk of bias remains unclear. This umbrella review summarized the current data on SB in relation to cancer incidence and mortality, with a particular emphasis on assessing the risk of bias. We searched PubMed, Web of Science and Cochrane Database for systematic reviews and meta-analyses on the association between SB and cancer incidence and mortality. We also searched for recent observational studies not yet included in existing meta-analyses. We re-calculated summary risk estimates for cancer incidence and mortality using random effects models. We included 14 meta-analyses covering 17 different cancer sites from 77 original studies. We found that high SB levels increase the risk for developing ovarian, endometrial, colon, breast, prostate, and rectal cancers, with relative risks of 1.29 (95% confidence interval (CI) = 1.08-1.56), 1.29 (95% CI = 1.16-1.45), 1.25 (95% CI = 1.16-1.33), 1.08 (95% CI = 1.04-1.11), 1.08 (95% CI = 1.00-1.17), and 1.07 (95% CI = 1.01-1.12), respectively. Also, we found an increased risk of cancer mortality of 1.18 (95% CI = 1.09-1.26). Most associations between SB and specific cancer sites were supported by a "suggestive" level of evidence. High levels of SB are associated with increased risk of several types of cancer and increased cancer mortality risk.

Understanding the consequences of educational inequalities on periodontitis: A Mendelian randomization study.

AIM: Higher educational attainment is associated with a lower risk of periodontitis, but the extent to which this association is causal and mediated by intermediate factors is unclear. MATERIALS AND METHODS: Using summary data from genetic association studies from up to 1.1 million participants of European descent, univariable and multivariable Mendelian randomization analyses were performed to infer the total effect of educational attainment on periodontitis and to estimate the degree to which income, smoking, alcohol consumption, and body mass index mediate the association. RESULTS: The odds ratio of periodontitis per 1 standard deviation increment in genetically predicted education was 0.78 (95% CI: 0.68-0.89). The proportions mediated of the total effect of genetically predicted education on periodontitis were 64%, 35%, 15%, and 46% for income, smoking, alcohol consumption, and body mass index, respectively. CONCLUSIONS: Using a genetic instrumental variable approach, this study triangulated evidence from existing observational epidemiological studies and suggested that higher educational attainment lowers periodontitis risk. Measures to reduce the burden of educational disparities in periodontitis risk may tackle downstream risk factors, particularly income, smoking, and obesity.

Cannabis use and the risk of periodontitis: A two-sample Mendelian randomization study.

AIM: This study aimed to leverage human genetic data to investigate whether cannabis use causally affects periodontitis. MATERIALS AND METHODS: Data were obtained from summary statistics of genome-wide association studies of lifetime cannabis use (N = 184,765), cannabis use disorder (17,068 cases; 357,219 controls), and periodontitis (17,353 cases; 28,210 controls). We performed two-sample Mendelian randomization (MR) analysis using 6 genetic variants as instrumental variables for lifetime cannabis use and 11 variants as instruments for cannabis use disorder to estimate associations with periodontitis. RESULTS: There was no evidence for an association between genetic liability for lifetime cannabis use or cannabis use disorder with periodontitis. The estimates from the primary analyses were supported in multivariable MR analysis, which considered potential pleiotropic pathways and in weak instrument analyses. CONCLUSIONS: This study provides little evidence to support a detrimental effect of genetic liability for cannabis use on periodontal health.

Relationship between periodontitis and psoriasis: A two-sample Mendelian randomization study.

AIM: Observational research suggests that periodontitis affects psoriasis. However, observational studies are prone to reverse causation and confounding, which hampers drawing causal conclusions and the effect direction. We applied the Mendelian randomization (MR) method to comprehensively assess the potential bi-directional association between periodontitis and psoriasis. MATERIALS AND METHODS: We used genetic instruments from the largest available genome-wide association study of European descent for periodontitis (17,353 cases, 28,210 controls) to investigate the relationship with psoriasis (13,229 cases, 21,543 controls), and vice versa. Causal Analysis Using Summary Effect (CAUSE) estimates and inverse variance-weighted (IVW) MR analyses were used for the primary analysis. Robust MR approaches were used for sensitivity analyses. RESULTS: Both univariable methods, CAUSE and IVW MR analyses, did not reveal any impact of periodontitis on psoriasis (CAUSE odds ratio [OR] = 1.00, p = 1.00; IVW OR = 1.02, p = .6247), or vice versa (CAUSE OR = 1.01, p = .5135; IVW OR = 1.00, p = .7070). The null association was corroborated by pleiotropy-robust methods with ORs close to 1 and p-values >.59. Overall, MR analyses did not suggest any effect of periodontitis on psoriasis. Similarly, there was no evidence to support an effect of psoriasis on periodontitis. CONCLUSIONS: Within the limitations of this MR study, the outcomes supported neither periodontitis affecting psoriasis nor psoriasis affecting periodontitis.

Association between physical activity, grip strength and sedentary behaviour with incidence of malignant melanoma: results from the UK Biobank.

BACKGROUND: Physical activity has been positively related to malignant melanoma. However, that association may be confounded by ultraviolet radiation (UV), a variable closely related to both outdoor physical activity and malignant melanoma. We examined physical activity, grip strength and sedentary behaviour in relation to risk of malignant melanoma, accounting for relevant confounders using data from a prospective cohort study. METHODS: In 350,512 UK Biobank participants aged 38-73 years at baseline, physical activity was assessed with a modified version of the International Physical Activity Questionnaire Short Form, grip strength was measured with a hand dynamometer, and sedentary behaviour was recorded with three specific questions. Multivariable hazard ratios (HR) and corresponding 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. RESULTS: During 7 years of follow-up, 1239 incident malignant melanoma diagnoses were recorded. Physical activity and sedentary behaviour were unrelated to malignant melanoma (HRs 1.01 (95% CI 0.95-1.07) and 1.04 (95% CI 0.97-1.12), respectively), and the initially positive association with grip strength in the basic model (HR 1.23, 95% CI 1.08-1.40) was attenuated after full adjustment (HR 1.10, 95% CI 0.96-1.26). CONCLUSION: Physical activity, grip strength and sedentary behaviour are not associated with malignant melanoma risk.

Stratum corneum lipidomics analysis reveals altered ceramide profile in atopic dermatitis patients across body sites with correlated changes in skin microbiome.

BACKGROUND: Atopic dermatitis (AD) is driven by the interplay between a dysfunctional epidermal barrier and a skewed cutaneous immune dysregulation. As part of the complex skin barrier dysfunction, abnormalities in lipid organization and microbiome composition have been described. We set out to systematically investigate the composition of the stratum corneum lipidome, skin microbiome and skin physiology parameters at three different body sites in patients with AD and healthy volunteers. METHODS: We analysed tape strips from different body areas obtained from 10 adults with AD and 10 healthy volunteers matched for FLG mutation status for 361 skin lipid species using the Metabolon mass spectrometry platform. 16S rRNA data were available from all probands. RESULTS: Our study showed that the lipid composition differs significantly between body sites and between AD patients and healthy individuals. Ceramide species NS was significantly higher in AD patients compared to healthy volunteers and was also higher in AD patients with a FLG mutation compared to AD patients without a FLG mutation. The correlation analysis of skin lipid alterations with the microbiome showed that Staphylococcus colonization in AD is positively correlated with ceramide subspecies AS, ADS, NS and NDS. CONCLUSION: This is the first study to reveal site-specific lipid alterations and correlations with the skin microbiome in AD.

Testing the association between tobacco smoking, alcohol consumption, and risk of periodontitis: A Mendelian randomization study.

AIM: To investigate the associations of tobacco smoking and alcohol consumption with periodontitis using Mendelian randomization (MR) analysis. MATERIALS AND METHODS: We used 17 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for the number of cigarettes per day from a genome-wide association study (GWAS) of 337,334 individuals, 109 SNPs for a lifetime smoking index from GWAS of 462,690 participants, and 33 SNPs for the number of drinks per week from GWAS of 941,280 individuals. The periodontitis GWAS included 12,289 cases and 22,326 controls. Wald ratios were obtained by dividing the SNP-periodontitis effects by SNP-exposure effects and pooled using an inverse-variance weighted model. RESULTS: Genetic liabilities for higher number of cigarettes per day (odds ratio [OR] per one standard deviation (1SD) increment = 1.56; 95% CI: 1.18-2.07, p-value = .0018, Q-value = .0054), lifetime smoking index (OR per 1SD = 1.26; 95% CI: 1.04-1.53, p-value = .0161, Q-value = .0242), and drinks per week (OR per 1SD = 1.41; 95% CI: 1.04-1.90, p-value = .0265, Q-value = .0265) were associated with increased odds of periodontitis. Estimates were consistent across robust and multivariable MR analyses. CONCLUSIONS: The findings of this MR analysis suggest an association between tobacco smoking and alcohol consumption with periodontitis.

Cannabis use does not impact on type 2 diabetes: A two-sample Mendelian randomization study.

Cannabis has effects on the insulin/glucose metabolism. As the use of cannabis and the prevalence of type 2 diabetes increase worldwide, it is important to examine the effect of cannabis on the risk of diabetes. We conducted a Mendelian randomization (MR) study by using 19 single-nucleotide polymorphisms (SNPs) as instrumental variables for lifetime cannabis use and 14 SNPs to instrument cannabis use disorder and linking these to type 2 diabetes risk using genome-wide association study data (lifetime cannabis use [N = 184,765]; cannabis use disorder [2387 cases/48,985 controls], type 2 diabetes [74,124 cases/824,006 controls]). The MR analysis suggested no effect of lifetime cannabis use (inverse-variance weighted odds ratio [95% confidence interval] = 1.00 [0.93-1.09], P value = 0.935) and cannabis use disorder (OR = 1.03 [0.99-1.08]) on type 2 diabetes. Sensitivity analysis to assess potential pleiotropy led to no substantive change in the estimates. This study adds to the evidence base that cannabis use does not play a causal role in type 2 diabetes.

Periodontitis and pulmonary function: a Mendelian randomization study.

OBJECTIVES: Observational research suggests that periodontitis affects pulmonary function; however, observational studies are subject to confounding and reverse causation, making causal inference and the direction of these associations difficult. We used Mendelian randomization (MR) to assess the potential causal association between genetic liability to periodontitis and pulmonary function. MATERIALS AND METHODS: We used six single-nucleotide polymorphisms (SNPs) associated with periodontitis (P < 5 × 10-6) from a genome-wide association study (GWAS) of 17,353 European descent periodontitis cases and 28,210 controls from the GeneLifestyle Interactions in Dental Endpoints consortium and the UK Biobank, and related these to SNPs from a lung function GWAS including 79,055 study participants of the SpiroMeta Consortium. RESULTS: MR analysis suggested no effect of periodontitis on the ratio of forced expiratory volume in one second to lower forced vital capacity (standard deviation increment in outcome per doubling of the odds of the exposure (95% confidence interval) = - 0.004 (- 0.028; 0.020)). Replication analysis using genetic instruments from two different GWAS and sensitivity analyses to address potential pleiotropy led to no substantial changes in estimates. CONCLUSIONS: Collectively, these findings do not support a relationship between genetic liability for periodontitis and pulmonary function. CLINICAL RELEVANCE: Periodontitis does not seem to be a risk factor for worsening of pulmonary function.

Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression.

BACKGROUND: Fifteen percent of atopic dermatitis (AD) liability-scale heritability could be attributed to 31 susceptibility loci identified by using genome-wide association studies, with only 3 of them (IL13, IL-6 receptor [IL6R], and filaggrin [FLG]) resolved to protein-coding variants. OBJECTIVE: We examined whether a significant portion of unexplained AD heritability is further explained by low-frequency and rare variants in the gene-coding sequence. METHODS: We evaluated common, low-frequency, and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 control subjects combined with whole-transcriptome data on lesional, nonlesional, and healthy skin samples of 27 patients and 38 control subjects. RESULTS: An additional 12.56% (SE, 0.74%) of AD heritability is explained by rare protein-coding variation. We identified docking protein 2 (DOK2) and CD200 receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with AD are further enriched in 5 genes (IL-4 receptor [IL4R], IL13, Janus kinase 1 [JAK1], JAK2, and tyrosine kinase 2 [TYK2]) of the IL13 pathway, all of which are targets for novel systemic AD therapeutics. Multiomics-based network and RNA sequencing analysis revealed DOK2 as a central hub interacting with, among others, CD200R1, IL6R, and signal transducer and activator of transcription 3 (STAT3). Multitissue gene expression profile analysis for 53 tissue types from the Genotype-Tissue Expression project showed that disease-associated protein-coding variants exert their greatest effect in skin tissues. CONCLUSION: Our discoveries highlight a major role of rare coding variants in AD acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of the novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.