Causal effects of GERD on ENT disorders: a Mendelian randomization study

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Gastroesophageal Reflux and Chronic Rhinosinusitis: A Mendelian Randomization Study." 1 Authors conducted a two-sample Mendelian randomization analysis to explore the association between gastroesophageal reflux disease (GERD) and chronic rhinosinusitis (CRS).They mainly used genome-wide association studies, which include data for several thousand asymptomatic individuals and patients with CRS, to explore the association with GERD.GERD was identified through the consumption of omeprazole, the international classification of disease, and self-reported GERD symptoms. 1We congratulate the authors for this article, which investigated a complicated topic.However, we would like to draw attention to some methodological points.The criteria used for the GERD diagnosis do not corroborate those of the Lyon consensus article, which consist of peptic esophageal stricture, grade C/D esophagitis, or acid exposure time >6% at the pH monitoring. 2 Many healthy individuals reported GERD symptom without having GERD, 3 which makes biased the only consideration of GERD symptoms for the GERD diagnosis confirmation.The potential association between reflux and respiratory disorders (e.g., CRS and asthma) needs to carefully consider the back-flow of gastroduodenal content into the respiratory mucosa, which includes pepsin, bile salts, or other enzymes. [4][5]5][6] The presence of reflux events (hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring [HEMII-pH]), enzymes, symptoms, and findings may suggest the presence of laryngopharyngeal reflux (LPR). 7LPR is unrelated to GERD, and GERD does not involve LPR. 7Indeed, twothirds of GERD patients do not report LPR, 3 whereas patients with >1 event at the HEMII-pH (LPR diagnosis) do not have GERD according to the Lyon consensus. 2,7Most reflux events in the distal esophagus do not reach the proximal esophagus, and one-to two-thirds of proximal esophageal reflux events reach the hypopharynx. 8espite of significant limitations, Guo and Xie have investigated an important topic.The results of this study highlight the need to improve the awareness about the differences between GERD and LPR and to consider "true" LPR patients at the 24-h HEMII-pH in future large database investigations.To date, there are few studies that considered the use of HEMII-pH for the LPR diagnosis, whereas most of the practitioners are unaware of the usefulness of HEMII-pH for the LPR diagnosis. 9The recent publication of the Dubai criteria for the LPR diagnosis 7 may improve patient care through the objective confirmation of the LPR diagnosis, whereas the investigation of gastroduodenal enzymes into CRS and asthma patient secretions may be an indicator of potential association.

To delve into the potential associations of blood glucose and lipid parameters with Sensorineural Hearing Loss (SHL) and Idiopathic Sudden Hearing Loss (ISHL) through a bidirectional two-sample Mendelian Randomization (MR) analysis, providing insights into the metabolic contributions to hearing loss. Genome-Wide Association Studies (GWAS) database from European populations were analyzed to assess the causal effects of blood glucose and lipid risk factors on SHL and ISHL. Single Nucleotide Polymorphisms (SNPs) meeting strict p-value thresholds were used as instrumental variables. MR methods, including Inverse Variance-Weighted (IVW), MR-Egger, and weighted median, were employed. Heterogeneity and pleiotropy were evaluated using Cochran's Q and MR-Egger intercept. Reverse MR analysis assessed the potential impact of SHL and ISHL on metabolic factors. Triglycerides (TG) exhibited a significant causal effect on SHL (OR = 1.162, 95% CI 1.072-1.260, p < 0.01), with findings consistent across MR methods. No other metabolic factors exhibited significant causal effects on SHL. Similarly, no associations were found between any metabolic factors and ISHL. Reverse MR analysis revealed that ISHL may causally influence fasting glucose (OR = 1.001, 95% CI 1.001-1.013, p < 0.01) and T2DM (OR = 1.039, 95% CI 1.029-1.049, p < 0.01), but SHL showed no significant reverse effects. TG is a causal risk factor for SHL, whereas ISHL may influence glucose metabolism. These findings underscore the metabolic distinctions between SHL and ISHL and their respective etiologies. Level 2.

Background: Observational studies have shown a bidirectional association between chronic obstructive pulmonary disease (COPD) and gastroesophageal reflux disease (GERD), but it is not clear whether this association is causal. In our previous study, we found that depression was a hot topic of research in the association between COPD and GERD. Is major depressive disorder (MDD) a mediator of the association between COPD and GERD? Here, we evaluated the causal association between COPD, MDD, and GERD using Mendelian randomization (MR) study. Methods: Based on the FinnGen, United Kingdom Biobank, and Psychiatric Genomics Consortium (PGC) databases, we obtained genome-wide association study (GWAS) summary statistics for the three phenotypes from 315,123 European participants (22,867 GERD cases and 292,256 controls), 462,933 European participants (1,605 COPD cases and 461,328 controls), and 173,005 European participants (59,851 MDD cases and 113,154 controls), respectively. To obtain more instrumental variables to reduce bias, we extracted relevant single-nucleotide polymorphisms (SNPs) for the three phenotypes from published meta-analysis studies. Bidirectional MR and expression quantitative trait loci (eQTL)-MR were performed using the inverse variance weighting method to assess the causal association between GERD, MDD, and COPD. Results: There was no evidence of a causal effect between GERD and COPD in the bidirectional MR analysis [forward MR for GERD on COPD: odds ratios (OR) = 1.001, p = 0.270; reverse MR for COPD on GERD: OR = 1.021, p = 0.303]. The causal effect between GERD and MDD appeared to be bidirectional (forward MR for GERD on MDD: OR = 1.309, p = 0.006; reverse MR for MDD on GERD: OR = 1.530, p < 0.001), while the causal effect between MDD and COPD was unidirectional (forward MR for MDD on COPD: OR = 1.004, p < 0.001; reverse MR for COPD on MDD: OR = 1.002, p = 0.925). MDD mediated the effect of GERD on COPD in a unidirectional manner (OR = 1.001). The results of the eQTL-MR were consistent with those of the bidirectional MR. Conclusion: MDD appears to play a vital role in the effect of GERD on COPD. However, we have no evidence of a direct causal association between GERD and COPD. There is a bidirectional causal association between MDD and GERD, which may accelerate the progression from GERD to COPD.

Background:To understand a causal role of modifiable lifestyle factors in angiotensin-converting enzyme 2 (ACE2) expression (a putative severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] receptor) across 44 human tissues/organs, and in coronavirus disease 2019 (COVID-19) susceptibility and severity, we conducted a phenome-wide two-sample Mendelian randomization (MR) study.Methods:More than 500 genetic variants were used as instrumental variables to predict smoking and alcohol consumption. Inverse-variance weighted approach was adopted as the primary method to estimate a causal association, while MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to identify potential horizontal pleiotropy.Results:We found that genetically predicted smoking intensity significantly increased ACE2 expression in thyroid (β=1.468, p=1.8×10−8), and increased ACE2 expression in adipose, brain, colon, and liver with nominal significance. Additionally, genetically predicted smoking initiation significantly increased the risk of COVID-19 onset (odds ratio=1.14, p=8.7×10−5). No statistically significant result was observed for alcohol consumption.Conclusions:Our work demonstrates an important role of smoking, measured by both status and intensity, in the susceptibility to COVID-19.Funding:XJ is supported by research grants from the Swedish Research Council (VR-2018–02247) and Swedish Research Council for Health, Working Life and Welfare (FORTE-2020–00884).

Smoking, measured by both initiation and intensity, are significantly associated with an elevated expression level of ACE2 in multiple human tissues/organs, subsequently increasing the susceptibility and severity of COVID-19.

ObjectivesPrevious research has suggested connections between specific inflammatory cytokines and nasal conditions, including Allergic Rhinitis (AR), Chronic Rhinosinusitis (CRS), and Nasal Polyps (NP). However, a lack of robust research establishing the causal underpinnings of them. This Mendelian Randomization (MR) study aims to evaluate the causal relationships between 41 inflammatory cytokines and the incidence of AR, CRS and NP.MethodsThis study employed a two-sample MR design, harnessing genetic variations derived from publicly accessible genome-wide association studies (GWAS) datasets. AR data was sourced from a GWAS with 25,486 cases and 87,097 controls (identifier: ukb-b-7178). CRS data originated from a GWAS encompassing 1,179 cases and 360,015 controls (identifier: ukb-d-J32). NP data was extracted from a GWAS involving 1,637 cases and 335,562 controls (identifier: ukb-a-541). The data for 41 inflammatory cytokines were obtained from an independent GWAS encompassing 8,293 participants. Inverse variance weighted (IVW), MR Egger regression and Weighted median were used to evaluate the causalities of exposures and outcomes. A range of sensitivity analyses were implemented to assess the robustness of the results.ResultsThe results revealed significant associations between elevated circulating levels of MIP-1α (odds ratio, OR: 1.01798, 95% confidence interval, CI: 1.00217–1.03404, p = 0.02570) and TNF-α (OR: 1.01478, 95% CI: 1.00225–1.02746, p = 0.02067) with an augmented risk of AR in the IVW approach. Heightened levels of circulating IL-2 exhibited a positive correlation with an increased susceptibility to NP in the IVW approach (OR: 1.00129, 95% CI: 1.00017–1.00242, p = 0.02434), whereas elevated levels of circulating PDGF-BB demonstrated a decreased risk of NP (OR: 0.99920, 95% CI: 0.99841–0.99999, p = 0.047610). The MR analysis between levels of 41 inflammatory cytokines and the incidence of CRS yielded no positive outcomes.ConclusionThis investigation proposes a potential causal association between elevated levels of MIP-1α and TNF-α with an elevated risk of AR, as well as an increased risk of NP linked to elevated IL-2 levels. Furthermore, there appears to be a potential association between increased levels of circulating PDGF-BB and a reduced risk of NP.

Gastroesophageal reflux disease (GERD) commonly coexists with childhood asthma, but observational evidence is confounded by adiposity, medications, and shared environments, and reverse causation cannot be excluded. Mendelian randomization (MR), using germline variants as instruments, can mitigate confounding and reverse causation. We conducted a bidirectional two-sample MR to clarify whether genetically proxied GERD liability causally increases childhood asthma risk and whether childhood asthma liability influences GERD. Summary-level genome-wide association study (GWAS) data for gastroesophageal reflux and childhood asthma were obtained from the OpenGWAS repository, and both GWAS were conducted in individuals of European ancestry, so the causal estimates are mainly applicable to European populations. Instrumental variables were selected according to standard two-sample MR criteria. Bidirectional MR analyses were performed in R using the TwoSampleMR package. Of 5 complementary MR methods, inverse-variance weighting (IVW) was prespecified as the primary analysis. Heterogeneity was assessed with Cochran Q under IVW and MR-Egger models. Robustness was evaluated by leave-one-out analysis, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, and the MR-Egger intercept (for directional pleiotropy). In the forward direction (gastroesophageal reflux → childhood asthma), IVW indicated increased risk (odds ratio = 1.792; 95% confidence interval, 1.661-1.933; P = 2.033 × 10-51 < .001). Results were consistent across the other 4 MR methods. There was no significant heterogeneity by Cochran Q, no evidence of directional pleiotropy by the MR-Egger intercept, no outliers by Mendelian Randomization Pleiotropy RESidual Sum and Outlier, and leave-one-out analysis supported stability. In the reverse direction (childhood asthma → gastroesophageal reflux), IVW showed no association (odds ratio = 1.029; 95% confidence interval, 0.983-1.078; P = .225 > .05), with concordant findings from the other MR methods and similarly negative sensitivity tests. Genetic evidence supports a positive causal effect of gastroesophageal reflux on the risk of childhood asthma, whereas childhood asthma does not appear to causally influence gastroesophageal reflux.

Background: Previous studies have shown an association between chronic rhinosinusitis (CRS) and gastroesophageal reflux disease (GERD). However, the findings of these studies are controversial, and evaluating this association could help in the treatment of CRS. Thus, we aimed to clarify the relationship between GERD and CRS. Methods: We conducted a Mendelian randomization (MR) study. Pooled data on CRS, GERD, and their associated risk factors were extracted from large genome-wide association studies. Independent single-nucleotide polymorphisms were rigorously screened as instrumental variables. Causal associations between GERD and CRS were assessed, and mediation analyses were performed using multivariate and 2-step MR. Asthma served as a mediator because of its association with both CRS and GERD. Sensitivity tests were also performed. Results: MR analysis showed that genetically predicted GERD was associated with an increased risk of CRS (P < .001). Multivariate MR analysis showed that the effect of GERD on CRS was relatively independent. Mediation analysis showed that asthma mediated the association with a mediation effect of 21.07% (95% CI, 2.70%-40.18%). Sensitivity analyses did not reveal any significant effects of pleiotropy and heterogeneity. Conclusions: We found a causal relationship between genetically predicted GERD and an increase in the risk of CRS. As a mediator, asthma contributed to the effect of GERD on CRS. This study provides high-quality causal evidence for the prevention of CRS.

The clinical incidence of sjogren's syndrome combined with gastroesophageal reflux disease is high. Existing observational studies have shown inconsistent results in the association between gastroesophageal reflux disease (GERD) and Sjogren's syndrome (SS).We observed that the symptoms of SS patients also improved after receiving GERD-related treatment. Therefore, we aimed to investigate the relationship between GERD and SS through a bidirectional two-sample Mendelian randomization (MR) study. Independent SNPs associated with GERD and SS were selected from a genome-wide association study (GWAS) as instrumental variables to conduct a bidirectional two-sample Mendelian analysis of GERD and SS. Genetic data were obtained from two databases for the following two outcomes: Gastroesophageal reflux (IEU Open GWAS) [sample size = 602,604 (patients = 129,080; nonpatients = 473,524)] and SS (FinnGen) [sample size = 392,423 (patients = 2,495; nonpatients = 389,928)]. Statistical methods for the MR analysis included the inverse-variance weighting method, weighted median, simple mode and weighted mode, as well as heterogeneity and sensitivity analyses using the Cochran Q statistic, MR‒Egger regression, outlier detection methods (MR-PRESSO). In addition, Steiger Test was conducted to test the direction of causality. MR analysis showed a positive correlation between GERD and SS risk [odds ratio (OR) = 1.3279 (95% confidence interval 1.0312–1.7099, P = 0.0280)]. However, in contrast, no significant causal effect of SS on GERD was observed [OR = 1.0024 (95% CI 0.9651–1.0412; P = 0.8995)]. This bidirectional two-sample Mendelian randomization study confirmed a causal relationship between SS and GERD, and suggested that GERD is a risk factor for SS, while SS does not affect GERD.

Vocal cord dysfunction (VCD) is characterised by paradoxical inspiratory laryngeal motion and is often misdiagnosed as asthma. Definitive diagnosis of VCD is difficult, because laryngoscopy is positive only during symptomatic episodes or upon provocation with exercise or inhaled irritants. The aims of the study were to better characterise the symptomatology of patients with VCD and to evaluate the potential usefulness of less-invasive diagnostic tools, namely provocation tests and spirometry. Retrospective case series of 84 patients with a typical clinical history of VCD, in whom at least one of the three following diagnostic tests were performed: laryngoscopy, provocation testing, or spirometry. The mean age of the patients was 51 years and 74% were women. The principal comorbidities were rhinosinusitis (60%), gastro-oesophageal reflux disease (56%) and atopy (54%). Diagnosis of VCD was confirmed in 73/84 cases (87%), by laryngoscopy (8%), spirometry (84%) and/or provocation tests (68%). VCD remains an underdiagnosed condition. A negative finding on laryngoscopy can lead to false negative diagnosis if it is done when the patient is asymptomatic. Here we show that a clinical suspicion of VCD, evoked by medical history, can be confirmed in many cases by less invasive diagnostic tools such as spirometry and provocation tests. Future well-conducted prospective case-control studies are needed to draw firmer conclusions and to improve the diagnostic accuracy of this condition. &nbsp.

Background:Adiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites.Methods:We assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases) and its subsites using a two-sample MR framework. We used inverse variance weighted (IVW) MR and multiple sensitivity analyses, including multivariable MR (MVMR), to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour (a well-known HNC risk factor).Results:In univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR = 1.17 per 1-SD higher BMI, 95% CI 1.02–1.34). However, the IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index = 0.96 per 1-SD higher BMI, 95% CI 0.80–1.15). Furthermore, we did not find a link between genetically predicted WHR (IVW OR = 1.05 per 1-SD higher WHR, 95% CI 0.89–1.24) or waist circumference and HNC risk (IVW OR = 1.01 per 1-SD higher waist circumference, 95% CI 0.85–1.21).Conclusions:Our findings suggest that adiposity does not play a major role in HNC risk.Funding:FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z). RCR was supported by a Cancer Research UK grant (C18281/A29019). MCB is supported by a University of Bristol Vice Chancellor’s Fellowship, the British Heart Foundation (AA/18/1/34219) and the UK Medical Research Council (MC_UU_00032/5). GDS works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00032/1). CLR was supported by the Medical Research Council (MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SV was funded by an EU Horizon 2020 grant (agreement number 825771) and NIDCR National Institutes of Dental and Craniofacial Health (R03DE030257). JK works in a unit that receives support from the University of Bristol, a Cancer Research UK grant (C18281/A29019) and the UK Medical Research Council (grant number: MC_UU_00032/7).

Background:Adiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites.Methods:We assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases) and its subsites using a two-sample MR framework. We used inverse variance weighted (IVW) MR and multiple sensitivity analyses, including multivariable MR (MVMR), to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour (a well-known HNC risk factor).Results:In univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR = 1.17 per 1-SD higher BMI, 95% CI 1.02–1.34). However, the IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index = 0.96 per 1-SD higher BMI, 95% CI 0.80–1.15). Furthermore, we did not find a link between genetically predicted WHR (IVW OR = 1.05 per 1-SD higher WHR, 95% CI 0.89–1.24) or waist circumference and HNC risk (IVW OR = 1.01 per 1-SD higher waist circumference, 95% CI 0.85–1.21).Conclusions:Our findings suggest that adiposity does not play a major role in HNC risk.Funding:FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z). RCR was supported by a Cancer Research UK grant (C18281/A29019). MCB is supported by a University of Bristol Vice Chancellor’s Fellowship, the British Heart Foundation (AA/18/1/34219) and the UK Medical Research Council (MC_UU_00032/5). GDS works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00032/1). CLR was supported by the Medical Research Council (MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SV was funded by an EU Horizon 2020 grant (agreement number 825771) and NIDCR National Institutes of Dental and Craniofacial Health (R03DE030257). JK works in a unit that receives support from the University of Bristol, a Cancer Research UK grant (C18281/A29019) and the UK Medical Research Council (grant number: MC_UU_00032/7).

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

Adiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites. We assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases) and its subsites using a two-sample MR framework. We used inverse variance weighted (IVW) MR and multiple sensitivity analyses, including multivariable MR (MVMR), to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour (a well-known HNC risk factor). In univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR = 1.17 per 1-SD higher BMI, 95% CI 1.02-1.34). However, the IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index = 0.96 per 1-SD higher BMI, 95% CI 0.80-1.15). Furthermore, we did not find a link between genetically predicted WHR (IVW OR = 1.05 per 1-SD higher WHR, 95% CI 0.89-1.24) or waist circumference and HNC risk (IVW OR = 1.01 per 1-SD higher waist circumference, 95% CI 0.85-1.21). Our findings suggest that adiposity does not play a major role in HNC risk. FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z). RCR was supported by a Cancer Research UK grant (C18281/A29019). MCB is supported by a University of Bristol Vice Chancellor's Fellowship, the British Heart Foundation (AA/18/1/34219) and the UK Medical Research Council (MC_UU_00032/5). GDS works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00032/1). CLR was supported by the Medical Research Council (MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SV was funded by an EU Horizon 2020 grant (agreement number 825771) and NIDCR National Institutes of Dental and Craniofacial Health (R03DE030257). JK works in a unit that receives support from the University of Bristol, a Cancer Research UK grant (C18281/A29019) and the UK Medical Research Council (grant number: MC_UU_00032/7).