Tea is one of the most widely consumed beverages in the world. However, the association between tea and risk of pancreatic adenocarcinoma remains controversial. This study aimed to investigate the causal relationship between tea consumption and risk of pancreatic adenocarcinoma and to explore their mediating effects. The two-sample Mendelian randomisation (MR) analysis showed an inverse causal relationship between tea intake and pancreatic adenocarcinoma (OR: 0·111 (0·02, 0·85), P < 0·04). To examine the mediating effects, we explored the potential mechanisms by which tea intake reduces the risk of pancreatic adenocarcinoma. Based on the oral bioavailability and drug-like properties in Traditional Chinese Medicine Systems Pharmacology database, we selected the main active ingredients of tea. We screened out the fifteen representative targeted genes by Pharmmapper database, and the gene ontology enrichment analysis showed that these targeted genes were related to vascular endothelial growth factor (VEGF) pathway. The two-step MR analysis of results showed that only VEGF-D played a mediating role, with a mediation ratio of 0·230 (0·066, 0·394). In conclusion, the findings suggest that VEGF-D mediates the effect of tea intake on the risk of pancreatic adenocarcinoma.

The associations between obesity and liver diseases are complex and diverse. To explore the causal relationships between obesity and liver diseases, we applied two-sample Mendelian randomisation (MR) and multivariable MR analysis. The data of exposures (BMI and WHRadjBMI) and outcomes (liver diseases and liver function biomarker) were obtained from the open genome-wide association study database. A two-sample MR study revealed that the genetically predicted BMI and WHRadjBMI were associated with non-alcoholic fatty liver disease, liver fibrosis and autoimmune hepatitis. Obesity was not associated with primary biliary cholangitis, liver failure, liver cell carcinoma, viral hepatitis and secondary malignant neoplasm of liver. A higher WHRadjBMI was associated with higher levels of biomarkers of lipid accumulation and metabolic disorders. These findings indicated independent causal roles of obesity in non-alcoholic fatty liver disease, liver fibrosis and impaired liver metabolic function rather than in viral or autoimmune liver disease.

Tea can improve the progression of some metabolic diseases through anti-inflammatory and antioxidant effects, but its impact on non-alcoholic fatty liver disease (NAFLD) is still controversial. The aim of this paper is to identify the relationship between tea and NAFLD by Mendelian randomisation (MR) and complete clinical validation using National Health and Nutrition Examination Survey (NHANES) database. MR used data from Genome Wide Association Study, with inverse-variance weighted (IVW) as principal analytical methods. The reliability of the results was verified by a series of sensitivity and heterogeneity tests. Subsequently, clinical validation was conducted using NHANES (2005–2018), involving 22 257 participants, grouped by the type of tea. Green tea drinkers were categorised into four groups (Q1–Q4) by quartiles of green tea intake, from lowest to highest (similar for black tea drinkers and other tea drinkers). Models were constructed by logistic regression to estimate the role of tea consumption (Q1–4) on NAFLD. Finally, using fibrosis-4 index (FIB-4) to evaluate the severity of hepatic fibrosis, the effect of tea consumption (Q1–4) on the degree of hepatic fibrosis was investigated by linear regression. IVW method (OR = 0·43, 95 % CI: 0·21, 0·85, P = 0·01) and weighted median method (OR = 0·35, 95 % CI: 0·14, 0·91, P = 0·03) revealed there was a causal relationship between tea and NAFLD. An array of sensitivity analyses validated the reliability of results. Analysis of NHANES indicated tea drinker present a slightly lower prevalence of NAFLD than non-tea drinker (green tea drinkers: 47·6 %, black tea drinkers: 46·3 %, other tea drinker: 43·2 %, non-tea drinkers: 48·1 %, P < 0·05). After adjusting for confounders, compared with the lowest black tea consumption (Q1), the population with the highest black tea consumption (Q4) was independently related to lower presence of NAFLD (Q4: OR = 0·69, 95 % CI: 0·50, 0·93, P < 0·05), such association remained stable in the overweight subgroup. As further analysed, Q4 also displayed a significant negative correlation with the level of hepatic fibrosis in patients with NAFLD (β = –0·073, 95 % CI: –0·126, −0·020, P < 0·01).Tea reduces the morbidity of NAFLD and ameliorates hepatic fibrosis degree in those already suffering from the disease.

Prior research has suggested an inverse correlation between dried fruit intake and type 2 diabetes mellitus (T2DM), yet the causal link remains uncertain. This study seeks to investigate the potential causal impact of dried fruit intake on T2DM, covering cases both with and without various complications, as well as glycaemic traits, using a two-sample Mendelian randomisation (MR) approach. Using MR analysis with genome-wide association study summary statistics, the primary analysis investigated the causal relationship between dried fruit intake and T2DM, both with and without complications, as well as glycaemic traits, employing the inverse variance weighted method. Supplementary analyses were conducted using MR-Egger and the weighted median method. Heterogeneity and intercept tests were utilised to evaluate the robustness of the study outcomes. The results show a significant association between dried fruit intake and T2DM without complications, as well as fasting insulin. Sensitivity analyses confirmed the robustness of the results and the independence from multicollinearity. However, no association was found between dried fruit intake and T2DM with various complications or other glycaemic traits. The significant association between dried fruit intake and T2DM without complications and fasting insulin persisted even after adjusting for BMI. This study offers genetic evidence endorsing the protective effects of dried fruit intake against T2DM, specifically for cases without complications, and in regulating fasting insulin. These findings suggest that dried fruit intake might serve as a primary preventive strategy for T2DM.

This study aimed to explore the potential causal association between PUFA and the risk of intrahepatic cholestasis of pregnancy (ICP) using Mendelian randomisation (MR) analysis. A two-sample MR analysis was conducted utilising large-scale European-based genome-wide association studies summary databases. The primary MR analysis was carried out using the inverse variance-weighted (IVW) method, complemented by other methods such as MR-egger, weighted-median and weighted mode. Sensitivity analysis was also performed to validate the robustness of the findings. Results indicated a 31 % reduced risk of ICP for every 1 standard deviation (sd) increase in n-3 fatty acids levels (OR = 0·69, 95 % CI: 0·54, 0·89, P = 0·004) and in the ratio of n-3 fatty acids to total fatty acids (OR = 0·69, 95 % CI: 0·53, 0·91, P = 0·008). Conversely, there was a 51 % increased risk of ICP for every 1 sd increase in the ratio of n-6 fatty acids to n-3 fatty acids (OR = 1·51, 95 % CI: 1·20, 1·91, P < 0·001) and a 138 % increased risk for every 1 sd increase in the ratio of linoleic fatty acids to total fatty acids (OR = 2·38, 95 % CI: 1·55, 3·66, P < 0·001). The findings suggest that n-3 fatty acids may have a protective effect against the risk of ICP, while n-6 fatty acids and linoleic fatty acids could be potential risk factors for ICP. The supplementation of n-3 fatty acids, as opposed to n-6 fatty acids, could be a promising strategy for the prevention and management of ICP.

Artificial sweeteners are generally used and recommended to alternate added sugar for health promotion. However, the health effects of artificial sweeteners remain unclear. In this study, we included 6371 participants from the National Health and Nutrition Examination Survey with artificial sweetener intake records. Logistic regression and Cox regression were applied to explore the associations between artificial sweeteners and risks of cardiometabolic disorders and mortality. Mendelian randomisation was performed to verify the causal associations. We observed that participants with higher consumption of artificial sweeteners were more likely to be female and older and have above medium socio-economic status. After multivariable adjustment, frequent consumers presented the OR (95 % CI) for hypertension (1·52 (1·29, 1·80)), hypercholesterolaemia (1·28 (1·10, 1·50)), diabetes (3·74 (3·06, 4·57)), obesity (1·52 (1·29, 1·80)), congestive heart failure (1·89 (1·35, 2·62)) and heart attack (1·51 (1·10, 2·04)). Mendelian randomisation confirmed the increased risks of hypertension and type 2 diabetes. Moreover, an increased risk of diabetic mortality was identified in participants who had artificial sweeteners ≥ 1 daily (HR = 2·62 (1·46, 4·69), P = 0·001). Higher consumption of artificial sweeteners is associated with increased risks of cardiometabolic disorders and diabetic mortality. These results suggest that using artificial sweeteners as sugar substitutes may not be beneficial.

Previous studies have indicated an association between vitamin D and thyroid- and parathyroid-related diseases. However, it remains unclear whether it is a cause of the disease, a side effect of treatment or a consequence of the disease. The Mendelian randomisation (MR) study strengthens the causal inference by controlling for non-heritable environmental confounders and reverse causation. In this study, a two-sample bidirectional MR analysis was conducted to investigate the causal relationship between serum vitamin D levels and thyroid- and parathyroid-related diseases. Inverse variance weighted, weighted median and MR-Egger methods were performed, the Cochran Q test was used to evaluate the heterogeneity and the MR-PRESSO and MR-Egger intercepts were utilised to assess the possibility of pleiotropy. The Bonferroni-corrected significance threshold was 0·0038. At the Bonferroni-corrected significance level, we found that vitamin D levels suggestively decreased the risk of benign parathyroid adenoma (OR = 0·244; 95 % CI 0·074, 0·802; P = 0·0202) in the MR analyses. In the reverse MR study, a genetically predicted risk of thyroid cancer suggestively increased the risk of elevated vitamin D (OR = 1·007; 95 % CI 1·010, 1·013; P = 0·0284), chronic thyroiditis significantly increased the risk of elevated vitamin D (OR = 1·007; 95 % CI 1·002, 1·011; P = 0·0030) and thyroid nodules was significantly decreased the vitamin D levels (OR = 0·991; 95 % CI 0·985, 0·997; P = 0·0034). The findings might be less susceptible to horizontal pleiotropy and heterogeneity (P > 0·05). This study from a gene perspective indicated that chronic thyroiditis and thyroid nodules may impact vitamin D levels, but the underlying mechanisms require further investigation.

Previous studies have revealed an association between dietary factors and atopic dermatitis (AD). To explore whether there was a causal relationship between diet and AD, we performed Mendelian randomisation (MR) analysis. The dataset of twenty-one dietary factors was obtained from UK Biobank. The dataset for AD was obtained from the publicly available FinnGen consortium. The main research method was the inverse-variance weighting method, which was supplemented by MR‒Egger, weighted median and weighted mode. In addition, sensitivity analysis was performed to ensure the accuracy of the results. The study revealed that beef intake (OR = 0·351; 95 % CI 0·145, 0·847; P = 0·020) and white bread intake (OR = 0·141; 95 % CI 0·030, 0·656; P = 0·012) may be protective factors against AD. There were no causal relationships between AD and any other dietary intake factors. Sensitivity analysis showed that our results were reliable, and no heterogeneity or pleiotropy was found. Therefore, we believe that beef intake may be associated with a reduced risk of AD. Although white bread was significant in the IVW analysis, there was large uncertainty in the results given the wide 95 % CI. Other factors were not associated with AD in this study.

This study aimed to investigate the association between n-3 PUFA and lung function. First, a cross-sectional study was conducted based on the National Health and Nutrition Examination Survey (NHANES) 2007–2012 data. n-3 PUFA intake was obtained from 24-h dietary recalls. A multivariable linear regression model was used to assess the observational associations of n-3 PUFA intake with lung function. Subsequently, a two-sample Mendelian randomisation (MR) was performed to estimate the potential causal effect of n-3 PUFA on lung function. Genetic instrumental variables were extracted from published genome-wide association studies. Summary statistics about n-3 PUFA was from UK Biobank. Inverse variance weighted was the primary analysis approach. The observational study did not demonstrate a significant association between n-3 PUFA intake and most lung function measures; however, a notable exception was observed with significant findings in the highest quartile for forced vital capacity (FVC) and % predicted FVC. The MR results also showed no causal effect of circulating n-3 PUFA concentration on lung function (forced expiratory volume in one second (FEV1), β = 0·01301, se = 0·01932, P = 0·5006; FVC, β = −0·001894, se = 0·01704, P = 0·9115; FEV1:FVC, β = 0·03118, se = 0·01743, P = 0·07359). These findings indicate the need for further investigation into the impact of higher n-3 PUFA consumption on lung health.

This study aimed to investigate the causal effect of dietary habits on COVID-19 susceptibility, hospitalisation and severity. We used data from a large-scale diet dataset and the COVID-19 Host Genetics Initiative to estimate causal relationships using Mendelian randomisation. The inverse variance weighted (IVW) method was used as the main analysis. For COVID-19 susceptibility, IVW estimates indicated that milk (OR: 0·82; 95 % CI (0·68, 0·98); P = 0·032), unsalted peanut (OR: 0·53; 95 % CI (0·35, 0·82); P = 0·004), beef (OR: 0·59; 95 % CI (0·41, 0·84); P = 0·004), pork (OR: 0·63; 95 % CI (0·42, 0·93); P = 0·022) and processed meat (OR: 0·76; 95 % CI (0·63, 0·92); P = 0·005) were causally associated with reduced COVID-19 susceptibility, while coffee (OR: 1·23; 95 % CI (1·04, 1·45); P = 0·017) and tea (OR: 1·17; 95 % CI (1·05, 1·31); P = 0·006) were causally associated with increased risk. For COVID-19 hospitalisation, beef (OR: 0·51; 95 % CI (0·26, 0·98); P = 0·042) showed negative correlations, while tea (OR: 1·54; 95 % CI (1·16, 2·04); P = 0·003), dried fruit (OR: 2·08; 95 % CI (1·37, 3·15); P = 0·001) and red wine (OR: 2·35; 95 % CI (1·29, 4·27); P = 0·005) showed positive correlations. For COVID-19 severity, coffee (OR: 2·16; 95 % CI (1·25, 3·76); P = 0·006), dried fruit (OR: 1·98; 95 % CI (1·16, 3·37); P = 0·012) and red wine (OR: 2·84; 95 % CI (1·21, 6·68); P = 0·017) showed an increased risk. These findings were confirmed to be robust through sensitivity analyses. Our findings established a causal relationship between dietary habits and COVID-19 susceptibility, hospitalisation and severity.

Over the years, numerous observational studies have substantiated that various dietary choices have opposing effects on CVD. However, the causal effect has not yet been established. Thus, we conducted a Mendelian randomisation (MR) analysis to reveal the causal impact of dietary habits on CVD. Genetic variants strongly associated with 20 dietary habits were selected from publicly available genome-wide association studies conducted on the UK Biobank cohort (n 449 210). Summary-level data on CVD were obtained from different consortia (n 159 836–977 323). The inverse-variance weighted method (IVW) was the primary outcome, while MR-Egger, weighted median and MR Pleiotropy RESidual Sum and Outlier were used to assess heterogeneity and pleiotropy. We found compelling evidence of a protective causal effect of genetic predisposition towards cheese consumption on myocardial infarction (IVW OR = 0·67; 95 % CI = 0·544, 0·826; P = 1·784 × 10−4) and heart failure (IVW OR = 0·646; 95 % CI = 0·513, 0·814; P = 2·135 × 10−4). Poultry intake was found to be a detrimental factor for hypertension (IVW OR = 4·306; 95 % CI = 2·158, 8·589; P = 3·416 × 10−5), while dried fruit intake was protective against hypertension (IVW OR = 0·473; 95 % CI = 0·348, 0·642; P = 1·683 × 10−6). Importantly, no evidence of pleiotropy was detected. MR estimates provide robust evidence for a causal relationship between genetic predisposition to 20 dietary habits and CVD risk, suggesting that well-planned diets may help prevent and reduce the risk of CVD.

Although previous studies suggested the protective effect of Zn for type 2 diabetes (T2D), the unitary causal effect remains inconclusive. We investigated the causal effect of Zn as a single intervention on glycaemic control for T2D, using a systematic review of randomised controlled trials and two-sample Mendelian randomisation (MR). Four primary outcomes were identified: fasting blood glucose/fasting glucose, HbA1c, homeostatic model assessment for insulin resistance (HOMA-IR) and serum insulin/fasting insulin level. In the systematic review, four databases were searched until June 2021. Studies, in which participants had T2D and intervention did not comprise another co-supplement, were included. Results were synthesised through the random-effects meta-analysis. In the two-sample MR, we used single-nucleotide polymorphisms (SNP) from MR-base, strongly related to Zn supplements, to infer the relationship causally, but not specified T2D. In the systematic review and meta-analysis, fourteen trials were included with overall 897 participants initially. The Zn supplement led to a significant reduction in the post-trial mean of fasting blood glucose (mean difference (MD): −26·52 mg/dl, 95 % CI (−35·13, −17·91)), HbA1c (MD: −0·52 %, 95 % CI: (−0·90, −0·13)) and HOMA-IR (MD: −1·65, 95 % CI (−2·62, −0·68)), compared to the control group. In the two-sample MR, Zn supplement with two SNP reduced the fasting glucose (inverse-variance weighted coefficient: −2·04 mmol/l, 95 % CI (−3·26, −0·83)). From the two methods, Zn supplementation alone may causally improve glycaemic control among T2D patients. The findings are limited by power from the small number of studies and SNP included in the systematic review and two-sample MR analysis, respectively.

Vulnerability to coronavirus disease (COVID)-19 varies due to differences in interferon gamma (IFNγ) immunity. We investigated whether a key modifiable interferon precursor, interleukin-18, was related to COVID-19, overall and by severity, using Mendelian randomisation. We used four established genome-wide significant genetic predictors of interleukin-18 applied to the most recent genome-wide association study of COVID-19 (June 2021) to obtain Mendelian randomisation inverse variance weighted estimates by severity, i.e. any (cases = 112 612, non-cases = 2 474 079), hospitalised (cases = 24 274, non-cases = 2 061 529) and very severe (cases = 8779, non-cases = 1 001 875) COVID-19. To be comprehensive, we also conducted an exploratory analysis for IFNγ and two related cytokines with less well-established genetic predictors, i.e. interleukin-12 and interleukin-23. Genetically predicted interleukin-18 was associated with lower risk of any COVID-19 (odds ratio (OR) 0.96 per standard deviation, 95% confidence interval (0.94–0.99, P-value 0.004)) and of very severe COVID-19 (OR 0.88, 95% CI 0.78–0.999, P-value 0.048). Sensitivity analysis and a more liberal genetic instrument selection gave largely similar results. Few genome-wide significant genetic predictors were available for IFNγ, interleukin-12 or interleukin-23, and no associations with COVID-19 were evident. Interleukin-18 could be a modifiable target to prevent COVID-19 and should be further explored in an experimental design.

Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (β = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.