Genetically predicted levels of folate, vitamin B12, and risk of autoimmune diseases: A Mendelian randomization study.

Background: Evidence from observational studies on the association of folate and vitamin B12 with autoimmune diseases are conflicting. Objective: We aimed to investigate the relationship of folate and vitamin B12 with autoimmune diseases using Mendelian randomization (MR). Materials and methods: We selected single-nucleotide polymorphisms associated with folate and vitamin B12 at the genome-wide significance level. Summary-level data for four common autoimmune diseases (vitiligo, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus) were obtained from large-scale genome-wide association studies, with a sample size of 44,266, 86,640, 58,284, and 23,210, respectively. MR analyses were conducted using the inverse variance weighted (IVW) approach, and sensitivity analyses were further performed to test the robustness. Results: We found that a higher genetically determined serum folate level per one standard deviation (SD) was associated with a decreased risk of vitiligo by the IVW method [odds ratios (OR) = 0.47; 95% confidence interval (CI): 0.32-0.69; P = 1.33 × 10-4]. Sensitivity analyses using alternative methods showed similar associations, and no evidence of pleiotropy was detected by MR-Egger regression (P = 0.919). In addition, we observed that vitamin B12 per one SD was positively associated with IBD (IVW: OR = 1.14, 95% CI: 1.03-1.26, P = 0.010; maximum likelihood: OR = 1.14, 95% CI: 1.01-1.29, P = 0.035; MR-PRESSO: OR = 1.14, 95% CI:1.01-1.28, P =0.037), while the association was not significant after Bonferroni correction. Conclusion: The study provides convincing evidence for an inverse association between serum folate level and risk of vitiligo. Further studies are warranted to elucidate the possible association between vitamin B12 and risk of IBD.

Genetic predisposition to smoking in relation to the risk of frailty in ageing.

Frailty causes emerging global health burden due to its high prevalence and mortality. In this study, we used Mendelian randomization (MR) approach to examine the potential causal relationship between smoking and frailty in ageing. Using inverse-variance weighted (IVW) method, genetically predicted smoking initiation was associated with an increased risk of frailty in ageing (odd ratio (OR) 1.23, 95% confidence interval (CI) 1.19-1.27, P = 3.21 × 10-39). Similarly, per year increase in age of initiation of regular smoking was associated with a 25% decrease in the risk of frailty (95% CI 7-39%, P = 7.79 × 10-3, per year), while higher number of cigarettes per day was associated with a 12% increased risk (95% CI 4-20%, P = 1.76 × 10-3). Compared with former smokers, current smokers were associated with an increased risk of frailty (OR 1.12, 95% CI 1.02-1.22, P = 0.01). Lifetime smoking was associated with a 46% higher risk of frailty (95% CI 37-56%, P = 2.63 × 10-29). Sensitivity analysis using alternative MR methods yielded similar results. Our study indicates that genetic predisposition to smoking is associated with the risk of frailty in ageing. Further studies are warranted to examine the exact role of smoking in the development of frailty.

Psychological Resilience among Left-Behind Children in a Rural Area of Eastern China.

Childhood is an important period for individuals' psychological development. Due to long-term separation from the parents, left-behind children (LBC) more easily develop deviation in cognition and abnormal personality. In this study, we aimed to explore the status of psychological resilience among LBC in a rural area of eastern China. We carried out a cross-sectional survey including middle and high school students from Qingyuan County of Zhejiang Province. Psychological resilience was measured using a modified scale developed for Chinese children. Data from a total of 1086 participants were collected, and the mean ± standard deviation score of psychological resilience was 4.11 ± 0.42. Multivariable linear regression analyses revealed that being a class leader (p = 0.010) and having high self-evaluation of academic performance (p < 0.001) were related with psychological resilience. Moreover, high contact frequency between parents and children (p = 0.019) was associated with better psychological resilience among LBC. In conclusion, we found that being a class leader and having high self-evaluation of academic performance were associated with better psychological resilience among the children in this rural area and contact between parent and child was an essential factor associated with psychological resilience among LBC.

Modifiable risk factors for intracranial aneurysms: Evidence from genetic studies.

BACKGROUND: Intracranial aneurysm (IA) is a crucial health concern with limited strategies for prevention and treatment. AIM: To identify potentially modifiable risk factors, such as socioeconomic, behaviors, dietary, and cardiometabolic factors, for IA and its subtypes. METHODS: Summary statistics for IA were derived from a genome-wide association study with an overall 79,429 participants. Single nucleotide polymorphisms associated with modifiable risk factors at genome-wide significance (P = 5 × 10-8) were used as instrumental variables. The inverse-variance-weighted method, weighted-median method, Mendelian randomization (MR)-Egger regression, MR-Pleiotropy RESidual Sum and Outlier, and multivariable MR analyses were performed to evaluate the effect estimates. RESULTS: Genetically predicted educational attainment, insomnia, smoking, and systolic and diastolic blood pressure (SBP and DBP) were significantly associated with the risk of IA. The odds ratios (ORs) were 0.44 (95% confidence interval (CI): 0.37-0.52) for educational attainment, 1.15 (95% CI: 1.08-1.23) for insomnia, 1.56 (95% CI: 1.38-1.75) for smoking initiation, 2.69 (95% CI: 1.77-4.07) for cigarette per day, 2.65 (95% CI: 1.72-4.08) for lifetime smoking, 1.07 (95% CI: 1.06-1.09), and 1.06 (95% CI: 1.04-1.10) for SBP and DBP, respectively. Similar effect estimates were observed for unruptured IAs and aneurysmal subarachnoid hemorrhage. CONCLUSIONS: This study provided genetic evidence that several modifiable risk factors, including blood pressure, smoking, educational attainment, and insomnia were associated with the risk of IA.

Genetically Predicted Circulating Levels of Cytokines and the Risk of Cancer.

Background: Inflammation plays a pivotal role in the pathogenesis of cancer. Though previous studies have reported a link between several inflammatory biomarkers and risk of certain types of cancer, there is a lack of systematic investigation. Therefore, we aimed to assess the role of circulating cytokines on the risk of cancer using a two-sample Mendelian randomization (MR) approach. Method: We used genetic variants associated with circulating levels of cytokines from a meta-analysis of genome-wide association studies (GWASs) of 8,293 Finns as instrumental variables. Summary level data of 20 site-specific cancer were obtained from the UK BioBank including up to 456,348 participants of European ancestry. We performed two-sample MR analyses using inverse-variance weighted (IVW) method as the main method, followed by weighted-median and likelihood-based methods as sensitivity analysis. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Results: 224 genetic variants associated with 27 circulating cytokines achieving genome-wide significance (P<5×10-8) were used as IVs. After Bonferroni correction, genetically predicted high levels of interleukin-18 (IL-18) were associated with a decreased risk of acute myeloid leukemia (odds ratio (OR) per 1 standard deviation (SD) increase = 0.55, 95% confidence interval (CI):0.43-0.69, P=5.39×10-7), and circulating levels of IL-17 were associated with altered stomach cancer risk (OR per 1 SD increase = 0.15, 95% CI: 0.07-0.36, P=1.25×10-5) by IVW. Results were stable across sensitivity analyses, and MR-Egger regression did not suggest the presence of directional pleiotropy. Additionally, we found suggestive evidence for 48 cytokine-cancer associations including tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and cutaneous T-cell attracting chemokine (CTACK) with the risk of several types of cancer (9.26×10-5≤P<0.05). Conclusions: By using a genetic epidemiological approach, our study systematically evaluated the role of circulating cytokines on the risk of cancer, and provided clues for potential therapeutic targets. However, the exact underlying biological mechanism warrants further investigation.

Genetically Predicted Serum Albumin and Risk of Colorectal Cancer: A Bidirectional Mendelian Randomization Study.

Purpose: Colorectal cancer (CRC) is the third-most frequently diagnosed cancer globally. Studies have linked low serum albumin with increased risk of CRC, but the causal nature of the association remains unclear. In the present study, we explored the potential causal relationship using bidirectional Mendelian randomization (MR). Methods: Instrumental variants for albumin were obtained from a genome-wide association study (GWAS) on 102,223 Eastern Asian participants to investigate the effect of albumin on CRC. Summary statistics of CRC were obtained from a GWAS on 7,062 CRC cases and 195,745 controls of Eastern Asian ancestry. Bidirectional MR analysis was performed using inverse variance weighting (IVW) for primary analysis, supplemented with a maximum likelihood-based method, MR-PRESSO test, leave-one-out analysis, and MR-Egger regression. Stratification analyses were further performed. Results: We found that genetically predicted serum albumin per unit was associated with a lower risk of CRC (OR 0.75, 95% CI 0.59-0.95 with IVW). No evidence of pleiotropy was observed. Sex-stratified MR analysis showed that serum albumin was inversely associated with risk of CRC in men (OR 0.71, 95% CI 0.53-0.96), but not in women (OR 0.81, 95% CI 0.55-1.19) using IVW. Reverse MR analysis suggested a genetic predisposition toward CRC was not associated with serum albumin. Conclusion: Our study revealed a suggestive sex disparity in the effect of albumin, which deserves further exploration of the potential biological mechanism.

Circulating phosphorus concentration and risk of prostate cancer: a Mendelian randomization study.

BACKGROUND: Recent observational studies have suggested that circulating phosphorus concentrations are positively associated with the risk of prostate cancer. However, little is known about the causal direction of the association. OBJECTIVES: To explore the potential causal relation between circulating phosphorus and risk of prostate cancer, we conducted a Mendelian randomization (MR) study. METHODS: Summary statistics of prostate cancer were obtained from a meta-analysis of genome-wide association studies (GWASs) consisting of 79,148 cases and 61,106 controls. Single-nucleotide polymorphisms (SNPs) associated with serum phosphorus concentration were selected from a GWAS of 291,408 individuals from the UK Biobank. MR analysis was performed using the inverse variance weighted (IVW) method, supplemented with simple median method, weighted median method, maximum likelihood-based method, MR-Egger regression, and the MR pleiotropy residual sum and outlier test. We also performed a meta-analysis of observational studies to assess the associations of dietary phosphorus intake and serum phosphorus concentration with risk of prostate cancer. RESULTS: In the MR analysis, a total of 125 independent SNPs associated with serum phosphorus concentrations were used as instrumental variables. Genetically predicted serum phosphorus concentrations were associated with a 19% increased risk of prostate cancer (95% CI: 9%, 31%) per 1-SD increment of serum phosphorus by IVW (P = 1.82 × 10-4). Sensitivity analyses using alternative MR methods produced similar positive associations, and no evidence of pleiotropy was detected by MR-Egger regression (P = 0.422). For meta-analysis, 8 studies for dietary phosphorus intake and 4 for serum phosphorus concentrations were included involving a total of 669,080 participants. Consistently, high dietary phosphorus intake and serum phosphorus concentrations were associated with an 8% (95% CI: 4%, 12%) and 7% (95% CI: 1%, 14%) increase in prostate cancer risk, respectively. CONCLUSIONS: Our study suggested a potential causal relation between circulating phosphorus and risk of prostate cancer. Further studies are warranted to elucidate the underlying mechanism of phosphorus in the development of prostate cancer.

Circulating Vitamin D Levels and Risk of Vitiligo: Evidence From Meta-Analysis and Two-Sample Mendelian Randomization.

Background: The association between circulating vitamin D levels and risk of vitiligo was inconsistent among observational studies, and whether these observed associations were causal remained unclear. Therefore, we aimed to evaluate the effect of vitamin D on the risk of vitiigo using meta-analysis and Mendelian randomization (MR). Methods: At the meta-analysis stage, literature search was performed in PubMed and Web of Science to identify eligible observational studies examining the association of circulating 25-hydroxyvitamin D [25(OH)D] or 25-hydroxyvitamin D3 [25(OH)D3] levels with risk of vitiligo up to April 30, 2021. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) of 25(OH)D and 25(OH)D3 in patients with vitiligo relative to controls were pooled. Then at the MR stage, genetic instruments for circulating 25(OH)D (N = 120,618) and 25(OH)D3 (N = 40,562) levels were selected from a meta-analysis of genome-wide association studies (GWAS) of European descent, and summary statistics of vitiligo were obtained from a meta-analysis of three GWASs including 4,680 cases and 39,586 controls. We used inverse-variance weighted (IVW) as main method, followed by weighted-median and likelihood-based methods. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Results: In the meta-analysis, patients with vitiligo had a lower level of circulating 25(OH)D compared with controls [SMD = -1.40; 95% confidence interval (CI): -1.91, -0.89; P < 0.001], while no statistically significant difference of 25(OH)D3 between vitiligo cases and controls was found (SMD = -0.63; 95% CI: -1.29, 0.04; P = 0.064). However, in the MR analyses, genetically predicted 25(OH)D [odds ratio (OR) = 0.93, 95% CI = 0.66-1.31, P = 0.66] and 25(OH)D3 levels (OR = 0.95, 95% CI = 0.80-1.14, P = 0.60) had null associations with risk of vitiligo using the IVW method. Sensitivity analyses using alternative MR methods and instrumental variables (IV) sets obtained consistent results, and no evidence of pleiotropy or outliers was observed. Conclusion: Our study provided no convincing evidence for a causal effect of 25(OH)D or 25(OH)D3 levels on the risk of vitiligo. Further longitudinal and experimental studies, as well as functional studies are warranted to elucidate the role of vitamin D in the development of vitiligo.