Thyroid dysfunction is a common endocrine disorder with significant systemic health consequences. Despite its high burden, data on the long-term prevalence, incidence, and risk factors for thyroid dysfunction remain limited and outdated. A total of 5483 adults aged ≥ 20 years from the Tehran Thyroid Study cohort were followed over 18 years. Prevalence and incidence rates were calculated and stratified by age, sex, anti-TPO status, TSH level, smoking, and BMI. Risk factors were analyzed using Cox proportional hazards models, and a mixed Poisson model was used to project prevalence trends to 2030. Over 18 years of follow-up, the incidence of subclinical hypothyroidism was 8.7 (95

Delirium is an acute neuropsychiatric syndrome characterized by disrupted attention and cognition, often triggered by systemic inflammation and physiological stress. Elevated serum ferritin is frequently observed in patients with delirium. Since ferritin couples iron handling to inflammatory signaling during acute-phase responses, it remains unclear whether genetically influenced baseline serum ferritin is a modifiable causal risk factor for delirium, or whether ferritin elevations observed during illness mainly reflect downstream systemic states leading to brain network failure. We used genetic triangulation to assess baseline causality and identify regulatory mechanisms influencing delirium susceptibility. Using harmonized GWAS summary statistics for ferritin (GCST90270865; N = 270,794) and delirium (GCST90473243; 8461 cases, 449,979 controls), we found no evidence that genetically proxied increases in ferritin causally raise delirium risk (primary MR: IVW random-effects OR = 1.09 per 1/SD ferritin, 95

Abstract Limited research has addressed the association between the dynamic trends of waist circumference (WC) and the incidence of type 2 diabetes mellitus (T2DM). This study aimed to identify the trajectories of WC and evaluate their association with the incidence of T2DM over an 18-year follow-up among the Iranian population. This study was derived from a large prospective cohort (Tehran Lipid and Glucose Study) and included 6,405 participants aged 20–70 years who were followed up every three years for 18 years; this period was divided into two 9-year intervals to track WC trajectories (measurement period) and record T2DM incidence (outcome assessment period). Three WC trajectory patterns were identified using latent class trajectory analysis. The Cox proportional hazards model was used to evaluate the association between WC trajectories and the risk of developing T2DM. Participants were classified into three WC trajectory patterns of low-increasing (n: 2019), moderate-increasing (n: 3248), and high-increasing (n: 1138). The hazard ratio (HR) of T2DM was 2.3 (95% CI 1.7–2.9) for the high-increasing versus the low-increasing WC trajectory class; the HRs were 2.0 (95% CI 1.1–3.7) in men and 2.5 (95% CI 1.8–3.5) in women. The HR of developing T2DM was 2.6 (95% CI 1.6–4.1) in the normoglycemic in comparison with 1.7 (95% CI 1.0–2.7) in the prediabetic high-increasing WC trajectory class. WC trajectory classes were also compared across baseline body mass index (BMI) categories, which high-increasing WC trajectory class showed the highest risk across all BMI groups. The high-increasing WC trajectory class showed a strong association with the development of T2DM independent of BMI and other important risk factors for T2DM which support continuous surveillance of central obesity for prevention of diabetes.

Hypertension (HTN) increasingly originates in childhood and adolescence, with obesity and smoking as modifiable risk factors. However, longitudinal evidence on their independent and joint effects on HTN risk into early adulthood remains limited in non-Western populations. Using data from the Tehran Lipid and Glucose Study (TLGS), we followed 985 adolescents (mean age 15.01 years) for a median of 15.05 years. Adolescent overweight/obesity was defined using national BMI percentiles, and smoking status was self-reported. Incident adulthood HTN was defined as blood pressure ≥ 140/90 mmHg or use of antihypertensive medication. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95

Background : Current evidence concerning a link between metabolic phenotypes and their dynamic changes over time and the risk of cancer is limited. The present study aimed to assess the association between different metabolic health statuses and the risk of cancer occurrence among adult individuals. Methods : This prospective cohort study enrolled 11,445 adults aged ≥18 years from the Tehran Lipid and Glucose Study and followed them for 18 years. We identified metabolic phenotypes based on the Joint Interim Statement. Accordingly, participants were divided into four groups: metabolically healthy normal weight/overweight (MHNW/OW), metabolically unhealthy normal weight/overweight (MUNW)/OW, metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). Cox proportional hazards modeling was performed to assess the association between metabolic phenotype and the risk of cancer occurrence. Results : The multivariable adjusted hazard ratio (HR) (95% confidence interval [CI]) for cancer risk in participants with the MUNW/OW phenotype was 1.37 (95% CI, 1.04 to 1.82) and that in those with the MUO phenotype was 1.84 (95% CI, 1.21 to 2.79) when compared to those with the MHNW/OW phenotype, respectively. More particularly, the risk of breast cancer was higher in women with the MHO phenotype (HR, 3.60; 95% CI, 1.34 to 9.60) as well as those with the MUO phenotype (HR, 4.69; 95% CI, 1.96 to 11.20) relative to those with the MHNW/OW phenotype. Ultimately, however, we found no relationship between phenotype transition and the risk of cancer occurrence. Conclusion : Based on our findings, metabolically unhealthy phenotypes may be associated with a higher overall incidence of cancer. In addition, obesity, independent of metabolic status, was linked to an increased risk of breast cancer incidence. No association between the transition from a metabolically healthy to unhealthy phenotype and cancer risk was established.

Context: Reference values (RVs) are essential tools for medical decision-making, used to interpret an individual’s health status and playing a crucial role in patient care. In addition to age, sex, and inherent biological variability, multiple determinants, including ethnicity, genetic background, dietary habits, environmental factors, and lifestyle, which vary across different populations, play a significant role in the establishment of RVs. Thus, each population requires its own RVs to ensure their effectiveness. Evidence Acquisition: In this review, we summarize RVs reported in the Tehran Lipid and Glucose Study (TLGS) between 2010 and 2026, covering 20 analytes measured in apparently healthy participants, including 16 in adults and 4 in pediatrics. Relevant TLGS publications were identified, and their findings were compared with corresponding international data. Results: RVs were provided for 20 parameters, classified into three categories: (1) Glucose, insulin, insulin resistance/sensitivity indices, and lipid profile; (2) thyroid function tests [thyroid-stimulating hormone (TSH) and free thyroxine (T4)] and autoimmunity [thyroid peroxidase antibody (TPO-Ab)]; (3) other variables, including creatinine and minerals (serum zinc and magnesium), and serum nitric oxide metabolites. Conclusions: The RVs determined by the TLGS provide a population-specific framework for the Iranian population and may serve as a more accurate tool for classification and clinical interpretation than common global RVs. These data emphasize the importance of developing localized RVs to enhance diagnostic precision and improve population health outcomes.

Background and Aims To evaluate the association between variability in systolic blood pressure (SBPV), diastolic blood pressure (DBPV), mean arterial pressure (MAPV), pulse pressure (PPV), and the risk of all-cause mortality, cardiovascular mortality (CV mortality), and sudden cardiac death (SCD) in general population. Methods and results 8,479 participants (5,425 women; mean age 49.0 years) underwent three visits between 2002-2011 at three-year intervals, then were followed up until 2020. Variability of the blood pressure components was assessed using standard deviation (SD) method. Underlying causes of mortality events were adjudicated by the outcome committee. Multivariable Cox proportional hazards regression models were applied and adjusted for a comprehensive set of confounders, including mean BP values and prevalent cardiovascular disease. During a median of 10.1 years, 681, 223, and 145 events of all-cause mortality, CV mortality, and SCD with incidence rates of 8.46, 2.77, and 1.80 per 1,000 person-years occurred, respectively. In multivariable-adjusted analyses, hazard ratios (95% confidence intervals) for the association between 1-SD increase in SBPV, DBPV, MAPV, and PPV and all-cause mortality were calculated as 1.08 (1.02-1.15), 1.12 (1.05-1.20), 1.12 (1.05-1.19), 1.05 (0.99-1.11); for CV mortality were 1.15 (1.04-1.28), 1.17 (1.05-1.30), 1.18 (1.06-1.31), 1.12 (1.02-1.23); regarding SCD were 1.10 (0.96-1.25), 1.16 (1.01-1.33), 1.13 (0.98-1.29), and 1.10 (0.98-1.25), respectively. Compared to participants with low-SBPV/low-DBPV, their counterparts with high-SBPV/high-DBPV had 43% and 49% significantly higher risk of all-cause- and CV mortality, respectively. Conclusions Higher SBP and DBP variability, independent of their mean values, was associated with mortality events, and the latter increased the risk of SCD.

BACKGROUND:The triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance (IR), may improve myocardial infarction (MI) risk prediction when combined with anthropometric indices (ANI). However, comparative evidence on their performance remains limited. OBJECTIVE:This study aimed to identify which TyG-ANI were most strongly associated with incident MI in a Middle Eastern population. METHODS:This cohort study included 5044 adults aged ≥40 years from the Tehran Lipid and Glucose Study, followed for up to 20 years. Eleven TyG-ANI were evaluated. Random survival forest (RSF) identified predictive indices, and associations with incident MI were examined using Cox proportional hazards models. Incremental predictive performance was assessed using the C-index, net reclassification improvement (NRI), integrated discrimination improvement (IDI), Akaike, and Bayesian information criteria (AIC, BIC). RESULTS:During a median follow-up of 19.8 years, 215 participants developed MI. The RSF identified 6 TyG-ANI as predictive indices. In fully adjusted continuous models, TyG-relative fat mass showed the strongest association with incident MI (hazard ratio per SD: 1.36; 95% CI: 1.04-1.80). Adding TyG-ANI to the base model, which included conventional cardiovascular risk factors, resulted in modest but significant improvements in MI risk prediction. TyG-waist-to-hip ratio (WHR) yielded the greatest improvement in discrimination (ΔC-index = 0.006), followed by TyG-a body shape index (ABSI), TyG-conicity index, and TyG-weight-adjusted waist index (ΔC-index ≈ 0.005). TyG-ABSI demonstrated the greatest improvement in NRI (0.144; P = .022) and IDI (0.003; P = .032). TyG-WHR and TyG-ABSI also improved model fit, as indicated by lower AIC and BIC than the base model. CONCLUSION:TyG-ABSI and TyG-WHR were independently associated with incident MI and provided modest improvements in risk prediction beyond traditional cardiovascular risk factors.

Current evidence on the association between food processing and metabolic dysfunction-associated steatotic liver disease (MASLD) is limited to the intake of ultra-processed food (UPF). We investigated the associations between different degrees of food processing and MASLD. This cross-sectional study was conducted among 2,376 adults aged ≥ 18 years who participated in the third examination of the Tehran Lipid and Glucose Study. Food intake was assessed using a food frequency questionnaire and classified according to the NOVA definitions into unprocessed or minimally processed food (MPF), processed culinary ingredients (PCI), processed food (PF), and UPF. MASLD was defined as the fatty liver index combined with cardiometabolic criteria. Using logistic regression, we determined the odds of MASLD across age- and sex-specific tertiles of each food group. Substitution analyses were also conducted to estimate the odds of MASLD associated with the iso-caloric replacement of 10

BACKGROUND:Alterations in levels of 25-hydroxyvitamin D have been associated with the risk of thyroid disease. This study uses Mendelian randomization (MR) to infer the possible causal association of 25-hydroxyvitamin D with hypothyroidism. METHODS:We performed two-sample MR using the summary statistics data from genome-wide association studies (GWAS) from populations with European ancestry to infer the causality of genetically controlled levels of 25-hydroxyvitamin D on the risk of hypothyroidism, Hashimoto's thyroiditis, and biochemical parameters of thyroid diseases. The inverse-variance-weighted (IVW) method was used as the primary method to calculate the combined effect of all SNPs. Other methods were adopted to evaluate the stability and reliability of the results. Comprehensive sensitivity analyses were conducted to ensure that none of the MR analysis's primary assumptions were violated. RESULTS:The results of the IVW analysis revealed a significant causal association between higher levels of 25-hydroxyvitamin D and lower risk of hypothyroidism (beta = -0.197, 95% CI [-0.301, -0.093]; SE = 0.053, Pbeta = 2.256 × 10-4) as well as increased levels of free T4 (beta = 0.204, 95% CI [0.094, 0.305]; SE = 0.056, Pbeta = 3.0506 × 10-4). On the other hand, no significant causality was determined for higher levels of 25-hydroxyvitamin D in association with Hashimoto's thyroiditis (beta = -0.047, 95% CI [-0.245, 0.151], p = 0.641) and TSH levels (IVW method: beta = -0.030, SE = 0.034, 95% CI [-0.097, 0.038]; P = 0.392). CONCLUSION:The results of this two-sample MR study provide evidence supporting the potential of 25-hydroxyvitamin D supplementation in reducing the risk of hypothyroidism.

Cardiometabolic diseases, including type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs) are escalating globally, posing significant health challenges. While dairy products and their bioactive peptides (BPs) may influence chronic diseases risk, the evidence remains inconsistent. These peptides may act via modulation of gut microbiota, reducing inflammation, and regulating lipid metabolism. The current study aimed to investigate the possible association between dairy-derived BPs (DDBPs) and the risk of T2DM and CVDs in Iranian adult population within the framework of Tehran Lipid and Glucose Study (TLGS). In this population-based cohort study, 5,469 participants (T2DM analysis) and 4,980 participants (CVDs analysis) from the TLGS were followed for a mean follow-up period of 6 years. Dietary intake data were determined using a validated food-frequency-questionnaire. Various types of DDBPs were estimated via in-silico proteolysis simulations. The association of bioactive peptides with T2DM and CVDs risk were determined using Cox proportional hazards regression models. Higher intake of k-casein-derived peptides (HR:1.21;95% CI: 1.01-1.64), Hepta-peptides (HR:1.31;95% CI:1.02-1.67), peptides with glycosylated residues (HR:1.29;95%CI: 1.01-1.65), glycosylated residues (HR:1.39;95% CI: 1.07-1.80), and disulfide bond- containing peptides (HR:1.34;95% CI: 1.05-1.71) was associated with an elevated T2DM risk in the adjusted model. Dairy protein intake (highest vs. lowest tertile: HR:1.29;95% CI: 1.02-1.62) Also increased T2DM risk, while total dairy intake showed no association. No significant associations were found between DDBPs, dairy intake, or dairy protein intake and the risk of CVDs. Our results showed that specific DDBPs particularly k-casein-derived fragments and structurally modified peptides (including hepta-peptides, glycosylated peptides, and peptides with disulfide bonds), were associated with an increased risk of T2DM in Tehranian adults. Further studies are warranted to elucidate these associations.

This population-based cohort study aimed to determine if longitudinal patterns of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are associated with the risk of developing chronic kidney disease (CKD) over 18 years. In this prospective cohort study, 3,851 adults aged ≥ 20 years from the Tehran Thyroid Study (TTS) who remained free of CKD during the thyroid trajectory assessment period (visits 1–3, approximately 9 years) were included. Serum TSH and FT4 were measured at three visits, and latent growth mixture modeling (LGMM) was used to identify distinct hormone trajectories. Incident CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², was prospectively ascertained during a subsequent outcome assessment period spanning visits 4–6 (approximately 9 years). Cox proportional hazards models were used to evaluate the association between thyroid hormone trajectories and CKD risk after adjustment for potential confounders. TSH trajectory patterns were characterized as high-increasing, mild-increasing, mild-decreasing, and moderate-decreasing, with 39

BACKGROUND:To investigate the association between serum uric acid (SUA) and incident type 2 diabetes mellitus (T2DM) and its potential role in improving the well-known predictive models of disease. METHODS:The study included 5719 subjects (2588 men) aged ≥ 30 years without T2DM at baseline. Multivariate Cox proportional hazard analyses were applied using SUA as continuous and categorical variables. The added value of SUA was examined by applying Harrell's concordance statistic (C-index) and integrated discrimination improvement (IDI). RESULTS:During a median follow-up of 8.2 years, 778 (376 men) incident T2DM occurred. Each 1-mg/dL increment in SUA was associated with a higher risk of disease in the whole population, men, and women (HR [95% CI]: 1.18 [1.11-1.26], 1.19 [1.09-1.31], and 1.26 [1.14-1.38], respectively). This association in the whole population persisted after adjustment for homeostasis model assessment of insulin resistance and nutritional data (1.15 [1.06-1.25] and 1.19 [1.10-1.30], respectively). A rising risk of incident T2DM was present across quartiles (Q1: reference) in the whole population, reaching 1.82 (1.39-2.37) for Q4 (p-trends < 0.001). Adding SUA to the well-known models did not significantly improve the risk prediction. CONCLUSION:Although SUA has a significant linear association with incident T2DM, its addition to the well-known models will not be accompanied by better risk prediction.

In the current study, we have investigated the association between dietary nitrate (NO3)/nitrite (NO2) intakes and the incidence of hypertension (HTN). This study included a total of 1576 men and women (mean age of 36.4 ± 11.7 and 39% men) in the third (2006-2008) phase of the Tehran Lipid and Glucose Study and were followed up until 2018-2022. At the beginning of the study, a semiquantitative food frequency questionnaire was applied to measure dietary intakes of NO3 and NO2. Multivariable-adjusted Cox proportional hazard models for multiple variables were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of incidence of HTN across different quartiles of NO3 and NO2 dietary intakes. Median (interquartile range) daily intake of NO3 and NO2 were 465 (253) mg/d and 9.6 (4.8) mg/d, which were mostly derived from plant-based sources (95.4% and 55.8%, respectively). Participants in the highest quartile of total and plant-based NO₃ intake were associated with a significantly lower risk of HTN (HRQ4 vs. Q1= 0.46; 95% CI, 0.23-0.91; HRQ4 vs. Q1=0.44; 95% CI, 0.22-0.87, in total and plant-based sources, respectively). No significant association was found between animal-based NO₃ intake and HTN incidence. The highest quartile of plant-based NO₂ intake, compared to the lowest, was associated with a lower risk of HTN (HRQ4 vs. Q1 = 0.57; 95% CI, 0.31-0.99) and there was no significant association between animal-based NO₂ intake and the risk of HTN. Higher intakes of total and plant-based NO3 and NO2, compared with lower intakes, were significantly associated with a lower risk of HTN.

Context:Evidence supports that adverse pregnancy outcomes (APOs) might affect women's health in later life. This review summarizes the findings of the Tehran Lipid and Glucose Study (TLGS) on the association between APOs and long-term chronic diseases over the past two decades. Evidence Acquisition:This narrative review was conducted on TLGS-published articles on the association between APOs and long-term chronic disease over the last decades. The search for articles was performed on PubMed from 1999 to September 2025. Results:As of September 2025, nine peer-reviewed English-language articles have been published from the TLGS dataset. Studies showed that a history of hypertensive disorders of pregnancy (HDP) was associated with a twofold increased risk of hypertension, a threefold risk of diabetes, and a 1.3 times risk of dyslipidemia. Moreover, women with a history of preeclampsia were 3.62 times more likely to experience hypertension progression. Women with a history of gestational diabetes mellitus (GDM) had a 2.23 times risk of diabetes and a 1.85 times risk of cardiovascular disease (CVD). Having a history of preterm delivery increased the risk of chronic kidney disease (CKD) 2.68 times more than that of women without such a history. The risk of metabolic syndrome (METS) was increased by 8% in women with a history of pregnancy loss. Moreover, a history of one, two, or three APOs was associated with an increased risk of developing CVD, with the risk rising progressively as the number of APOs increased. Conclusions:Over the past two decades, the TLGS has published a number of peer-reviewed articles that collectively provide a unique perspective on the long-term health consequences of APOs. These studies indicate that pregnancy is not only an obstetric event but also a vital period for assessing women's long-term health. Women with a history of APOs require early preventive evaluations and ongoing monitoring to identify and treat chronic conditions linked to increased risks of premature mortality.

AIMS:To evaluate the prevalence of cardiovascular-kidney-metabolic syndrome (CKM) and its association with cardiovascular disease (CVD) risk across CKM stages in a Middle Eastern population. METHODS:We analyzed data from 7770 CVD-free adults aged 30-79 years. Multivariable Cox models assessed associations of CKM with incident CVD, coronary heart disease (CHD), myocardial infarction (MI), stroke, and CVD mortality. We also evaluated the impact of CKM stage transitions over approximately 3 years on cardiovascular endpoints. RESULTS:Baseline prevalence of CKM stages 0-3 was 11.2%, 12.0%, 72.8%, and 4.0%, respectively. Over a median 19.9 years of follow-up, 1450 CVD events occurred, including 338 CVD deaths. Compared with stage 0, the HRs (95% CIs) for CVD were 2.03 (1.59-2.58) for stage 2 and 2.76 (2.05-3.73) for stage 3; similar associations were observed for CHD, stroke, and MI. For CVD mortality, stage 3 conferred a risk of 2.61 (1.53-4.45). Each 1-stage progression in CKM over ∼ 3 years was associated with 1.40-2.01 times significantly greater risk of endpoints, except for MI. CONCLUSIONS:Nearly 77% of participants were classified in poor CKM stages (2-3), strongly associated with excess cardiovascular risk. These findings highlight the importance of early CKM detection and targeted interventions.

BACKGROUND:Uncertainty surrounds the relationship between metabolic decline and fatty liver disease. The purpose of this study was to evaluate the effect of hepatic steatosis (HS) on the transition from metabolically healthy obesity (MHO) to metabolically unhealthy obesity (MUO) and to determine whether the Fatty Liver Index (FLI) can predict this progression. METHODS:In this prospective cohort research, participants in the Tehran Lipid and Glucose Study (TLGS) comprised 593 MHO adults who were at least 40 years old at baseline. The subjects were followed up for a period of 12 years to see if the subjects' metabolically healthy obesity phenotype changed to an unhealthy one. The body mass index (BMI) of 30.0 kg/m2 was used to characterise obesity. The concept of metabolically healthy (less than two variables) or metabolically abnormal (two or more) was based on four metabolic parameters: low high density lipoprotein-cholesterol (HDL-c) concentration, hypertension, hypertriglyceridemia, and impaired fasting glucose. The technique used to construct the fatty liver index (FLI), which serves as an indication of HS, was based on waist circumference (WC), triglycerides, BMI, and gamma-glutamyl transferase. RESULTS:During a median of 4.81 years of follow-up (interquartile range 1.75-10.74 years), 72.2% (n = 428) of MHO individuals transitioned to the MUO phenotype. Transitioning participants exhibited higher FLI scores, BMI, waist circumference, and unfavourable metabolic profiles compared to non-transitioning participants. Cox regression analysis revealed that hepatic steatosis (HR: 1.369; 95% CI: 1.014-1.848), lower physical activity (HR: 1.267; 95% CI: 1.035-1.551), and a higher TyG index (HR: 3.208; 95% CI: 1.546-6.657) were significant predictors of transition to MUO. CONCLUSION:Hepatic steatosis at baseline is an independent risk factor for progression from metabolically healthy status to metabolically abnormal phenotype in obese individuals.

BACKGROUND AND AIMS:Antioxidants are known to combat oxidative stress, a key factor in the development of cardiovascular diseases(CVDs) and mortality. In the current study, we aimed to prospectively investigate the relationship between the composite dietary antioxidant index(CDAI) and the incidence of CVDs and mortality in the Iranian population. METHODS AND RESULTS:This study was conducted within the framework of the Tehran Lipid and Glucose Study(TLGS) among 5048 adults≥30 years, selected from the third and fourth phases of the TLGS. Dietary intake was assessed using a validated food frequency questionnaire, and the CDAI was calculated based on intakes of vitamins A, C, E, selenium, zinc, and manganese from food sources. A multivariable Cox proportional hazard regression model was used to estimate the risk CVDs, coronary heart disease(CHD), stroke, and mortality across CDAI tertiles. Median(interquartile) of CDAI score for all participants was -0.69(-3.12, 2.43). During 9-year follow-up period, 357 cases of CVDs(7.10%) and 131 cases of all-cause mortality(2.60%) were ascertained. In the multivariable adjusted model, the CVDs risk reduced across the tertiles of CDAI(HR = 0.60; 95%CI:0.40-0.89; P-trend = 0.013). Also, a one SD increase in CDAI score was associated with reduced risk of CVDs(HR = 0.77; 95%CI:0.64-0.93; P-trend = 0.007) and CHD(HR = 0.78; 95%CI:0.64-0.95; P-trend = 0.016). No significant associations were found between the CDAI score and the incidence risk of stroke and mortality. CONCLUSION:The findings of this study showed that a higher CDAI score is associated with a lower risk of CVDs in Iranian adults. However, there is no significant relationship between the CDAI score and risk of mortality and stroke.

While prior research has indicated a possible association between serum 25 hydroxyvitamin D [25(OH)D] and celiac disease (CD), key questions remain unresolved without clear consensus. To assess association, we perform Mendelian randomization and a systematic review and meta-analysis of existing studies in European ancestry. A systematic review and meta-analysis performed by using both standardized mean difference and a Bayesian framework. Moreover, Mendelian randomization conducted via Generalized Summary-data-based Mendelian randomization (GSMR) and two-sample Mendelian randomization. Data on serum 25(OH)D levels were obtained from the Medical Research Council's Integrative Epidemiology Unit (GWAS ID: ebi-a-GCST90000618; N = 4,96,946), while data on CD included 11,812 cases and 229 controls (GWAS ID: ebi-a-GCST005523). The main method used was the random inverse variance weighted (IVW) approach, supplemented by various sensitivity analyses to strengthen the findings. Both the meta-analysis and Mendelian randomization analysis indicate that vitamin D levels have no effect on the risk of developing celiac disease. Using a random-effects model, the standardized mean difference was calculated as -0.79 (95% CI: -2.02, 0.45), which was not statistically significant (TStatistic=-1.77, P = .152). The Bayesian meta-analysis reinforced these results, showing a point estimate of -0.6 with a wide 95% credible interval of (-13.6, 13.2), highlighting substantial uncertainty regarding the true effect size. The GSMR also found no significant association between 25(OH)D levels and CD (OR = 0.988; 95% CI: 0.853-1.145; P = .878). This null finding was corroborated by two-sample Mendelian randomization (ORIVW = 0.72, 95% CI: 0.49-1.05, P = .091). The Steiger test confirmed the absence of a directional relationship, and cluster analysis revealed no heterogeneity patterns (ORIVW = 0.374, 95% CI: 0.238-0.588). These findings were consistent across multiple MR methods, including penalized MR, robust MR, penalized robust MR, MR-Egger (both t-distribution and radial approaches), SIMEX, MR-PRESSO, Maximum likelihood, MR-Mix, RAPS, MR-Least Absolute Shrinkage and Selection Operator, debiased IVW, and contamination mixture models. By questioning the presumed direct connection between 25(OH)D and CD, it appears that 25(OH)D may not be a primary contributor to CD, which could impact future prevention approaches and alter clinical guidelines.