Investigating the Bidirectional Association of Rheumatoid Arthritis and Thyroid Function: A Methodologic Assessment of Mendelian Randomization.

OBJECTIVE: Rheumatoid arthritis (RA) and thyroid dysfunction are frequently observed in the same patient. However, whether they co-occur or exhibit a causal relationship remains uncertain. We aimed to systematically investigate the causal relationship between RA and thyroid function using a large sample and advanced methods. METHODS: Bidirectional two-sample Mendelian randomization (MR) analysis was performed based on RA and six thyroid function trait data sets from the European population. The robustness of the results was demonstrated using multiple MR methods and a series of sensitivity analyses. Multivariable MR using Bayesian model averaging (MR-BMA) was performed to adjust for possible competing risk factors. A sensitivity data set, which included data from patients with seropositive RA and controls, was used to repeat the analyses. Furthermore, enrichment analysis was employed to discover the underlying mechanism between RA and thyroid functions. RESULTS: A significantly positive causal effect was identified for RA on autoimmune thyroid disease (AITD) as well as for AITD on RA (P < 0.001). Further sensitivity analyses showed consistent causal estimates from a variety of MR methods. After removing the outliers, MR-BMA results showed that RA and AITD were independent risk factors in their bidirectional causality, even in the presence of other competing risk factors (adjusted P < 0.05). Enrichment analysis showed immune cell activation and immune response play crucial roles in them. CONCLUSION: Our results illustrate the significant bidirectional causal effect of RA and AITD, which holds even in multiple competing risk factors. Clinical screening for thyroid dysfunction in patients with RA deserves further attention, and vice versa.

Association of phthalate exposure with type 2 diabetes and the mediating effect of oxidative stress: A case-control and computational toxicology study.

Phthalic acid esters (PAEs) are widely used as plasticizers and have been suggested to engender adverse effects on glucose metabolism. However, epidemiological data regarding the PAE mixture on type 2 diabetes (T2DM), as well as the mediating role of oxidative stress are scarce. This case-control study enrolled 206 T2DM cases and 206 matched controls in Guangdong Province, southern China. The concentrations of eleven phthalate metabolites (mPAEs) and the oxidative stress biomarker 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine were determined. Additionally, biomarkers of T2DM in paired serum were measured to assess glycemic status and levels of insulin resistance. Significantly positive associations were observed for mono-(2-ethylhexyl) phthalate (MEHP) and Mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with T2DM (P < 0.001). Restricted cubic spline modeling revealed a non-linear dose-response relationship between MEHHP and T2DM (Pnon-linear = 0.001). The Bayesian kernel machine regression and quantile g-computation analyses demonstrated a significant positive joint effect of PAE exposure on T2DM risk, with MEHHP being the most significant contributor. The mediation analysis revealed marginal evidence that oxidative stress mediated the association between the mPAEs mixture and T2DM, while 8-OHdG respectively mediated 26.88 % and 12.24 % of MEHP and MEHHP on T2DM risk individually (Pmediation < 0.05). Di(2-ethylhexyl) phthalate (DEHP, the parent compound for MEHP and MEHHP) was used to further examine the potential molecular mechanisms by in silico analysis. Oxidative stress may be crucial in the link between DEHP and T2DM, particularly in the reactive oxygen species metabolic process and glucose import/metabolism. Molecular simulation docking experiments further demonstrated the core role of Peroxisome Proliferator Activated Receptor alpha (PPARα) among the DEHP-induced T2DM. These findings suggest that PAE exposure can alter oxidative stress via PPARα, thereby increasing T2DM risk.

Association between polycyclic aromatic hydrocarbons and infertility in U.S. women: National Health and Nutrition Examination Survey 2013-2016.

Although there is a body of research indicating the potential impact of polycyclic aromatic hydrocarbons (PAHs) exposure on male infertility, the understanding of how PAH might affect female infertility is still limited. This study aimed to evaluate associations of PAHs, both individually and as a mixture, with female infertility using multiple logistic regression, Bayesian kernel machine regression (BKMR), and quantile g-computation (QGC) models based on data from the National Health and Nutrition Examination Survey (NHANES) 2013-2016. The study included 729 female participants. Multiple logistic regression results indicated that there was a significant association between the third tertile of 2-hydroxy fluorene (2-OHFLU) and female infertility, and the OR was 2.84 (95% CI: 1.24-6.53, P value = 0.015) compared with the first tertile after adjusting for the potential covariates. The BKMR model revealed a positive overall trend between mixed PAH exposure and female infertility, particularly when the mixture was at or above the 55th percentile, where 2-hydroxynaphthalene (2-OHNAP) and 1-hydroxypyrene (1-OHPYR) were the primary influences of the mixture. The univariate exposure-response function indicated positive associations between individual PAH exposure, specifically 2-OHNAP, 2-OHFLU, and 1-OHPYR, and female infertility. The QGC model also indicated a positive trend between exposure to a mixture of PAHs and female infertility, although it did not reach statistical significance (OR = 1.33, 95%CI: 0.86-2.07), with 1-OHPYR having the greatest positive effect on the outcome. This study suggested that exposure to PAHs may be associated with female infertility and further research is needed to consolidate and confirm these findings.

Association between Psoriasis and Renal Functions: An Integration Study of Observational Study and Mendelian Randomization.

Psoriasis is an autoimmune-mediated disease with several comorbidities in addition to typical skin lesions. Increasing evidence shows the relationships between psoriasis and renal functions, but the relationship and causality remain unclear. We aimed to investigate the associations and causality between psoriasis and four renal functions, including the estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), urine albumin to creatinine ratio (UACR), and chronic kidney disease (CKD). For the population-based study, we analyzed the National Health and Nutrition Examination Survey (NHANES) data from five cycles (2003-2006 and 2009-2014) on psoriasis and renal functions. Subgroup analyses were conducted among different categories of participants. Meanwhile, a bidirectional two-sample Mendelian randomization (TSMR) study in European populations was also performed using summary-level genetic datasets. Causal effects were derived by conducting an inverse-variance weighted (MR-IVW) method. A series of pleiotropy-robust MR methods was employed to validate the robustness. Multivariable MR (MVMR) was conducted to complement the result when five competing risk factors were considered. A total of 20,244 participants were enrolled in the cross-sectional study, where 2.6% of them had psoriasis. In the fully adjusted model, participants with psoriasis had significantly lower eGFR (p = 0.025) compared with the healthy group. Individuals who are nonoverweight are more likely to be affected by psoriasis, leading to an elevation of BUN (Pint = 0.018). In the same line, TSMR showed a negative association between psoriasis and eGFR (p = 0.016), and sensitive analysis also consolidated the finding. No causality was identified between psoriasis and other renal functions, as well as the inverse causality (p > 0.05). The MVMR method further provided quite consistent results when adjusting five confounders (p = 0.042). We detected a significant negative effect of psoriasis on eGFR, with marginal association between BUN, UACR, and CKD. The adverse of psoriasis on the renal should merit further attention in clinical cares.

Association between phthalates and sleep problems in the U.S. adult females from NHANES 2011-2014.

There is little research on the relationship between phthalates exposure and sleep problems in adult females, with existing studies only assessing the association between exposure to individual phthalates with sleep problems. We aimed to analyse the relationship between phthalates and sleep problems in 1366 US females aged 20 years and older from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) by age stratification. Multivariate logistic regression showed that the fourth quartile of MECPP increased the risk of sleep problems in females aged 20-39 compared with the reference quartile (OR: 1.87, 95% CI: 1.14, 3.08). The WQS index was significantly associated with the sleep problems in females aged 20-39. In the BKMR, a positive overall trend between the mixture and sleep problems in females aged 20-39. In this study, we concluded that phthalates might increase the risk of sleep problems in females aged 20-39.

The Association between Prenatal Per- and Polyfluoroalkyl Substances Exposure and Neurobehavioral Problems in Offspring: A Meta-Analysis.

Exposure to per- and polyfluoroalkyl substances (PFAS) during pregnancy has been suggested to be associated with neurobehavioral problems in offspring. However, current epidemiological studies on the association between prenatal PFAS exposure and neurobehavioral problems among offspring, especially attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are inconsistent. Therefore, we aimed to study the relationship between PFAS exposure during pregnancy and ADHD and ASD in offspring based on meta-analyses. Online databases, including PubMed, EMBASE, and Web of Science, were searched comprehensively for eligible studies conducted before July 2021. Eleven studies (up to 8493 participants) were included in this analysis. The pooled results demonstrated that exposure to perfluorooctanoate (PFOA) was positively associated with ADHD in the highest quartile group. Negative associations were observed between perfluorooctane sulfonate (PFOS) and ADHD/ASD, including between perfluorononanoate (PFNA) and ASD. There were no associations found between total PFAS concentration groups and neurobehavioral problems. The trial sequential analyses showed unstable results. Our findings indicated that PFOA and PFOS exposure during pregnancy might be associated with ADHD in offspring and that prenatal PFOS and PFNA exposure might be associated with ASD in offspring. According to the limited evidence obtained for most associations, additional studies are required to validate these findings.

Association between blood metal exposures and hyperuricemia in the U.S. general adult: A subgroup analysis from NHANES.

BACKGROUND: The relationship between metal exposure and hyperuricemia is still controversial, especially in certain population groups. METHODS: This cross-sectional study included adults from NHANES 2011-2016. Seven metals, including Pb, Cd, Hg, Mn, Se, Cu, and Zn, were detected in blood by ICP‒MS. Multivariable logistic regression, LASSO, and BKMR models were used to assess the effects of single and mixed metal exposures and hyperuricemia. Moreover, this association was analyzed by sex, BMI, and age. RESULTS: A total of 4074 individuals were included in our final analysis, and 825 (20.3%) people were classified as having hyperuricemia. In logistic regression, Pb (Q4: OR [95% CI]: 1.50 [1.00, 2.24]) was associated with hyperuricemia after adjusting for all covariates. LASSO penalized regression analysis further indicated positive associations of lead and zinc with hyperuricemia. In BKMR analysis, U-shaped dose‒response curves were generated for Se, Mn, Cu, and Zn when fixing the other metals in the 50th percentile. A significant positive trend was found between mixed metal exposure and hyperuricemia, in which blood Se, Zn, and Cd had the highest PIP (PIP = 0.651, 0.549, and 0.530, respectively). In weighted logistic regression, subgroup analyses revealed a significant association between Pb and hyperuricemia among the non-overweight group. Significant positive trends between mixed metals and hyperuricemia were found in the male and non-overweight groups in the BKMR models. CONCLUSION: Our study suggests that a higher concentration of mixed metal might increase the risk of hyperuricemia in U.S. adults. Males and people with a BMI under 25 are more likely to be affected.

Relationship between phthalates exposures and hyperuricemia in U.S. general population, a multi-cycle study of NHANES 2007-2016.

BACKGROUND: Phthalates exposure might cause kidney damage and a potential risk for hyperuricemia. However, direct evidence on phthalates and hyperuricemia is somewhat limited. OBJECTIVE: To examine associations between 10 phthalates metabolites and hyperuricemia in a large-scale representative of the U.S. METHODS: A cross-sectional study of 6865 participants aged over 20 from NHANES 2007-2016 was performed. All participants had complete data on ten phthalate metabolites (MECPP, MnBP, MEHHP, MEOHP, MiBP, cx-MiNP, MCOP, MCPP, MEP, MBzP), hyperuricemia, and covariates. We used multivariable logistics regression, restricted cubic splines (RCS) model, and Bayesian kernel machine regression (BKMR) models to assess single, nonlinear, and mixed relationships between phthalate metabolites and hyperuricemia. As a complement, we also assessed the relationship between phthalate metabolites and serum uric acid (SUA) levels. RESULTS: The multivariable logistics regression showed that MECPP, MEOHP, MEHHP, MBzP, and MiBP were generally positively associated with hyperuricemia (PFDR < 0.05), especially in MiBP (Q3 (OR (95 %): 1.31 (1.02, 1.68)) and Q4 (OR (95 %): 1.68 (1.27, 2.24)), compared to Q1). All ten phthalate metabolites had a linear dose-response relationship with hyperuricemia in the RCS model (P for non-linear >0.05). BKMR showed that mixed phthalate metabolites were associated with a higher risk of hyperuricemia, with MBzP contributing the most (groupPIP = 0.999, condPIP = 1.000). We observed the consistent results between phthalate metabolites and SUA levels in three statistical models. The relationship between phthalate metabolites and hyperuricemia remained in the sensitivity analysis. CONCLUSIONS: The present study suggests that exposure to phthalates, individually or jointly, might increase the risk of hyperuricemia. Since hyperuricemia influences on the quality of life, more explorations are needed to confirm these findings.

Association between Perfluoroalkyl and Polyfluoroalkyl Substances and Women's Infertility, NHANES 2013-2016.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are widely used in consumer products. However, the role of PFAS in infertility is still poorly understood. A total of 788 women from the 2013-2016 nationally representative NHANES were included to explore the association between PFAS exposure and self-reported infertility. Six PFAS, including PFDE, PFNA, PFHxS, n-PFOA, n-PFOS, and Sm-PFOS, were detected by online SPE-HPLC-TIS-MS/MS. We used the generalized linear regression model (GLM), generalized additive models (GAM), and Bayesian kernel machine regression (BKMR) to assess the single effects, non-linear relationships, and mixed effects on women's infertility, respectively. The prevalence of self-reported infertility was 15.54% in this study. In GLM, n-PFOA showed a negative association with self-reported infertility in women for the Q3 (OR: 0.396, 95% CI: 0.119, 0.788) and Q4 (OR: 0.380, 95% CI: 0.172-0.842) compared with Q1 (p for trend = 0.013). A negative trend was also observed in n-PFOS and ∑PFOS (p for trend < 0.05). In GAM, a non-linear relationship was revealed in Sm-PFOS, which exhibits a U-shaped relationship. The BKMR model indicated that there might be a joint effect between PFAS and women's infertility, to which PFNA contributed the highest effect (PIP = 0.435). Moreover, age stratification analysis showed a different dose-response curve in under and above 35 years old. Women under the age of 35 have a more noticeable U-shaped relationship with infertility. Therefore, the relatively low level of mixed PFAS exposure was negatively associated with self-reported infertility in women in general, and the impact of PFAS on infertility may vary among women of different age groups. Further studies are needed to determine the etiological relationship.

Association between mixed exposure of phthalates and cognitive function among the U.S. elderly from NHANES 2011-2014: Three statistical models.

BACKGROUND: Studies on the relationship between phthalate exposure and cognition in adults are sparse and inconsistent. These studies only assessed their association of single phthalates for one-time and the tools for assessing cognitive function were different. OBJECTIVE: We aimed to examine the association between mixed phthalates and cognition in the U.S elderly using three statistical models. METHODS: The generalized linear (GLM), weighted quantile sum (WQS), and Bayesian kernel machine regression (BKMR) models were used to evaluate the associations between mixed phthalates and the standardized z-scores of four cognitive tests [Immediate Recall test (IRT), Delayed Recall test (DRT), Animal Fluency test (AFT), and Digit Symbol Substitution test (DSST)] in participants aged over 60 years from NHANES 2011-2014. RESULTS: 835 individuals were included and the median raw scores of IRT, DRT, AFT, and DSST were 19 (IQR: 16-23), 6 (IQR: 5-8), 16 (IQR: 13-20), 46 (IQR: 35-59). In adjusted GLM, negative associations were observed between MECPP, MnBP, MCOP, MCPP, and the IRT z-scores; MCPP, MBzP, and the DRT z-scores. Positive relationships were found between MCOP, MCPP, and the AFT z-scores; MCPP and the DSST z-scores. The WQS index was associated with the IRT z-scores (ß(95%CI): -0.069(-0.118, -0.020)), where MCPP weighted the highest. In the BKMR, negative overall trends between the mixture and the IRT, DRT z-scores were observed when the mixture was at 40th to 65th percentile, 65th percentile or above it, respectively, where MnBP and MBzP drove the main effect of the mixture. CONCLUSION: This study is an academic exploration of the association between phthalates exposure and cognitive function, suggesting that exposure to phthalates might be associated with bad performance in IRT and DRT in the U.S. elderly.