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Smoking has caused great public health burdens in the global. Although socioeconomic factors have been confirmed to substantially influence smoking behaviors, the impact of comprehensive social deprivations on smoking behavior and related biological mechanisms are still unclear. Supported by UK Biobank cohort, we randomly divided 369,915 participants into discovery cohort (60%) and replication cohort (40%). We first tested the associations for index of multiple deprivation (IMD) and 7 IMD subdomains with ever-smoking and daily smoking frequency using regression models in both cohorts. Genome-wide by environment interaction study (GWEIS) was further conducted by using PLINK2.0 to detect the effects of the interactions between SNPs and IMD subdomains on two smoking behaviors. In discovery and replication cohorts, we observed the more deprivation status the individuals were in, the higher daily smoking frequency or risk to be ever smokers. And among the subdomains of IMD, income, education, health, living environment, and crime deprivation were positively associated with the risk of smoking behaviors, while employment deprivation was negatively correlated with smoking behaviors (all P < 0.0125). Totally, GWEIS analysis detected 23 shared significant socioeconomic-deprivation interacted loci for daily smoking frequency in two cohorts, such as rs116680599 at 2p16.3 (NRXN1, Pdiscovery = 7.68 × 10−14, Preplication = 1.96 × 10−2) and rs150451424 at 16p13.3 (RBFOX1, Pdiscovery = 1.89 × 10−10, Preplication = 1.96 × 10−2) interacting with employment deprivation. We illustrated the diverse effects of IMD on smoking behaviors and provided insights for the biological mechanisms of the interaction effects between socioeconomic deprivation with genetic factors on smoking behaviors. [ABSTRACT FROM AUTHOR]

Cigarette smoke (CS) facilitates adverse effects on the airway inflammation and treatment of asthma. Here, we investigated the mechanisms by which CS exacerbates asthma. The roles of IL-33 and IL-35 in asthma development were examined by treatment with IL-33 knockout (IL-33 KO) or transfection of adenovirus encoding IL-35 (Ad-IL-35) in a murine model of cigarette smoke-exposure asthma. Furthermore, the involvement of IL-33 and IL-35 in regulating DCs and Th2/Th17 cells was examined in a coculture system of DCs with CD4+ T cells. Additionally, we observed the effect of CpG-ODNs on the balance of IL-33 and IL-35. We show that CS and house dust mite (HDM) exposure induced IL-33 and suppressed IL-35 levels in cigarette smoke-exposure asthma in vivo and in vitro. Treatment with IL-33 KO or Ad-IL-35 significantly attenuated airway hyperreactivity, goblet hyperplasia, airway remodelling, and eosinophil and neutrophil infiltration in the lung tissues from asthmatic mice. Furthermore, we demonstrated reciprocal regulation between CS and HDM-modulated IL-33 and IL-35. Mechanistically, IL-33 KO (or anti-ST2) and Ad-IL-35 attenuated Th2- and Th17-associated inflammation by downregulating TSLP-DC signalling. Finally, administration of CpG-ODNs suppressed the expression of IL-33/ST2 and elevated the levels of IL-35, which is mainly derived from CD4+Foxp+ Tregs, to alleviate Th2- and Th17-associated inflammation by inhibiting the activation of BMDCs. Taken together, the IL-33/ST2 pathway drives the DC-Th2 and Th17 responses of cigarette smoke-exposure asthma, while IL-35 has the opposite effect. CpG-ODNs represent a potential therapeutic strategy for modulating the balance of IL-33 and IL-35 to suppress allergic airway inflammation. [ABSTRACT FROM AUTHOR]

We aim to explore the combined effects of the smoking and breastfeeding on offspring mental health outcomes. We used data from UK biobank (N = 342,846) to evaluate joint effect of breastfeeding and maternal smoke during pregnancy (MSDP) on seven adult offspring mental health outcomes (self-reported depression, depression score, self-reported anxiety, anxiety score, neuroticism score, self-harm, suicide). We stratified individuals to MSDP group and non-MSDP group as well as breastfeeding group and non-breastfeeding group. Multiple linear regression and logistic regressions analysis were performed between independent variables (MSDP or breastfeeding) and dependent variables separately (seven mental health outcomes) in each stratum. Effect estimates were expressed as β values and OR values. Sex, age, 10 principle components of population structure, smoking, alcohol use, and Townsend deprivation index were examined as covariates. At MSDP grouping level, coefficients (odds ratio [OR]) for association of breastfed as a baby with self-reported anxiety (category variable) were 0.87 (95%CI, (0.82–0.93), P = 1.74 × 10–5) in the MSDP group and 0.83 (95%CI, (0.79–0.87), P = 2.76 × 10–17) in the non-MSDP group. At breastfeeding grouping level, OR for association of MSDP and self-reported anxiety were 1.15 (95%CI, (1.10–1.20), P = 5.36 × 10–11) in breastfeeding group and 1.12(95%CI, (1.06–1.20), P = 2.02 × 10–4) in non-breastfeeding group. At MSDP grouping level, negatively associations were found for breastfeeding and anxiety score (continuable variable) in MSDP group (-0.04 SD change per SD change in MSDP, 95% CI, (− 0.06, − 0.02), P = 2.42 × 10–3) and non-MSDP group (-0.06 SD change per SD change in MSDP, 95%CI, (− 0.07, − 0.04), P = 1.70 × 10–11). At breastfeeding grouping level, positive association was found for MSDP and anxiety score in the breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.06–0.09), P = 1.49 × 10–20) and non-breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.05–0.09), P = 7.19 × 10–8). Compared with non-MSDP group, the protective effect (reflected by coefficients) of breastfeeding on anxiety in the MSDP decreased. Our preliminary study found MSDP may lower the protective effect of breastfeeding on the adult offspring anxiety, depression and neuroticism, providing useful recommendations for health care service via quitting smoking during pregnancy and encouraging prolonged breastfeeding. [ABSTRACT FROM AUTHOR]

We aim to explore the potential interaction effects of brain aging and gut microbiota on the risks of sleep, anxiety and depression disorders. The genome-wide association study (GWAS) datasets of brain aging (N = 21,407) and gut microbiota (N = 3,890) were obtained from published studies. Individual level genotype and phenotype data of psychiatric traits (including sleep, anxiety and depression) were all from the UK Biobank (N = 107,947–374,505). We first calculated the polygenic risk scores (PRS) of 62 brain aging modes and 114 gut microbiota taxa as the instrumental variables, and then constructed linear and logistic regression analyses to systematically explore the potential interaction effects of brain aging and gut microbiota on psychiatric disorders. We observed the interaction effects of brain aging and gut microbiota on sleep, anxiety and depression disorders, such as Putamen/caudate T2* vs. Rhodospirillales (β = -0.012, P = 8.4 × 10–4) was negatively associated with chronotype, Fornix MD vs. Holdemanella (β = -0.007, P = 1.76 × 10–2) was negatively related to general anxiety disorder (GAD) scores, and White matter lesions vs. Acidaminococcaceae (β = 0.019, P = 1.29 × 10–3) was positively correlated with self-reported depression. Interestingly, Putamen volume vs. Intestinibacter was associated with all three psychiatric disorders, including chronotype (negative correlation), GAD scores (positive correlation) and self-reported depression (positive correlation). Our study results suggest the significant impacts of brain aging and gut microbiota on the development of sleep, anxiety and depression disorders, providing new clues for clarifying the pathogenesis of these disorders. [ABSTRACT FROM AUTHOR]

Kashin-Beck disease (KBD) is a chronic, degenerative osteoarthropathy related to selenium (Se) deficiency. Se participates in the synthesis of selenoprotein in the form of selenocysteine. In total, 25 selenoproteins, encoded by 25 genes, are currently found in humans; however, the effects of selenoprotein genes on chondrocyte apoptosis, particularly in apoptosis-related genes, remain poorly elucidated. Therefore, in the current study, the expression of selenoprotein genes and apoptosis-related genes were determined by RT-qPCR in patients and chondrocytes and the correlations between them were analyzed using Pearson and Spearman's rank correlation, and the chondrocyte apoptosis rate was detected by Annexin V-FITC/PI. The results showed that the mRNA levels of 17 selenoprotein genes were downregulated, whereas two genes were upregulated in patients with KBD. The BAX/BCL2 ratio and the mRNA levels of BAX and P53 were increased, but the mRNA levels of BCL2 and NF-κB p65 were decreased in patients with KBD. The mRNA levels of GPX2, GPX3, DIO1, TXNRD1, TXNRD3, and SPS2 were most closely associated with apoptosis-related genes in patients with KBD. Moreover, in the Se deficiency group, the mRNA levels of GPX3, DIO1, and TXNRD1 were downregulated and GPX activity was decreased, but the late apoptosis rate, the mRNA levels of BAX and P53, and the BAX/BCL2 ratio were increased; the opposite trend was observed in the Se supplement group. Collectively, these results indicate that selenoprotein transcription profile is dysregulated in patients with KBD. Furthermore, the expression of GPX3, DIO1, and TXNRD1 genes might be involved in the development of chondrocyte apoptosis by affecting antioxidant capacity. [ABSTRACT FROM AUTHOR]

Introduction: The aims of the study were to investigate the relationship between aldehyde dehydrogenase 1 family member A2 (ALDH1A2) and Kashin-Beck disease (KBD), explore the effects of the rs3204689 polymorphism and methylation status on the expression levels of ALDH1A2, and further clarify the pathogenesis of KBD. Materials and methods: The genotype of ALDH1A2 rs3204689 was detected by PCR–RFLP in 103 KBD patients and 109 healthy controls in the whole blood. The mRNA level of ALDH1A2 was measured by qRT-PCR, and the protein expression was detected using IHC staining and Western blotting. The MSP-PCR was used to identify the ALDH1A2 methylation level. Results: There were significant differences in G/G, G/C, and C/C frequencies of ALDH1A2 rs3204689 between the KBD and control groups (χ2 = 7.113, P = 0.029); the minor allele G of ALDH1A2 was associated with the risk of KBD (χ2 = 5.984, P = 0.014). The mRNA and protein levels of ALDH1A2 were increased in the whole blood and cartilage of KBD patients compared with the controls (P = 0.049, P < 0.0001, P = 0.019). Meanwhile, a statistically significant difference was observed between G/G, G/C and C/C genotype on mRNA expression (P = 0.039). The methylation level of the ALDH1A2 gene promoter region showed no significant difference between the KBD and control groups (χ2 = 0.317, P = 0.573). Conclusion: Our case–control study indicates that the common variant rs3204689 near ALDH1A2 is associated with KBD in Chinese population. The risk allele G of rs3204689 is statistically linked to the high expression of ALDH1A2, which is up-regulated in the cartilage and whole blood of KBD patients. Our findings suggest a potential role of ALDH1A2 in the pathogenesis of KBD. [ABSTRACT FROM AUTHOR]

The abnormal timing of pubertal development is a risk factor for addictive disorders among adolescents. However, whether the precocious or late puberty has influence on addiction in adults remains unclear. Based on the data of 336,398 European participants in the UK Biobank, we explored the associations between secondary sexual characteristics (SSCs) outset time abnormality and addiction with observational analyses. Linkage disequilibrium score regression (LDSC) was conducted to test for the genetic correlation between them. For significant genetic associations, two-sample Mendelian randomization (MR) analyses were further performed for causal inferences. The genetic instruments were derived from genome-wide association studies of early menarche (N = 165,862), late first facial hair grows (N = 141,210) and late voice broke (N = 138,461). Observational analyses detected several significant associations between SSCs outset time abnormality and addiction, such as early menarche vs addiction to any substance or behavior (OR = 1.37, PFDR = 3.31 × 10−4) and late first facial hair grows vs alcohol addiction (OR = 1.24, PFDR = 2.40 × 10−15). MR analyses found genetically predicted early menarche was causally associated with higher risk of tobacco addiction (OR = 1.35, 95% CI: 1.15–1.58, PIVW = 0.0002) and addiction to any substance or behavior (OR = 1.39, 95% CI: 1.12–1.73, PIVW = 0.003). Our findings suggest the prevention and treatment for precocious puberty might be protective factors for addiction in female adults. Early preventive interventions for addictive behaviors are needed for females at high risk. [ABSTRACT FROM AUTHOR]