Type 2 diabetes, glycaemic traits, structural brain capacity and cognitive function: A Mendelian randomization analysis.

AIM: To estimate the causal associations of type 2 diabetes and glycaemic traits with cognitive function, and to determine the potential mediating role of various brain imaging-derived phenotypes (IDPs) using Mendelian randomization (MR) analysis. METHODS: Using publicly available summary data, we performed a series of univariable and multivariable MR analysis to infer causality. Two-step MR analysis was then conducted in turn to evaluate the potential mediating role of each brain IDP. RESULTS: There was no evidence of causal associations between type 2 diabetes and cognitive function outcomes. Each 1-SD unit higher genetically predicted fasting proinsulin was associated with worse cognitive performance, as evidenced by both univariable (beta: -0.022; 95% confidence interval [CI] -0.038, -0.007) and multivariable MR analysis (beta: -0.027; 95% CI -0.048, -0.005). In addition, the univariable MR analysis identified several causal associations between fasting proinsulin and brain IDPs, and between brain IDPs and cognitive performance. The inverse association of genetically predicted fasting proinsulin with cognitive performance did not attenuate after adjusting for each of the brain IDPs in multivariable MR analysis. CONCLUSIONS: The present MR study provided credible evidence for the causal association between genetically predicted fasting proinsulin and cognitive function, informing a potential diagnosis and intervention target for patients with cognitive impairment. No significant brain IDP included in this study was identified as lying on the causal pathway from fasting proinsulin to cognitive performance. Future research involving more specific and granular brain IDP or other brain process is warranted to explore the potential biological mechanism underlying the association.

Causal relationship between air pollution and chronic obstructive pulmonary disease in European and East Asian populations: a Mendelian randomization study.

Epidemiologic studies have suggested a possible association between air pollution and chronic obstructive pulmonary disease (COPD), but it is controversial and difficult to draw causal inferences. Five methods were adopted to evaluate the causal relationship between air pollution and COPD in European and East Asian populations by using MR Analysis. A statistically significant causal relationship between PM2.5 and COPD was observed in the European population (OR: 2.34; 95% CI: 1.06-5.05; p = 0.033). Statistical significance remained after adjustment for confounding factors (adjusted OR: 2.28; 95% CI: 1.01-5.20; p = 0.048). In East Asian populations, PM2.5 absorbance, a proxy for black carbon, was statistically associated with COPD (OR: 1.41; 95% CI: 1.09-1.81; p = 0.007). We did not adjust for confounders in East Asian populations, as the association was independent of known confounders (e.g. smoking, respiratory tract infections, etc.). In conclusion, increased concentrations of PM2.5 and PM2.5 absorbance were associated with an increased risk of COPD.

Associated factors of undernutrition in children with congenital heart disease: a cross-sectional study.

Objective: To evaluate the prevalence and associated factors of undernutrition among children with congenital heart disease (CHD) who have not undergone surgeries in China. Methods: This cross-sectional study included 734 CHD children along with their parents. The outcome of interest was undernutrition, including underweight, wasting, and stunting, defined as Z-scores (i.e., weight-for-age, weight-for-height, and height-for-age) ≤-2, according to the World Health Organization (WHO) growth standard. Exposures of interest, containing demographics, obstetric factors, maternal dietary factors, parents' life behaviors and habits, birth-related factors, cardiac-related factors, and preoperative factors, were analyzed using a multivariate logistic regression model to test their associations with undernutrition in CHD children. Results: Overall, 36.1%, 29.7%, and 21.3% of cases were underweight, wasted, and stunted, respectively. Multivariate logistic regression indicated that underweight was associated with demographic factors (including parents' occupational status, family income, and maternal body mass index pre-pregnancy), low birth weight (OR = 4.60, 2.76-7.70), pulmonary hypertension (OR = 4.46, 3.09-6.43), and pneumonia (OR = 1.88, 1.28-2.76). Artificially-fed children were 2.34 (1.36-4.01) times more likely to be underweight. Occupied mothers (OR = 0.62, 0.44-0.88) and fathers (OR = 0.49, 0.26-0.92) served as protective factors, while mothers having gestational complications (OR = 1.56, 1.11-2.18) and exposed to noisy environment (OR = 1.64, 1.11-2.42) during this pregnancy, and pulmonary hypertension (OR = 3.21, 2.30-4.49) increased the chance of wasting in offspring. The odds of being stunted were greater in families with >2 children (OR = 1.88, 1.13-3.14), placental abruption during this pregnancy (OR = 25.15, 2.55-247.89), preterm births (OR = 1.84, 1.02-3.31), low birth weight (OR = 3.78, 2.16-6.62), pulmonary hypertension (OR = 2.35, 1.56-3.53) and pneumonia (OR = 1.93, 1.28-2.90). In subgroup analyses, the associations differed between patients with different feeding patterns (breastfeeding vs. non-breastfeeding), CHD classifications (cyanotic vs. acyanotic), and prematurity (preterm vs. non-preterm). Conclusion: Undernutrition is common in preoperative CHD children. Familial demographics, maternal factors (including having gestational complications and exposure to noisy environment during pregnancy), and patient-related factors (encompassing preterm births, low birth weight, pulmonary hypertension, pneumonia, and feeding pattern) were found to contribute to undernutrition in CHD cases. However, associated factors among the three subgroups of distinct feeding patterns, CHD categorization, and prematurity exhibited varied outcomes, suggesting the necessity for targeted interventions.

Maternal anaemia during early pregnancy and the risk of neonatal outcomes: a prospective cohort study in Central China.

BACKGROUND: The purpose of this study was to explore the association between anaemia during early pregnancy and the risk of neonatal outcomes. METHODS: We collected clinical data from pregnant women (≥18 years) who received their first antenatal care between 8 and 14 weeks of gestation in Hunan Provincial Maternal and Child Health Care Hospital. Multiple logistic regression models and restricted cubic spline regression models were used to analyse the association between anaemia during early pregnancy and the risk of neonatal outcomes. In addition, sensitivity analysis was further performed to assess the robustness of the results. RESULTS: The prospective cohort study ultimately included 34 087 singleton pregnancies. In this study, the rate of anaemia during early pregnancy was 16.3%. Our data showed that there was a positive relationship between the rate of preterm birth, low birth weight as well as small for gestational age (SGA) and the severity of maternal anaemia (Ptrend<0.05). After adjustment, the association of early pregnancy anaemia and haemoglobin (Hb) levels with the risk of preterm birth (mild anaemia adjusted OR (aOR) 1.37 (95% CI 1.25 to 1.52), moderate anaemia aOR 1.54 (95% CI 1.35 to 1.76) and severe anaemia aOR 4.03 (95% CI 2.67 to 6.08), respectively), low birth weight (mild anaemia aOR 1.61 (95% CI 1.44 to 1.79), moderate anaemia aOR 2.01 (95% CI 1.75 to 2.30) and severe anaemia aOR 6.11 (95% CI 3.99 to 9.36), respectively) and SGA (mild anaemia aOR 1.37 (95% CI 1.25 to 1.52), moderate anaemia aOR 1.54 (95% CI 1.35 to 1.76) and severe anaemia aOR 2.61 (95% CI 1.74 to 4.50), respectively; Pnon-linear<0.05) was observed. However, no association was found between early pregnancy anaemia or Hb levels and the risk of congenital malformations. Sensitivity analysis verified the stability of the results. CONCLUSIONS: Maternal anaemia during early pregnancy was associated with an increased risk of preterm birth, low birth weight and SGA and their rates may increase with the severity of maternal anaemia. TRIAL REGISTRATION NUMBER: ChiCTR1800016635.

The risk of attention-deficit hyperactivity disorder among children with congenital heart disease: A systematic review and meta-analysis.

BACKGROUND: Although current treatments are effective in dealing with congenital heart disease (CHD), non-cardiac comorbidities such as attention-deficit hyperactivity disorder (ADHD) have received widespread attention. The purpose of this systematic review and meta-analysis is to assess the risk of ADHD associated with CHD. METHODS: The literature search was carried out systematically through eight different databases by the end of September 2022. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. The heterogeneity of the studies was assessed by the Cochran Q test and the I2 statistic. Subgroup and sensitivity analyses were used to explore the potential sources of heterogeneity. RESULTS: Eleven studies were included in this study, which involved a total of 296 741 participants. Our study showed that the children with CHD were at a significantly increased risk of ADHD compared with the reference group (OR = 2.98, 95% CI: 2.18-4.08). The results were moderately heterogeneous. These factors including study design, geographic region and study quality were identified as the first three of the most relevant heterogeneity moderators by subgroup analyses. Sensitivity analysis yielded consistent results. There was no evidence of publication bias. CONCLUSIONS: The present study suggests that CHD children have a significantly higher risk of ADHD when compared with those without CHD. Early identification and intervention of ADHD is important to reduce its symptoms and adverse effects; therefore, clinicians should increase screening for ADHD in children with CHD and intervene promptly to reduce its effects whenever possible.

Associations between maternal syphilis infection during pregnancy and low birth weight and preterm birth: a prospective cohort study.

BACKGROUND: In recent years, syphilis is still the most common sexually transmitted disease worldwide. Pregnant women infected with syphilis can transmit it to the fetus in utero through mother-to-child transmission, which can directly lead to adverse pregnancy outcomes. The aim of this study was to investigate the associations between maternal syphilis infection and low birth weight and preterm birth in offspring. METHODS: Multinomial logistic regression model was used to analyze the associations between maternal syphilis infection and low birth weight and preterm birth, and to explore its stability through subgroup analysis. RESULTS: A total of 34,074 subjects were included in the study. After adjusting for potential confounders, maternal syphilis infection during pregnancy was associated with a 2.60-fold (95% CI 1.83-3.69) increased risk of low birth weight and a 1.91-fold (95% CI 1.35-2.69) increased risk of preterm birth. Subgroup analysis showed that the association was stable. CONCLUSION: We found that maternal syphilis infection during pregnancy was significantly associated with an increased risk of low birth weight and preterm birth. The implementation of reasonable syphilis screening and standardized treatment and follow-up of pregnant syphilis may have important practical significance in reducing the low birth weight and preterm birth rate in offspring.

Relationships between Maternal Folic Acid Supplementation and GATA4 Gene Polymorphisms in Patients with Non-Chromosomal Congenital Heart Disease: A Hospital-Based Case-Control Study in China.

This study aimed to investigate the relationships between maternal FA supplementation and nine single-nucleotide variants of the GATA4 gene in non-chromosomal CHD and further explore the gene-environment interactions associated with CHD. A total of 585 CHD patients and 600 controls were recruited in the case-control study. Maternal FA (FA-containing multivitamin) supplementation information and nine polymorphisms of the GATA4 gene were collected in this study. Adjusted ORs (aOR) and their 95% confidence intervals (CIs) were calculated using proper statistical methods to analyze the relationships between the two main exposures of interest with respect to CHD. After adjusting the suspicious confounding factors, a significantly increased risk for CHD in offspring was found with non-FA supplementation before/during the pregnancy to CHD in offspring (aOR = 1.58, 95% CI: 1.01-2.48). We suggested taking FA supplementation before/during the pregnancy to prevent CHD in offspring, especially in the preconception period (aOR = 0.53, 95% CI: 0.32-0.90). The genetic results showed that the polymorphisms of rs4841588, rs12458, and rs904018 under specific genotypes and genetic models were significantly related to CHD. The gene-environment interaction between rs10108052 and FA supplementation before/during pregnancy could increase the risk of CHD (aOR = 5.38, 95% CI: 1.67-17.09, Pinteraction = 0.004). Relationships between maternal FA supplementation and specific polymorphisms of the GATA4 gene, as well as the gene-environment interaction, were significantly associated with CHD in offspring.

Association between gut microbiome and intracerebral hemorrhage based on genome-wide association study data. / 基于GWASæ•°æ®åˆ†æžè‚ é“èŒç¾¤ä¸Žè„‘å‡ºè¡€çš„å ³ç³».

OBJECTIVES: Intracerebral hemorrhage (ICH) has the highest mortality and disability rates among various subtypes of stroke. Previous studies have shown that the gut microbiome (GM) is closely related to the risk factors and pathological basis of ICH. This study aims to explore the causal effect of GM on ICH and the potential mechanisms. METHODS: Genome wide association study (GWAS) data on GM and ICH were obtained from Microbiome Genome and International Stroke Genetics Consortium. Based on the GWAS data, we first performed Mendelian randomization (MR) analysis to evaluate the causal association between GM and ICH. Then, a conditional false discovery rate (cFDR) method was conducted to identify the pleiotropic variants. RESULTS: MR analysis showed that Pasteurellales, Pasteurellaceae, and Haemophilus were negatively correlated with the risk of ICH, whileVerrucomicrobiae, Verrucomicrobiales, Verrucomicrobiaceae, Akkermansia, Holdemanella, and LachnospiraceaeUCG010 were positively correlated with ICH. By applying the cFDR method, 3 pleiotropic loci (rs331083, rs4315115, and rs12553325) were found to be associated with both GM and ICH. CONCLUSIONS: There is a causal association and pleiotropic variants between GM and ICH.

Association of Maternal Folate Intake and Offspring MTHFD1 and MTHFD2 Genes with Congenital Heart Disease.

Existing evidence supported that congenital heart defect (CHD) was associated with a combination of environmental and genetic factors. Based on this, this study aimed at assessing the association of maternal folic acid supplementation (FAS), genetic variations in offspring methylenetetrahydrofolate dehydrogenase (MTHFD)1 and MTHFD2 genes, and their interactions with CHD and its subtypes. A hospital-based case-control study, including 620 cases with CHD and 620 healthy children, was conducted. This study showed that the absence of FAS was significantly associated with an increased risk of total CHD and its subtypes, such as atrial septal defect (ASD). FAS during the first and second trimesters was associated with a significantly higher risk of CHD in offspring compared to FAS during the three months prior to conception. The polymorphisms of offspring MTHFD1 and MTHFD2 genes at rs2236222, rs11849530, and rs828858 were significantly associated with the risk of CHD. Additionally, a significantly positive interaction between maternal FAS and genetic variation at rs828858 was observed for the risk of CHD. These findings suggested that pregnant women should carefully consider the timing of FAS, and individuals with higher genetic risk may benefit from targeted folic acid supplementation as a preventive measure against CHD.

Association between air pollution and primary liver cancer in European and east Asian populations: a Mendelian randomization study.

Purpose: The incidence of primary liver cancer is increasing year by year, with environmental factors playing a non-negligible role. At present, many studies are still disputing whether air pollution is associated with primary liver cancer incidence, and it is difficult to draw causal inferences. Therefore, in this study, we used two-sample Mendelian randomization (MR) to assess the causal relationship between air pollution (including PM2.5, PM2.5-10, PM10, nitrogen dioxide and nitrogen oxides) and primary liver cancer risk and its related biomarkers (Alpha-fetoprotein, Osteopontin, Glypican-3 and Arginase-1). Patients and methods: We used large-scale publicly available genome-wide association studies (GWAS) summary data to conduct MR analyses of European and East Asian populations. Inverse variance weighted (IVW) method was used as the main analysis method, and weighted median model, MR-Egger, simple model and weighted model methods were selected for quality control. Heterogeneity was checked by the Cochran's Q test. The MR-Egger regression and the MR-PRESSO global test detect pleiotropy. The sensitivity analysis was performed using the leave-one-out method. Results: Between air pollution and primary liver cancer in either European (PM2.5: p = 0.993; PM2.5-10: p = 0.833; PM10: p = 0.257; nitrogen dioxide: p = 0.215; nitrogen oxides: p = 0.614) or East Asian (PM2.5: p = 0.718; PM2.5-10: p = 0.362; PM10: p = 0.720; nitrogen dioxide: p = 0.101; nitrogen oxides: p = 0.760) populations were found no statistical association. Notably, there was a causal relationship between nitrogen oxides and Arginase-1, a biomarker associated with hepatocellular differentiation, statistically significant associations remained after deletion for single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency, Body mass index (BMI) and cancers (Beta: 4.46; 95%CI: 0.83-8.08; p = 0.015). There was no heterogeneity or pleiotropy in the results. Conclusion: This MR study found no evidence to support a causality between air pollution and primary liver cancer in European and East Asian populations, but nitrogen oxides may affect hepatocellular differentiation.

Association of the rs1990760, rs3747517, and rs10930046 polymorphisms in the IFIH1 gene with susceptibility to autoimmune diseases: a meta-analysis.

Objective: Interferon induced with helicase C domain 1 (IFIH1) single-nucleotide polymorphisms (SNP) rs1990760, rs3747517, and rs10930046 have been shown to be closely related to the risk of autoimmune diseases. The aim of this study was firstly to examine the association of the rs1990760 with type 1 diabetes (T1D) in a Chinese population. Secondly, to assess the association of SNP rs1990760, rs3747517, and rs10930046 with autoimmune diseases susceptibility. Methods: A total of 1,273 T1D patients and 1,010 healthy control subjects in a Chinese population were enrolled in this case-control study. Subsequently, we performed a meta-analysis on the association of the SNP rs1990760, rs3747517, and rs10930046 in the IFIH1 gene with susceptibility to autoimmune diseases. The random and fixed genetic effects models were used to evaluate the association and the effect sizes, including odds ratios (OR) and 95% confidence intervals (CI). Stratification analyses based on ethnicity and the type of autoimmune diseases were performed. Results: IFIH1 SNP rs1990760 was not associated with a significant risk of T1D in the Chinese population in the case-control study. A total of 35 studies including 70,966 patients and 124,509 controls were identified and included in the meta-analysis. The results displayed significant associations between IFIH1 rs1990760 A allele and rs3747517 C allele and autoimmune diseases risk (OR=1.09, 95% CI: 1.01~1.17; OR=1.24, 95% CI: 1.15~1.25, respectively). Stratified analysis indicated a significant association rs1990760 and rs3747517 with autoimmune diseases risk in the Caucasian population (OR=1.11, 95% CI: 1.02~1.20, OR=1.29, 95% CI: 1.18~1.41, respectively). Conclusions: This study revealed no association between IFIH1 SNP rs1990760 and T1D in Chinese. Furthermore, the meta-analysis indicated that rs1990760 and rs3747517 polymorphisms, confer susceptibility to autoimmune diseases, especially in the Caucasian population.

Fertility intentions to have a second or third child among the childbearing-age population in Central China under China's three-child policy: A cross-sectional study.

Background: On May 31, 2021, the Chinese authorities announced that couples can have up to three children, aiming to stimulate a rise in fertility levels. However, there is limited research on second and third birth intentions of the childbearing-age population under China's three-child policy, and the existing results are inconsistent. Methods: A cross-sectional survey was performed in Central China from June to August 2022. A total of 13 479 respondents aged 20-49 were enrolled in the study through a multi-stage sampling method. Data on the intentions to have a second or third child were collected using anonymized questionnaires. Descriptive statistics were performed to assess fertility intentions. Multivariate logistic regression analyses were used to assess the associations between fertility intentions and the related factors. Results: Among families with a single child, 29.7% (1444 / 4859) of the respondents intended to have a second child, while among two-child families, 10.6% (750 / 7056) respondents intended to have a third child. Overall, participants indicated that the ideal number of children was 1.85 ± 0.52. The age-specific fertility intentions of the one-child families were always higher than those of two-child families; however, based on couples' age groups, the number of ideal children reported by two-child families was always higher than that of one-child families. Fertility intentions were influenced by the respondents' gender, age, residence, marital status, educational level, average working time, childcare support, marital satisfaction, accessibility of educational resources, health condition of both spouses, loan situation, size of living house and the gender of the first child or second child. Conclusions: The general prevalence of the second and third birth intention of the childbearing-age population in Central China is not high. To increase the birth rate, it is necessary to create a favourable fertility context and offer supportive measures.

Gut microbiota and type 1 diabetes: a two-sample bidirectional Mendelian randomization study.

Objective: The real causal relationship between human gut microbiota and T1D remains unclear and difficult to establish. Herein, we adopted a two-sample bidirectional mendelian randomization (MR) study to evaluate the causality between gut microbiota and T1D. Methods: We leveraged publicly available genome-wide association study (GWAS) summary data to perform MR analysis. The gut microbiota-related GWAS data from 18,340 individuals from the international consortium MiBioGen were used. The summary statistic data for T1D (n = 264,137) were obtained from the latest release from the FinnGen consortium as the outcome of interest. The selection of instrumental variables conformed strictly to a series of preset inclusion and exclusion criteria. MR-Egger, weighted median, inverse variance weighted (IVW), and weighted mode methods were used to assess the causal association. The Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis were conducted to identify heterogeneity and pleiotropy. Results: At the phylum level, only Bacteroidetes was indicated to have causality on T1D (OR = 1.24, 95% CI = 1.01-1.53, P = 0.044) in the IVW analysis. When it comes to their subcategories, Bacteroidia class (OR = 1.28, 95% CI = 1.06-1.53, P = 0.009, P FDR = 0.085), Bacteroidales order (OR = 1.28, 95% CI = 1.06-1.53, P = 0.009, P FDR = 0.085), and Eubacterium eligens group genus (OR = 0.64, 95% CI = 0.50-0.81, P = 2.84×10-4, P FDR = 0.031) were observed to have a causal relationship with T1D in the IVW analysis. No heterogeneity and pleiotropy were detected. Conclusions: The present study reports that Bacteroidetes phylum, Bacteroidia class, and Bacteroidales order causally increase T1D risk, whereas Eubacterium eligens group genus, which belongs to the Firmicutes phylum, causally decreases T1D risk. Nevertheless, future studies are warranted to dissect the underlying mechanisms of specific bacterial taxa's role in the pathophysiology of T1D.

Association of MTR gene polymorphisms with the occurrence of non-syndromic congenital heart disease: a case-control study.

To exhaustively explore the association of infant genetic polymorphisms of methionine synthase (MTR) gene with the risk of non-syndromic congenital heart disease (CHD). A hospital-based case-control study involving 620 CHD cases and 620 health controls was conducted from November 2017 to March 2020. Eighteen SNPs were detected and analyzed. Our date suggested that the genetic polymorphisms of MTR gene at rs1805087 (GG vs. AA: aOR = 6.85, 95% CI 2.94-15.96; the dominant model: aOR = 1.77, 95% CI 1.35-2.32; the recessive model: aOR = 6.26, 95% CI 2.69-14.54; the addictive model: aOR = 1.81, 95% CI 1.44-2.29) and rs2275565 (GT vs. GG: aOR = 1.52, 95% CI 1.15-1.20; TT vs. GG: aOR = 4.93, 95% CI 1.93-12.58; the dominant model: aOR = 1.66, 95% CI 1.27-2.17; the recessive model: aOR = 4.41, 95% CI 1.73-11.22; the addictive model: aOR = 1.68, 95% CI 1.32-2.13) were significantly associated with the higher risk of CHD. And three haplotypes of G-A-T (involving rs4659724, rs95516 and rs4077829; OR = 5.48, 95% CI 2.58-11.66), G-C-A-T-T-G (involving rs2275565, rs1266164, rs2229276, rs4659743, rs3820571 and rs1050993; OR = 0.78, 95% CI 0.63-0.97) and T-C-A-T-T-G (involving rs2275565, rs1266164, rs2229276, rs4659743, rs3820571 and rs1050993; OR = 1.60, 95% CI 1.26-2.04) were observed to be significantly associated with risk of CHD. Our study found that genetic polymorphisms of MTR gene at rs1805087 and rs2275565 were significantly associated with higher risk of CHD. Additionally, our study revealed a significant association of three haplotypes with risk of CHD. However, the limitations in this study should be carefully taken into account. In the future, more specific studies in different ethnic populations are required to refine and confirm our findings.Trial registration: Registration number: ChiCTR1800016635; Date of first registration: 14/06/2018.

Association of maternal methionine synthase reductase gene polymorphisms with the risk of congenital heart disease in offspring: a hospital-based case-control study.

BACKGROUND: Evidence suggests that periconceptional folic acid supplementation may prevent congenital heart disease (CHD). Methionine synthase reductase (MTRR) is one of the key regulatory enzymes in the folate metabolic pathway. This study aimed to comprehensively evaluate the association of single nucleotide polymorphisms (SNPs) in the maternal MTRR gene with CHD risk in offspring. METHODS: A hospital-based case-control study involving 740 mothers of CHD cases and 683 health controls was conducted. RESULTS: The study showed that maternal MTRR gene polymorphisms at rs1532268 (C/T vs. C/C: aOR = 1.524; T/T vs. C/C: aOR = 3.178), rs1802059 (G/A vs. G/G: aOR = 1.410; A/A vs. G/G: aOR = 3.953), rs2287779 (G/A vs. G/G: aOR = 0.540), rs16879334 (C/G vs. C/C: aOR = 0.454), and rs2303080 (T/A vs. T/T: aOR = 0.546) were associated with the risk of CHD. And seven haplotypes were observed to be associated with the risk of CHD, T-G-A haplotype (OR = 1.298), C-A-C-C (OR = 4.824) and A-G haplotype (OR = 1.751) were associated with increased risk of CHD in offspring; A-A-A (OR = 0.773), T-A-A (OR = 0.557), G-A-C-C (OR = 0.598) and G-C (OR = 0.740) were associated with decreased risk of CHD in offspring. CONCLUSIONS: Maternal MTRR gene polymorphisms were associated with CHD in offspring, and its haplotypes have affected the occurrence of CHD. Furthermore, given the complexity and heterogeneity of CHD, the mechanisms by which these factors influence offspring cardiac development remain unknown, and studies in larger samples in an ethnically diverse population are needed.

Effect of the interaction between advanced maternal age and pre-pregnancy BMI on pre-eclampsia and GDM in Central China.

INTRODUCTION: To investigate the independent and combined effects of advanced maternal age and pre-pregnancy body mass index (BMI) on the risk of pre-eclampsia and gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: Logistic regression models were used to estimate the OR and 95% CIs of pre-eclampsia and GDM with advanced maternal age and pre-pregnancy BMI, respectively, and the interaction between advanced maternal age and pre-pregnancy BMI. We also used causal mediation analysis to assess the mediating role of pre-pregnancy BMI on maternal age-pre-eclampsia/GDM associations. RESULTS: In this study, 788 cases (2.31%) were diagnosed with pre-eclampsia and 5430 cases (15.92%) were diagnosed with GDM. We found that advanced maternal age was associated with a higher risk for pre-eclampsia and GDM, with adjusted ORs (aORs) of 1.74 (95% CI 1.49-2.05) and 1.76 (95% CI 1.65-1.89) after adjusting for potential confounders, respectively. In addition, maternal pre-pregnancy overweight/obesity was associated with the risk of pre-eclampsia and GDM, with the corresponding aORs of 3.64 (95% CI 3.12-4.24) and 1.71 (95% CI 1.60-1.85), respectively. We also observed the interaction between maternal age and pre-pregnancy BMI for the risk of pre-eclampsia/GDM (all p for interaction <0.001). In the mediating effect analysis, we found that maternal pre-pregnancy BMI mediated the associations between maternal age and the development of pre-eclampsia and GDM. CONCLUSIONS: Advanced maternal age and pre-pregnancy BMI were respectively associated with the risk of pre-eclampsia/GDM, and there was an interaction between the two risk factors. In addition, we found that pre-pregnancy BMI served as a mediator of the association between advanced maternal age and the risk of pre-eclampsia/GDM, providing an essential target for the prevention of maternal overweight/obesity.

Obesity and risk of gestational diabetes mellitus: A two-sample Mendelian randomization study.

AIMS: To estimate genetically predicted causal associations of general and central obesity with GDM, and to determine the mediating role of circulating lipids. METHODS: Summary-level data was obtained from the largest available genome-wide association studies of five obesity traits, five lipid traits and GDM. Two-sample univariate Mendelian randomization (MR), multivariate MR, and MR-based mediation analysis was applied to determine the total effect, direct effect and the mediating effect, respectively. RESULTS: Univariate MR showed that the odds of GDM increased per 1-SD increase in body mass index (BMI) (OR = 1.64, P = 5.05 × 10-17), waist-to-hip ratio (WHR) (OR = 1.57, P = 2.27 × 10-14) and WHR adjusted for BMI (OR = 1.42, P = 6.11 × 10-15). The heterogeneous associations of waist circumference (OR = 1.64, P = 5.57 × 10-14) and hip circumference (OR = 1.20, P = 0.002) on GDM further reflected that body fat distribution could influence GDM risk. Mediation analysis suggested that triglycerides, high-density lipoprotein-cholesterol and apolipoprotein A-I each mediated between 5% and 10% of the association between obesity and GDM. CONCLUSION: Our findings supported a deleterious causal effect of obesity on GDM risk, where lipid metabolism acted as potential drivers of the relationships between both general and central obesity and GDM.

Association of Maternal Betaine-Homocysteine Methyltransferase (BHMT) and BHMT2 Genes Polymorphisms with Congenital Heart Disease in Offspring.

To systematically explore the association of single nucleotide polymorphisms (SNPs) of maternal BHMT and BHMT2 genes with the risk of congenital heart disease (CHD) and its three subtypes including atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) in offspring. A hospital-based case-control study involving 683 mothers of CHD children and 740 controls was performed. Necessary exposure information was captured through epidemiological investigation. Totally twelve SNPs of maternal BHMT and BHMT2 genes were detected and analyzed systematically. The study showed that maternal BHMT gene polymorphisms at rs1316753 (CG vs. CC: OR = 1.96 [95% CI 1.41-2.71]; GG vs. CC: OR = 1.99 [95% CI 1.32-3.00]; dominant model: OR = 1.97 [95% CI 1.44-2.68]) and rs1915706 (TC vs. TT: OR = 1.93 [95% CI 1.44-2.59]; CC vs. TT: OR = 2.55 [95% CI 1.38-4.72]; additive model: OR = 1.77 [95% CI 1.40-2.24]) were significantly associated with increased risk of total CHD in offspring. And two haplotypes were observed to be significantly associated with risk of total CHD, including C-C haplotype involving rs1915706 and rs3829809 in BHMT gene (OR = 1.30 [95% CI 1.07-1.58]) and C-A-A-C haplotype involving rs642431, rs592052, rs626105, and rs682985 in BHMT2 gene (OR = 0.71 [95% CI 0.58-0.88]). Besides, a three-locus model involving rs1316753 (BHMT), rs1915706 (BHMT), and rs642431 (BHMT2) was identified through gene-gene interaction analyses (P < 0.01). As for three subtypes including ASD, VSD, and PDA, significant SNPs and haplotypes were also identified. The results indicated that maternal BHMT gene polymorphisms at rs1316753 and rs1915706 are significantly associated with increased risk of total CHD and its three subtypes in offspring. Besides, significant interactions between different SNPs do exist on risk of CHD. Nevertheless, studies with larger sample size in different ethnic populations and involving more SNPs in more genes are expected to further define the genetic contribution underlying CHD and its subtypes.

Parental pre-pregnancy body mass index and risk of low birth weight in offspring: A prospective cohort study in central China.

Background: Low birth weight (LBW) is one of the most common adverse pregnancy outcomes. Previous studies have consistently shown that maternal body mass index (BMI) status before and during pregnancy is associated with LBW. However, previous studies lacked an association between paternal BMI and the conjunction effect of a couple's BMI and LBW in the offspring. Therefore, we established a cohort of pre-pregnancy couples to prospectively assess the relationship between maternal and paternal pre-pregnancy BMI and offspring LBW, very low birth weight (VLBW), and extremely low birth weight (ELBW). Methods: A prospective cohort study was established in Central China. A total of 34,104 pregnant women with singleton pregnancies at 8-14 gestational weeks and their husbands were finally enrolled and followed to 3 months postpartum. The multivariate logistic regression and restrictive cubic spline model were used to explore the relationship between parental pre-pregnancy BMI and the risk of LBW, VLBW, and ELBW in offspring. Results: Of the 34,104 participants, maternal pre-pregnancy overweight and obesity were associated with a higher risk of LBW (overweight: OR = 1.720, 95% CI = 1.533 ~ 1.930; obesity: OR = 1.710, 95% CI = 1.360 ~ 2.151), VLBW (overweight: OR = 2.283, 95% CI = 1.839 ~ 2.834; obesity: OR = 4.023, 95% CI = 2.855 ~ 5.670), and ELBW (overweight: OR = 3.292, 95% CI = 2.151 ~ 5.036; obesity: OR = 3.467, 95% CI = 1.481 ~ 8.115), while underweight was associated with a higher risk of LBW (OR = 1.438, 95% CI = 1.294 ~ 1.599) and a lower risk of ELBW (OR = 0.473, 95% CI = 0.236 ~ 0.946). Paternal pre-pregnancy overweight and obesity were associated with a higher risk of LBW (overweight: OR = 1.637, 95% CI = 1.501 ~ 1.784; obesity: OR = 1.454, 95% CI = 1.289 ~ 1.641) and VLBW (overweight: OR = 1.310, 95% CI = 1.097 ~ 1.564; obesity: OR = 1.320, 95% CI = 1.037 ~ 1.681), while underweight was associated with a lower risk of LBW (OR = 0.660, 95% CI = 0.519 ~ 0.839). Parents who were both excessive-weights in pre-pregnancy BMI, as well as overweight mothers and normal-weight fathers before pre-pregnancy, were more likely to have offspring with LBW, VLBW, and ELBW. Dose-response relationship existed between parental pre-pregnancy and LBW, VLBW, and ELBW, except for paternal BMI and ELBW. Conclusions: Parental pre-pregnancy BMI was associated with the risk of LBW in offspring. Management of weight before pregnancy for couples might help reduce their adverse pregnancy outcomes in future intervention studies.

Association between paternal pre-pregnancy body mass index with preterm birth and low birth weight.

Background: With the current global epidemic of obesity, especially among men, there is a need to understand its impact on adverse pregnancy outcomes. This study aimed to assess whether paternal pre-pregnancy body mass index (BMI) was associated with preterm birth and low birth weight in offspring. Methods: Multinomial logistic regression model was used to analyze associations between paternal BMI and preterm birth and low birth weight in different subgroups, the final model was adjusted for confounding factors of mothers and fathers. Further subgroup analysis was conducted to explore the stability of the risk associations. Results: A total of 34,104 participants were included in this study, including 1,442 (4.2%) underweight, 13,930 (40.9%) overweight and 5,008 (14.7%) obese according to paternal BMI. The total incidence of preterm birth was 11.85% (4041/34104), and the incidence of low birth weight was 8.86% (3020/34104). In the total study population, compared with normal weight men, paternal pre-pregnancy overweight or obese was associated with a significantly increased risk of preterm birth [aOR; 95% CI respectively (1.34; 1.25-1.45 vs. 1.26; 1.14-1.40)] and low birth weight [aOR; 95% CI respectively (1.60; 1.46-1.74 vs. 1.40; 1.25-1.58)] in offspring. The results of subgroup analysis showed that the direction of the risk association was consistent, indicating good stability. Conclusion: Paternal pre-pregnancy overweight and obesity were associated with an increased risk of preterm birth and low birth weight in their offspring.