Transcriptome-wide summary data-based Mendelian randomization analysis reveals 38 novel genes associated with severe COVID-19.

Severe COVID-19 has a poor prognosis, while the genetic mechanism underlying severe COVID-19 remains largely unknown. We aimed to identify genes that are potentially causally associated with severe COVID-19. We conducted a summary data-based Mendelian randomization (SMR) analysis using expression quantitative trait loci (eQTL) data from 49 different tissues as the exposure and three COVID-19-phenotypes (very severe respiratory confirmed COVID-19 [severe COVID-19], hospitalized COVID-19, and SARS-CoV-2 infection) as the outcomes. SMR using multiple SNPs was used as a sensitivity analysis to reduce false positive rate. Multiple testing was corrected using the false discovery rate (FDR) q-value. We identified 309 significant gene-trait associations (FDR q value < 0.05) across 46 tissues for severe COVID-19, which mapped to 64 genes, of which 38 are novel. The top five most associated protein-coding genes were Interferon Alpha and Beta Receptor Subunit 2 (IFNAR2), 2'-5'-Oligoadenylate Synthetase 3 (OAS3), mucin 1 (MUC1), Interleukin 10 Receptor Subunit Beta (IL10RB), and Napsin A Aspartic Peptidase (NAPSA). The potential causal genes were enriched in biological processes related to type I interferons, interferon-gamma inducible protein 10 production, and chemokine (C-X-C motif) ligand 2 production. In addition, we further identified 23 genes and 5 biological processes which are unique to hospitalized COVID-19, as well as 13 genes that are unique to SARS-CoV-2 infection. We identified several genes that are potentially causally associated with severe COVID-19. These findings improve our limited understanding of the mechanism of COVID-19 and shed light on the development of therapeutic agents for treating severe COVID-19.

Association of maternal levothyroxine use during pregnancy with offspring birth and neurodevelopmental outcomes: a population-based cohort study.

BACKGROUND: The influence of maternal levothyroxine treatment during pregnancy remains unclear. This study aimed to evaluate the associations of maternal levothyroxine treatment during pregnancy with the birth and neurodevelopmental outcomes in offspring. METHODS: This population-based cohort study was conducted among pregnant women using the Hong Kong Clinical Data Analysis and Reporting System. Mother-child pairs in Hong Kong from 2001 to 2015 were included and children were followed up till 2020. We defined the exposure group as mothers who were exposed to levothyroxine during pregnancy. Preterm birth and small for gestational age (SGA) were included as birth outcomes. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) were included as neurodevelopmental outcomes. Odds ratios (OR) or hazard ratios (HRs) with a 95% confidence interval (CI) were evaluated to assess the association of gestational levothyroxine use with offspring birth and neurodevelopmental outcomes respectively, using propensity score fine-stratification weighting and a Cox proportional hazards regression model. RESULTS: Among 422,156 mother-child pairs, 2125 children were born from mothers exposed to levothyroxine during pregnancy. A significantly increased risk of preterm birth was observed in children with maternal levothyroxine exposure during pregnancy, when compared to mothers who had no history of thyroid-related diagnoses or prescriptions (weighted OR [wOR]: 1.22, 95% CI: 1.07, 1.39). Similarly, an increased risk of preterm birth was found among children of gestational levothyroxine users, when compared to children of mothers who had used levothyroxine before but stopped during pregnancy (wOR: 2.16, 95% CI: 1.09, 4.25). Sensitivity analysis, by excluding mothers exposed to psychotropic or antiepileptic medications before or during pregnancy, also indicated a similar increased risk of preterm birth regarding the gestational use of levothyroxine (wOR: 1.26, 95% CI: 1.10, 1.45). No significant association was observed for the risk of SGA, ADHD, and ASD. CONCLUSIONS: There is no evidence that gestational use of levothyroxine is associated with SGA, ADHD, or ASD in offspring. Gestational levothyroxine treatment is associated with a higher risk of preterm birth. Such risk might be confounded by the underlying maternal thyroid disease itself, however, we cannot completely exclude the possible effect of gestational L-T4 treatment on offspring preterm birth. Our findings provided support to the current guidelines on the cautious use of levothyroxine treatment during pregnancy.

COVID-19 and platelet traits: A bidirectional Mendelian randomization study.

This study aimed to evaluate the host genetic liability of coronavirus disease 2019 (covid-19) with platelet traits using the Mendelian randomization (MR) approach. We conducted a bidirectional two-sample MR using summary statistics from the largest genome-wide association study of three variables, covid-19 severity (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection, covid-19 hospitalization, and severe covid-19, N = ~1 059 456-1 557 411) and four platelet traits (mean platelet volume [MPV], plateletcrit, platelet distribution width, and platelet count; N = 408 112). Inverse-variance weighted (IVW), median weighted, MR-Egger, and contamination mixture methods were used to estimate the causal association. Null and inconsistent associations in the IVW and sensitivity analyses were observed for SARS-CoV-2 infection and covid-19 hospitalization with platelet traits. For severe covid-19, significant associations with MPV and platelet count were observed in the IVW and sensitivity analyses, with the betaIVW of 0.01 (95% confidence interval [CI]: 0.005-0.016, p = 3.51 × 10-4 ) and -0.009 (95% CI: -0.015 to -0.002, p = 0.008) per doubling in odds of severe covid-19, respectively. Conversely, null associations were observed for platelet traits with covid-19 traits. In conclusion, host genetic liability to severe covid-19 was causally associated with increased MPV and reduced platelet count, which may provide insights into evaluating hypercoagulability and thromboembolic events in covid-19 patients.

Treatment with direct oral anticoagulants or warfarin and the risk for incident diabetes among patients with atrial fibrillation: a population-based cohort study.

BACKGROUND: Diabetes mellitus is a common comorbidity of atrial fibrillation (AF), which can complicate the management of AF. The pharmacology of oral anticoagulants (OACs) have been implicated in pathogenesis of diabetes, but the relationship between different OACs and risk of diabetes remains unexamined. This study aimed to evaluate the risk of diabetes with use of different OACs in AF patients. METHODS: Population-based retrospective cohort study using an electronic healthcare database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with AF from 2014 through 2018 and prescribed OACs were included and followed till December 31, 2019. Inverse probability of treatment weighting based on the propensity score (PS) is used to address potential bias due to nonrandomized allocation of treatment. The risks ofdiabetes were compared between different new OAC users using propensity score-weighted cumulative incidence differences (CID). RESULTS: There were 13,688 new users of OACs (warfarin: n = 3454; apixaban: n = 3335; dabigatran: n = 4210; rivaroxaban: n = 2689). The mean age was 75.0 (SD, 11.2), and 6,550 (47.9%) were women. After a median follow-up of 0.93 years (interquartile range, 0.21-1.92 years), 698 incident diabetes cases were observed. In Cox-regression analysis, dabigatran use was significantly associated with reduced risk of diabetes when compared with warfarin use [HR 0.69 (95% CI 0.56-0.86; P < 0.001)], with statistically insignificant associations observed for use of apixaban and rivaroxaban. The corresponding adjusted CIDs at 2 years after treatment with apixaban, dabigatran, and rivaroxaban users when compared with warfarin were - 2.06% (95% CI - 4.08 to 0.16%); - 3.06% (95% CI - 4.79 to - 1.15%); and - 1.8% (- 3.62 to 0.23%). In head-to-head comparisons between women DOAC users, dabigatran was also associated with a lower risk of diabetes when compared with apixaban and rivaroxaban. CONCLUSIONS: Among adults with AF receiving OACs, the use of dabigatran had the lowest risk of diabetes when compared with warfarin use.

Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.

Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.

Low Bone Mineral Density With Risk of Dementia: A Prospective Cohort Study.

OBJECTIVES: Osteoporosis and dementia often coexist, but the association between the 2 diseases remains unclear. This study aimed to investigate the relationship between bone mineral density (BMD) and the risk of incident dementia. DESIGN: Prospective cohort study, the Hong Kong Osteoporosis Study (HKOS). SETTING AND PARTICIPANTS: Data were from the HKOS and the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong. A total of 5803 participants aged ≥40 years and free of dementia were included in the HKOS. METHODS: The baseline BMD at the lumbar spine, femoral neck, trochanter, and total hip were measured using dual-energy x-ray absorptiometry (DXA). The incidence of dementia was identified using their International Classification of Diseases, Ninth Revision, codes. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: The median follow-up time of the HKOS was 16.8 years. Higher BMD T scores at the lumbar spine, trochanter, and total hip were significantly associated with the reduced risk of dementia with the respective HR of 0.85 (95% CI 0.76-0.95; P = .004), 0.78 (95% CI 0.68-0.90; P < .001), and 0.82 (95% CI 0.72-0.93; P = .003). The subgroup analyses showed that associations were significant in women but not in men, whereas the associations were unaltered after adjusting for serum estradiol. CONCLUSIONS AND IMPLICATIONS: Low BMD was associated with an increased risk of dementia, particularly in women. Future studies evaluating the clinical usefulness of BMD on dementia prediction and management are warranted.

Hip Fracture as a Predictive Marker for the Risk of Dementia: A Population-Based Cohort Study.

OBJECTIVES: This study aimed to investigate the association between hip fracture and the risk of dementia. DESIGN: A retrospective real-world propensity score-matched cohort study was conducted using the real-world hip fracture cohort (RHFC). SETTING AND PARTICIPANTS: Electronic health record data from the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong were used. A total of 52,848 patients aged ≥65 years and with at least an event of fall from 2006 to 2015 were included in the RHFC. METHODS: The incidence of fall, hip fracture, and dementia was determined using their International Classification of Diseases, Ninth Revision (ICD-9) codes. Competing risk regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Hip fracture was associated with an increased risk of dementia (HR 1.09, 95% CI 1.04-1.15, P < .001). The subgroup analysis showed that association was significant in women but not in men. CONCLUSIONS AND IMPLICATIONS: Hip fracture was associated with the increased risk of dementia among older adults. Further studies investigating the potential roles of hip fracture in the development of dementia could benefit the management of both conditions in older adults.

Immediate Risk for Cardiovascular Events in Hip Fracture Patients: A Population-Based Cohort Study.

BACKGROUND: Emerging evidence showed that bone metabolism and cardiovascular disease (CVD) are closely related. We previously observed a potential immediate risk of cardiovascular mortality after hip fracture. However, whether there is an immediate risk of cardiovascular events after hip fracture is unclear. The aim of this study was to evaluate the risk for major adverse cardiovascular events (MACEs) between patients having experienced falls with and without hip fracture. METHODS: This retrospective population-based cohort study used data from a centralized electronic health record database managed by Hong Kong Hospital Authority. Patients having experienced falls with and without hip fracture were matched by propensity score (PS) at a 1:1 ratio. Adjusted associations between hip fracture and risk of MACEs were evaluated using competing risk regression after accounting for competing risk of death. RESULTS: Competing risk regression showed that hip fracture was associated with increased 1-year risk of MACEs (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.21-1.33; p < .001), with a 1-year cumulative incidence difference of 2.40% (1.94%-2.87%). The HR was the highest in the first 90-days after hip fracture (HR of 1.32), and such an estimate was continuously reduced in 180 days, 270 days, and 1 year after hip fracture. CONCLUSIONS: Hip fracture was associated with increased immediate risk of MACEs. This study suggested that a prompt evaluation of MACE among older adults aged 65 years and older who are diagnosed with hip fracture irrespectively of cardiovascular risk factors may be important, as early management may reduce subsequent risk of MACE.

Identification of genes for bone mineral density variation by computational disease gene identification strategy.

We previously used five freely available bioinformatics tools (Prioritizer, Geneseeker, PROSPECTR and SUSPECTS, Disease Gene Prediction, and Endeavour) to analyze the thirteen well-replicated osteoporosis susceptibility loci and identify a subset of most likely candidate osteoporosis susceptibility genes (Huang et al. in J Hum Genet 53:644-655, 2008). In the current study, we experimentally tested the association between bone mineral density (BMD) and the 9 most likely candidate genes [LAMC2(1q25-q31), MATN3(2p24-p23), ITGAV(2q31-q32), ACVR1(2q23-q24), TDGF1(3p21.31), EGF(4q25), IGF1(12q22-q23), ZIC2(13q32), BMP2(20p12)] which were pinpointed by 4 or more bioinformatics tools. Forty tag SNPs in nine candidate genes were genotyped in a southern Chinese female case-control cohort consisting of 1643 subjects. Single- and multi-marker association analyses were performed using logistic regression analysis implemented by PLINK. Potential transcription factor binding sites were predicted by MatInspector. The strongest association was observed between rs10178256 (MATN3) and trochanter (P < 0.001) and total hip BMD (P = 0.002). The SNP rs6214 (IGF1) showed consistent association with BMD at all the four measured skeletal sites (P = 0.005-0.044). Prediction of transcription factor binding suggested that the minor allele G of rs10178256 might abolish the binding of MESP1 and MESP2 which play vital roles in bone homeostasis, whereas the minor allele G of rs6214 might create an additional binding site for XBP1, a constitutive regulator of endoplasmic reticulum stress response. Our data suggested that variants in MATN3 and IGF1 were involved in BMD regulation in southern Chinese women.

Secular trends in fall-related hospitalizations in adolescents, youth and adults: a population-based study.

BACKGROUND: Falls are one of the major causes of injury globally. However, there is a lack of population-based studies on falls among adolescents, young and middle-aged adults. We therefore aimed to conduct a large-scale population study on the secular trend in incidence of fall-related hospitalization. METHODS: A population-wide electronic database, Hong Kong's Clinical Data Analysis and Reporting System (CDARS), was used in this retrospective cohort study. Patients aged≥10, hospitalized with diagnosis of accidental falls (ICD-9-CM E880-E888) from 2005-2018, were included. Outcome measures included the number, age- and sex-standardized incidence rate of fall-related hospital admissions, their length of stay (LOS) and 1-year all-cause mortality. Linear regression and average annual percentage change (AAPC) using joinpoint regression were computed for trend analysis. FINDINGS: From 2005 to 2018, a total of 336,439 patients aged≥10 were identified with fall-related hospitalization. Among these fall patients, 33.7% occurred at age<60. The number of fall-related hospital admissions episodes increased significantly by 83.7% during the study period. The standardized incidence rate of falls per 1000 person-years increased from 3.67 (95% CI 3.62-3.72) in 2005 to 4.79 (95% CI 4.74-4.84) in 2018. Although the total hospitalized bed-days increased from 178,723 days in 2005, to 299,273 days in 2018 (+67.5%,p<.0001), the median length of stay per episode of falls decreased from 4.90 days to 3.79 days (p<.0001). INTERPRETATION: Continuous increase in the incidence of fall-related hospitalization in people aged≥10 was observed. This suggested that falls are a public health issue in all ages. Further studies on the differences in the underlying risk factors and comorbidities between younger and older fall patients are warranted. FUNDING: None.

Development and Validation of a Risk Score to Predict the First Hip Fracture in the Oldest Old: A Retrospective Cohort Study.

BACKGROUND: To evaluate whether the common risk factors and risk scores (FRAX, QFracture, and Garvan) can predict hip fracture in the oldest old (defined as people aged 80 and older) and to develop an oldest-old-specific 10-year hip fracture prediction risk algorithm. METHODS: Subjects aged 80 years and older without history of hip fracture were studied. For the derivation cohort (N = 251, mean age = 83), participants were enrolled with a median follow-up time of 8.9 years. For the validation cohort (N = 599, mean age = 85), outpatients were enrolled with a median follow-up of 2.6 years. A five-factor risk score (the Hong Kong Osteoporosis Study [HKOS] score) for incident hip fracture was derived and validated, and its predictive accuracy was evaluated and compared with other risk scores. RESULTS: In the derivation cohort, the C-statistics were .65, .61, .65, .76, and .78 for FRAX with bone mineral density (BMD), FRAX without BMD, QFracture, Garvan, and the HKOS score, respectively. The category-less net reclassification index and integrated discrimination improvement of the HKOS score showed a better reclassification of hip fracture than FRAX and QFracture (all p < .001) but not Garvan, while Garvan, but not HKOS score, showed a significant over-estimation in fracture risk (Hosmer-Lemeshow test p < .001). In the validation cohort, the HKOS score had a C-statistic of .81 and a considerable agreement between expected and observed fracture risk in calibration. CONCLUSION: The HKOS score can predict 10-year incident hip fracture among the oldest old in Hong Kong. The score may be useful in identifying the oldest old patients at risk of hip fracture in both community-dwelling and hospital settings.

Serum metabolomic profiling and its association with 25-hydroxyvitamin D.

INTRODUCTION: The beneficial effect of vitamin D on the risk of non-musculoskeletal diseases has been investigated in observational studies and randomized clinical trials, but the findings were inconsistent. Identification of the metabolomic profile associated with vitamin D helps to identify novel biomarkers and increase the understanding of the biochemical and physiological role of vitamin D in different health conditions. METHOD: Serum metabolomic profiling was performed using liquid chromatography/tandem mass spectrometry [LC/MS] and their association with serum 25(OH)D was evaluated using multivariable linear regression in the baseline cohort of 316 participants (aged 20 or above; 92 men, 224 women; mean age±SD: 48.1 ± 15.8 years) and in the follow-up cohort of 275 participants (aged 20 or above; 12 men, 263 women; mean age: 56.2 ± 9.6) of the Hong Kong Osteoporosis Study. We discovered and validated potential metabolites; and by meta-analysis of these associations in two cohorts, we identified metabolites that were significantly associated with serum 25(OH)D levels. RESULTS: Among 835 known metabolites, 102 metabolites showed significant correlation with 25(OH)D levels at baseline visit. Of these metabolites, 27 were validated in the follow-up visit. In meta-analysis of data from these two visits, 13 metabolites were highly correlated with 25(OH)D. The majority of metabolites identified were lipid in nature. Docosahexaenoylcarnitine and eicosapentaenoylcholine had the highest correlations, with effect estimates 0.2554 (p = 9.60 × 10-9) and 0.1682 (p = 4.94 × 10-7) respectively. CONCLUSION: In Hong Kong Chinese at least, serum vitamin D level is closely related to lipid metabolism. Our finding highlights an important new direction in the study of vitamin D in different health conditions.

Serum Metabolome of Coffee Consumption and its Association With Bone Mineral Density: The Hong Kong Osteoporosis Study.

BACKGROUND: Inconsistent associations between coffee consumption and bone mineral density (BMD) have been observed in epidemiological studies. Moreover, the relationship of bioactive components in coffee with BMD has not been studied. The aim of the current study is to identify coffee-associated metabolites and evaluate their association with BMD. METHODS: Two independent cohorts totaling 564 healthy community-dwelling adults from the Hong Kong Osteoporosis Study (HKOS) who visited in 2001-2010 (N = 329) and 2015-2016 (N = 235) were included. Coffee consumption was self-reported in an food frequency questionnaire. Untargeted metabolomic profiling on fasting serum samples was performed using liquid chromatography-mass spectrometry platforms. BMD at lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable linear regression and robust regression were used for the association analyses. RESULTS: 12 serum metabolites were positively correlated with coffee consumption after Bonferroni correction for multiple testing (P < 4.87 × 10-5), with quinate, 3-hydroxypyridine sulfate, and trigonelline (N'-methylnicotinate) showing the strongest association. Among these metabolites, 11 known metabolites were previously identified to be associated with coffee intake and 6 of them were related to caffeine metabolism. Habitual coffee intake was positively and significantly associated with BMD at the lumbar spine and femoral neck. The metabolite 5-acetylamino-6-formylamino-3-methyluracil (AFMU) (ß = 0.012, SE = 0.005; P = 0.013) was significantly associated with BMD at the lumbar spine, whereas 3-hydroxyhippurate (ß = 0.007, SE = 0.003, P = 0.027) and trigonelline (ß = 0.007, SE = 0.004; P = 0.043) were significantly associated with BMD at the femoral neck. CONCLUSIONS: 12 metabolites were significantly associated with coffee intake, including 6 caffeine metabolites. Three of them (AFMU, 3-hydroxyhippurate, and trigonelline) were further associated with BMD. These metabolites could be potential biomarkers of coffee consumption and affect bone health.

Causal associations between urinary sodium with body mass, shape and composition: a Mendelian randomization study.

Observational studies have found associations between urinary sodium (UNa) with obesity, body shape and composition; but the findings may be biased by residual confounding. The objective of this two-sample Mendelian randomization (MR) study was to analyze their causal associations in both sex-combined and sex-specific models. Genome-wide association studies of UNa, body mass index (BMI), BMI-adjusted waist-to-hip ratio (WHR), body fat (BF) percentage and estimated glomerular filtration rate (eGFR) were identified. We initially extracted fifty SNPs associated with UNa at significance level of 5 × 10-8, but further removed those SNPs with potential horizontal pleiotropy. Univariable and multivariable MR with adjustment for eGFR were performed. Inverse-variance weighted MR was performed as the primary analysis, with MR-Egger methods as sensitivity analysis. The potential bidirectional association between BMI and UNa was investigated. All exposure and outcomes were continuous, and the effect measure was regression coefficients (beta) and their 95% confidence intervals (95% CI). The total sample size was up to 322 154. UNa was causally associated with increased BMI in both men [eGFR-adjusted beta 0.443 (0.163-0.724)] and women [0.594 (0.333-0.855)]. UNa caused BF percentage increase in men [0.622 (0.268-0.976)] and women [0.334 (0.007-0.662)]. UNa significantly elevated BMI-adjusted WHR in men [0.321 (0.094-0.548)], but not in women [0.170 (- 0.052 to 0.391)]. Additionally, we found that BMI causally increased UNa [0.043 (0.023-0.063)]. UNa increased BMI and BF percentage. Salt intake affects male body shape by increasing BMI-adjusted WHR, but showed no effects on female body shape. The bidirectional association between BMI and UNa suggested that salt reduction measures and weight reduction measures should be implemented simultaneously to break the vicious cycle and gain more health benefits.

Maternal Thyroid Dysfunction During Pregnancy and the Risk of Adverse Outcomes in the Offspring: A Systematic Review and Meta-Analysis.

CONTEXT: Previous studies suggested a potential link of maternal thyroid dysfunction with adverse neurocognitive outcomes and impaired development of internal organs in offspring. OBJECTIVE: To review the association between maternal thyroid dysfunction and the risk of adverse outcomes in offspring. DATA SOURCES: PubMed, EMBASE, and Cochrane Library. STUDY SELECTIONS: Eligible studies reported the association between maternal thyroid hormone function and the risk of adverse outcomes in their children. DATA EXTRACTION: Reviewers extracted data on study characteristics and results independently. DATA SYNTHESIS: Estimates were pooled and reported as odds ratio (OR) with 95% confidence interval (CI). I2 tests were applied to assess the heterogeneity across studies. RESULTS: We identified 29 eligible articles and found an association between maternal hyperthyroidism and attention deficit hyperactivity disorder (ADHD) (OR: 1.18, 95% CI: 1.04-1.34, I2 = 0%) and epilepsy (OR: 1.19, 95% CI: 1.08-1.31, I2 = 0%) in offspring; as well as an association of maternal hypothyroidism with increased risk of ADHD (OR: 1.14, 95% CI: 1.03-1.26, I2 = 25%), autism spectrum disorder (OR: 1.41, 95% CI: 1.05-1.90, I2 = 63%), and epilepsy (OR: 1.21, 95% CI: 1.06-1.39, I2 = 0%) in offspring. CONCLUSION: Routine measurement and timely treatment on thyroid function should be considered for pregnant women.

Gene expression profile in colon cancer cells with respect to XIAP expression status.

BACKGROUND AND AIMS: We observed a marked synergism between peroxisome proliferator-activated receptor gamma (PPARgamma) ligands and X-linked inhibitor of apoptosis (XIAP) down-regulation in colon cancer. In the current study, we detected the gene expression profile in HCT116 cells treated with or without PPARgamma ligand troglitazone. MATERIALS AND METHODS: HCT116-XIAP(+/+) and HCT116-XIAP(-/-) cells were treated with or without 50 microM troglitazone for 48 h. Gene expressions were detected by microarray, and selected genes were validated by reverse-transcriptase polymerase chain reaction (PCR), real-time PCR, and Western blot. RESULTS: Relative to HCT116-XIAP(+/+) cells, 58 genes were up-regulated and 33 genes down-regulated in HCT116-XIAP(-/-) cells, all by > or =4-fold. These genes could be classified into a wide variety of functional classes, but we focused on those related to angiogenesis, apoptosis, and proliferation. Thus, two pro-apoptotic genes and one pro-proliferation gene were up-regulated in HCT116-XIAP(-/-) cells. Two pro-proliferation genes, one pro-angiogenesis gene, one anti-angiogenesis gene, and one anti-apoptosis gene were down-regulated in HCT116-XIAP(-/-) cells. Relative to HCT116-XIAP(+/+) cells treated with troglitazone, 137 genes were up-regulated, and 31 genes were down-regulated in troglitazone-treated HCT116-XIAP(-/-) cells, all by > or =4-fold. Among the up-regulated genes were two anti-angiogenesis genes, seven pro-apoptosis genes, and six anti-proliferation genes. Among the down-regulated genes were one anti-angiogenesis gene, one pro-angiogenesis gene, one anti-apoptosis gene, one anti-proliferation gene, and two pro-proliferation genes. CONCLUSION: Down-regulation of XIAP in HCT116 cells with or without troglitazone treatment was associated with changes of gene expression that favor increased tendency of apoptosis, decreased cell proliferation, and angiogenesis potential.

Evaluation of GDF15 as a therapeutic target of cardiometabolic diseases in human: A Mendelian randomization study.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a key regulator of body weight in animals by regulating food intake. Its receptor, glial cell-derived neurotrophic factor receptor alpha-like (GFRAL), was identified recently. Pre-clinical studies showed that it is a promising therapeutic target for cardiometabolic diseases and anorexia/cachexia. Although many pharmaceutical companies are developing drugs targeting GFRAL, whether the findings from animal studies can be extrapolated to man is unknown. Mendelian randomization (MR) is useful in investigating the relationship between risk factors and disease outcomes. We aimed to use a two-sample MR approach to evaluate the clinical usefulness of targeting GDF15 for cardiometabolic diseases. METHODS: Genetic instruments and summary statistics for MR analyses were obtained from a large genome-wide association study (GWAS) of GDF15 and cardiometabolic outcomes (n = 27,394 to 644,875), including body mass index, waist-hip ratio, waist circumference, whole-body lean mass, fat percentage, Type 2 Diabetes, fasting glucose, glycated haemoglobin, fasting insulin, LDL-cholesterol, HDL-cholesterol, total cholesterol, triglycerides, coronary artery disease, and estimated BMD (eBMD). Conventional inverse variance weighted (IVW) method was adopted to obtain the causal estimates of GDF-15 with different outcomes; weighted median and MR-egger were used for sensitivity analyses. FINDINGS: There was null association between GDF15 levels and anthropometric outcomes. One SD increase in genetically-determined GDF15 was significantly associated with reduced HDL-C (beta: -0.048SD; SE: 0.014; P = .001) but the result was not significant in sensitivity analyses. A consistent significant causal association was observed between GDF15 and eBMD in IVW (beta: 0.026 SD; SE: 0.005; P < .001) and subsequent sensitivity analyses. INTERPRETATION: This study sheds lights on the potential of drugs targeting the GDF15/GFRAL axis. It suggested that the effect of targeting GDF15/GFRAL axis for weight control in human may be different from the effects observed in animal studies. GDF15 treatment may improve BMD in humans. FUND: No specific funding was received for this study.

Multiple osteoporosis susceptibility genes on chromosome 1p36 in Chinese.

INTRODUCTION: Chromosome 1p36 is a region that has previously shown good evidence of linkage to bone mineral density (BMD) in multiple studies, but the genes that are responsible for the linkage signals are unknown. MATERIALS AND METHODS: We performed a gene-wide and tag SNP-based association study of four positional and functional candidate genes (TNFRSF1B, PLOD, CNR2, and MTHFR) at 1p36 in 1, 243 case-control Chinese subjects. Twenty-three tag SNPs were selected and genotyped using the high-throughput Sequenom genotyping platform. Binary logistic regression analyses were performed to test for genotype associations between each SNP and BMD. Allelic and haplotype association analyses were conducted by Haploview. Gene-gene interactions were investigated using multifactor dimensionality reduction method. RESULTS: The PLOD rs7529452 (C385T; F98F) and MTHFR rs1801133 (C677T; A429E) showed significant genotypic/allelic associations with BMDs at all sites measured (P=0.08-0.001), and a promising two-locus gene-gene interaction for femoral neck BMD. The CNR2 rs2501431 (A592G; G155G) showed nominally significant allelic associations with trochanter and hip BMD. The TNFRSF1B rs976881 showed genotypic associations with BMDs (P=0.08-0.04). CONCLUSIONS: Our results suggest that multiple genes at 1p36, individually or in different combinations, contribute to osteoporosis susceptibility in Chinese.

The -9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPalpha and FOXA1 binding is associated with osteoporosis.

Accumulating evidence shows that genes that cause monogenic diseases also contribute to similar complex disease in the general population. We sought to determine whether the allelic variation in seven monogenic bone disease genes (CLCN7, TCIRGI, SOST, CA2, CSTK, TGFB1 and SLC26A2) contributes to osteoporosis/bone mineral density (BMD) variation in the normal Chinese population. We conducted a gene-wide tag SNP-based association study in 1243 Chinese subjects with low BMD (Z-scores < or = -1.28, equivalent to the lowest 10% of the population) and high BMD (Z-score > or = +1.0). Twenty-two tag SNPs were selected and genotyped by using the high-throughput Sequenom genotyping platform. Allelic and haplotype association tests were conducted by Haploview and binary logistic regression analyses. The -9247 polymorphism rs1230399 in the upstream regulatory region of the sclerostin gene showed significant genotypic/allelic associations with spine, femoral neck, trochanter and total hip BMD (P=0.03-0.004). The T-allele of rs1230399 increased the risk of osteoporosis (OR=1.52, P=0.005). Computational analysis showed that rs1230399 is located at the core consensus recognition site of two cooperating transcription factors C/EBPalpha and FOXA1 that modulate estrogen receptor function. T-->C polymorphism abolishes the binding of both C/EBPalpha and FOXA1 to the sclerostin gene. Our data suggest a mechanistic link between rs1230399 and BMD through estrogen ERalpha/FOXA1 signaling pathways driven by long-distance enhancers.