Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy.

Introduction: Pompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels. Method: In a single-center, open-label prospective study, we assessed ITI therapy's efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI. Results: This study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea. Conclusion: ITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.

Multiple polygenic risk scores can improve the prediction of systemic lupus erythematosus in Taiwan.

OBJECTIVE: To identify new genetic variants associated with SLE in Taiwan and establish polygenic risk score (PRS) models to improve the early diagnostic accuracy of SLE. METHODS: The study enrolled 2429 patients with SLE and 48 580 controls from China Medical University Hospital in Taiwan. A genome-wide association study (GWAS) and PRS analyses of SLE and other three SLE markers, namely ANA, anti-double-stranded DNA antibody (dsDNA) and anti-Smith antibody (Sm), were conducted. RESULTS: Genetic variants associated with SLE were identified through GWAS. Some novel genes, which have been previously reported, such as RCC1L and EGLN3, were revealed to be associated with SLE in Taiwan. Multiple PRS models were established, and optimal cut-off points for each PRS were determined using the Youden Index. Combining the PRSs for SLE, ANA, dsDNA and Sm yielded an area under the curve of 0.64 for the optimal cut-off points. An analysis of human leucocyte antigen (HLA) haplotypes in SLE indicated that individuals with HLA-DQA1*01:01 and HLA-DQB1*05:01 were at a higher risk of being classified into the SLE group. CONCLUSIONS: The use of PRSs to predict SLE enables the identification of high-risk patients before abnormal laboratory data were obtained or symptoms were manifested. Our findings underscore the potential of using PRSs and GWAS in identifying SLE markers, offering promise for early diagnosis and prediction of SLE.

Genetic predisposition to bone mineral density and their health conditions in East Asians.

Osteoporosis, a condition defined by low bone mineral density (BMD) (typically < -2.5 SD), cause a higher fracture risk and lead to significant economic, social, and clinical impacts. Genome-wide studies mainly in Caucasians have found many genetic links to osteoporosis, fractures, and BMD, with limited research in East Asians. We investigated the genetic aspects of BMD in 86,716 individuals from the Taiwan Biobank and their causal links to health conditions within East Asians. A genome-wide association study (GWAS) was conducted, followed by observational studies, polygenic risk score assessments, and genetic correlation analyses to identify associated health conditions linked to BMD. GWAS and gene-based GWAS studies identified 78 significant SNPs and 75 genes related to BMD, highlighting pathways like Hedgehog, WNT-mediated, and TGF-ß. Our cross-trait linkage disequilibrium score regression analyses for BMD and osteoporosis consistently validated their genetic correlations with body mass index (BMI) and type 2 diabetes (T2D) in East Asians. Higher BMD was linked to lower osteoporosis risk but increased BMI and T2D, whereas osteoporosis linked to lower BMI, waist circumference, HbA1c, and reduced T2D risk. Bidirectional Mendelian randomization (MR) analyses revealed that a higher BMI causally increases BMD in East Asians. However, no direct causal relationships were found between BMD and T2D, or between osteoporosis and either BMI or T2D. This study identified key genetic factors for bone health in Taiwan, and revealed significant health conditions in East Asians, particularly highlighting the genetic interplay between bone health and metabolic traits like T2D and BMI.

We investigated how genetics affect bone health and related conditions like diabetes and obesity in 86,716 East Asians. Previously, most studies focused on Caucasian populations, but our work helps to understand these issues in East Asians. Our findings show that stronger bones are linked to a lower chance of osteoporosis but a higher risk of obesity and type 2 diabetes. On the other hand, those with osteoporosis tend to have lower body weight and a decreased risk of diabetes, illustrating a complex relationship between bone health and body metabolism. Future research will focus on deeper genetic interactions and developing targeted interventions for bone health and related metabolic disorders in East Asians.

Antihypertensive medication and dementia risk in patients with hypertension: A nationwide population-based study.

The claim between hypertension and dementia needs more evidence due to limited data. We aim to examine the risk of dementia in patients with hypertension, and determine whether the use of antihypertensive medications (AHMs) could decrease the incidence of dementia diagnosed following the onset of hypertension. We employed the Taiwan National Health Insurance Research Database from 2000 to 2016 and performed a retrospective cohort study. We also carried out a case-control study to see if AHMs could reduce the incidence of newly diagnosed dementia in hypertensive patients. In the retrospective cohort study, we selected 587,762 participants with age and gender matched in experimental and control groups. The hypertension group had significantly higher adjusted hazard ratios (aHRs) of getting newly diagnosed dementia, including all-cause dementia, Alzheimer's disease, and vascular dementia (aHR, 2.86; 95 % confidence interval (CI), 2.74-2.99) than the control group. Three kinds of specific AHMs, namely, angiotensin II receptor blockers (aHR, 0.55; 95 % CI, 0.53-0.57), calcium channel blockers (aHR, 0.76; 95 % CI, 0.73-0.80), and diuretics (aHR,0.93; 95 % CI, 0.89-0.97) could significantly decrease the incidence of getting newly diagnosed dementia. Also, the application of traditional Chinese medicine (TCM) significantly associates with the lower aHRs of newly diagnosed dementia in hypertensive patients compared to patients without TCM (aHR, 0.90; 95 % CI, 0.81-1.00). Hypertension may be a significant risk factor for dementia. Both AHMs and TCM significantly associate with the lower incidence of newly diagnosed dementia in hypertensive patients.

Genome­wide association study and polygenic risk scores predict psoriasis and its shared phenotypes in Taiwan.

Psoriasis is a chronic inflammatory dermatological disease, and there is a lack of understanding of the genetic factors involved in psoriasis in Taiwan. To establish associations between genetic variations and psoriasis, a genome­wide association study was performed in a cohort of 2,248 individuals with psoriasis and 67,440 individuals without psoriasis. Using the ingenuity pathway analysis software, biological networks were constructed. Human leukocyte antigen (HLA) diplotypes and haplotypes were analyzed using Attribute Bagging (HIBAG)­R software and chi­square analysis. The present study aimed to assess the potential risks associated with psoriasis using a polygenic risk score (PRS) analysis. The genetic association between single nucleotide polymorphisms (SNPs) in psoriasis and various human diseases was assessed by phenome­wide association study. METAL software was used to analyze datasets from China Medical University Hospital (CMUH) and BioBank Japan (BBJ). The results of the present study revealed 8,585 SNPs with a significance threshold of P<5x10­8, located within 153 genes strongly associated with the psoriasis phenotype, particularly on chromosomes 5 and 6. This specific genomic region has been identified by analyzing the biological networks associated with numerous pathways, including immune responses and inflammatory signaling. HLA genotype analysis indicated a strong association between HLA­A*02:07 and HLA­C*06:02 in a Taiwanese population. Based on our PRS analysis, the risk of psoriasis associated with the SNPs identified in the present study was quantified. These SNPs are associated with various dermatological, circulatory, endocrine, metabolic, musculoskeletal, hematopoietic and infectious diseases. The meta­analysis results indicated successful replication of a study conducted on psoriasis in the BBJ. Several genetic loci are significantly associated with susceptibility to psoriasis in Taiwanese individuals. The present study contributes to our understanding of the genetic determinants that play a role in susceptibility to psoriasis. Furthermore, it provides valuable insights into the underlying etiology of psoriasis in the Taiwanese community.

Increased Risk of Inflammatory Bowel Disease Among Patients With Nontyphoidal Salmonella Infections: A Population-Based Cohort Study.

BACKGROUND: Despite the known association between microorganisms and development of inflammatory bowel disease (IBD), the role of nontyphoidal Salmonella (NTS) in IBD is not adequately addressed. We aimed at elucidating the relationship between NTS infection and the risk of IBD. METHODS: Based on the National Health Insurance Research Database in Taiwan, this retrospective cohort study enrolled patients with NTS infection (exposure group; n = 4651) and those without NTS infection (comparator group; n = 4651) who were propensity score matched (1:1) by demographic data, medications, comorbidities, and index date. All patients were followed until IBD onset, individual mortality, or December 31, 2018. Cox proportional hazards regression analysis was performed to determine the hazard ratios and 95% confidence intervals (CIs). Sensitivity analyses were used for cross-validation. RESULTS: The NTS group demonstrated an increased risk of IBD compared with the non-NTS groups (adjusted hazard ratio [aHR], 2.12; 95% CI, 1.62-2.78) with a higher risk of developing ulcerative colitis in the former (aHR, 2.27; 95% CI, 1.69-3.04). Nevertheless, the small sample size may contribute to lack of significant difference in Crohn's disease. Consistent findings were noted after excluding IBD diagnosed within 6 months of NTS infection (aHR, 2.28; 95% CI, 1.71-3.03), excluding those with enteritis/colitis before index date (aHR, 1.85; 95% CI, 1.28-2.68), excluding those using antibiotics for 1 month in the year before IBD onset (aHR, 1.81; 95% CI, 1.34-2.45), inverse probability of treatment weighting (aHR, 1.64; 95% CI, 1.31-2.04), and inclusion of individuals regardless of age (n = 10 431; aHR, 1.83; 95% CI, 1.53-2.19). CONCLUSIONS: Patients with NTS were associated with an increased risk of developing IBD, especially ulcerative colitis.

Investigating causal relationships between extensive peripheral immune cell phenotypes and preeclampsia: A bi-directional Mendelian randomization analysis.

PROBLEM: Preeclampsia, a multifaceted condition during pregnancy characterized by hypertension and organ dysfunction, poses significant risks to both maternal and fetal health. This study aims to investigate the bidirectional causal relationship between peripheral immune cell phenotypes and preeclampsia using a two-sample Mendelian randomization (MR) approach. METHOD OF STUDY: Genetic data from two sizable cohorts were utilized: 3757 individuals from Sardinia, providing information on 731 immune traits, and 200 929 Finnish adult females, encompassing 6663 preeclampsia cases. Single-nucleotide polymorphisms served as instrumental variables. The MR analyses employed the inverse variance-weighted (IVW) method as the primary tool, supplemented by MR-Egger, weighted median, and weighted mode methods to enhance reliability and address potential heterogeneity and horizontal pleiotropy. RESULTS: Among the 731 immune cell phenotypes studied, 18 displayed a suggestive positive association (IVW p < .05) with heightened preeclampsia risk, while 20 exhibited a suggestive negative association linked to reduced risk. Following false discovery rate (FDR) adjustment, four immune phenotypes showed significant associations with decreased preeclampsia risk: CD27 on CD24+ CD27+ B cells (B-cell panel) (odds ratio [OR] = 0.927, PFDR = 0.061), CD33+ HLA DR+ CD14- absolute count (OR = 0.963, PFDR = 0.061), CD80 on plasmacytoid dendritic cells (OR = 0.923, PFDR = 0.061); and CD80 on CD62L+ plasmacytoid dendritic cells (OR = 0.923, PFDR = 0.061). In the reverse-direction MR analysis, no significant causal effects of preeclampsia on immune cell phenotypes were observed. CONCLUSIONS: This study provides quantifiable evidence linking specific immune cell phenotypes to the risk of developing preeclampsia. This novel understanding of the immunological aspects underlying preeclampsia's pathogenesis could lead to innovative therapeutic strategies centered on immune modulation.

The Incidence, Mortality and Medical Expenditure in Patients with Asthma in Taiwan: Ten-year Nationwide Study.

BACKGROUND: This study examines incidence, mortality, medical expenditure and prescription patterns for asthma on a national scale, particularly in Asian countries for asthma is limited. Our aim is to investigate incidence, mortality, prescription patterns and provide a comprehensive overview of healthcare utilization trends for asthma from 2009 to 2018. METHODS: We included patients diagnosed with asthma between 2009 and 2018. We excluded patients with missing demographic data. Our analysis covered comorbidities, including diabetes mellitus, hypertension, allergic rhinitis, eczema, atopic dermatitis, coronary artery disease, congestive heart failure, chronic kidney disease, chronic hepatitis, stroke, and cancer. Investigated medications comprised oral and intravenous steroids, short-acting beta-agonists, inhaled corticosteroids (ICS), combinations of ICS and long-acting beta-agonists, long-acting muscarinic antagonists, and leukotriene receptor antagonists montelukast. We also assessed the number of outpatient visits, emergency visits, and hospitalizations per year, as well as the average length of hospitalization and average medical costs. RESULTS: The study included a final count of 88,244 subjects from 1,998,311 randomly selected samples between 2000 and 2019. Over the past decade, there was a gradual decline in newly diagnosed asthma patients per year, from 10,140 to 6,487. The mean age annually increased from 47.59 in 2009 to 53.41 in 2018. Over 55% of the patients were female. Eczema was diagnosed in over 55% of the patients. Around 90% of the patients used oral steroids, with a peak of 97.29% in 2018, while the usage of ICS varied between 86.20% and 91.75%. Intravenous steroids use rose from 40.94% in 2009 to 54.14% in 2018. The average annual hospital stay ranged from 9 to 12 days, with a maximum of 12.26 days in 2013. Lastly, the average medical expenses per year ranged from New Taiwan dollars 5558 to 7921. CONCLUSIONS: In summary, both asthma incidence and all-cause mortality rates decreased in Taiwan from 2009 to 2018. Further analysis of medical expenses in patients with asthma who required multiple hospitalizations annually revealed an increase in outpatient and emergency visits and hospitalizations, along with longer hospital stays and higher medical costs.

GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease.

BACKGROUND: Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient's cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.

Genome-wide association study identifies DRAM1 associated with Tourette syndrome in Taiwan.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Several susceptibility loci associated with TS have been identified previously in populations of European descent using genome-wide association studies (GWAS). However, the exact pathogenic mechanism underlying TS is unknown; additionally, the results of previous GWAS for TS were based on Western populations, which may not translate to other populations. Therefore, we conducted a GWAS in Taiwanese patients with TS and chronic tic disorders (CTDs), with an aim to elucidate the genetic basis and potential risk factors for TS in this population. METHODS: GWAS was performed on a Taiwanese TS/CTDs cohort with a sample size of 1,007 patients with TS and 25,522 ancestry-matched controls. Additionally, polygenic risk score was calculated and assessed. RESULTS: Genome-wide significant locus, rs12313062 (p=1.43 × 10-8) and other 9 single nucleotide polymorphisms, were identified in chromosomes 12q23.2, associated with DRAM1 and was a novel susceptibility locus identified in TS/CTDs group. DRAM1, a lysosomal transmembrane protein regulated by p53, modulates autophagy and apoptosis, with potential implications for neuropsychiatric conditions associated with autophagy disruption. CONCLUSIONS: This study conducted the first GWAS for TS in a Taiwanese population, identifying a significant locus on chromosome 12q23.2 associated with DRAM1. These findings provide novel insights into the neurobiology of TS and potential directions for future research in this area.

Utility of polygenic scores across diverse diseases in a hospital cohort for predictive modeling.

Polygenic scores estimate genetic susceptibility to diseases. We systematically calculated polygenic scores across 457 phenotypes using genotyping array data from China Medical University Hospital. Logistic regression models assessed polygenic scores' ability to predict disease traits. The polygenic score model with the highest accuracy, based on maximal area under the receiver operating characteristic curve (AUC), is provided on the GeneAnaBase website of the hospital. Our findings indicate 49 phenotypes with AUC greater than 0.6, predominantly linked to endocrine and metabolic diseases. Notably, hyperplasia of the prostate exhibited the highest disease prediction ability (P value = 1.01 × 10-19, AUC = 0.874), highlighting the potential of these polygenic scores in preventive medicine and diagnosis. This study offers a comprehensive evaluation of polygenic scores performance across diverse human traits, identifying promising applications for precision medicine and personalized healthcare, thereby inspiring further research and development in this field.

Associations between organic erectile dysfunction and the risk of herpes zoster and postherpetic neuralgia in men.

BACKGROUND: Whether erectile dysfunction (ED) leads to considerable stress for affected men remains unclear? In this study, we investigated whether organic ED (OED) is associated with increased risks of herpes zoster (HZ) and postherpetic neuralgia (PHN). METHODS: A representative subset of Taiwan's National Health Insurance Research Database was employed for this study. Enrollees with OED from the years 2000 to 2018 were selected. To ensure comparability between the case and control groups, we implemented 1:1 propensity score matching based on age, index year, comorbidities, and medications. RESULTS: The case group included 20,808 patients with OED, while the control group consisted of 20,808 individuals without OED. The OED group exhibited a significantly elevated risk of HZ (adjusted hazard ratio [aHR] = 1.74) and PHN (aHR = 1.56) compared to the non-OED group. CONCLUSIONS: Men experiencing OED seem to face elevated risks of HZ and PHN compared to those without OED. ED may serve as a warning sign for individuals at HZ risk.

Identification of Genetic Variants for Risk Prediction and Early Diagnosis of Age-Related Macular Degeneration in the Taiwanese Population.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. The prevalence and phenotypes of AMD differ among populations, including between people in Taiwan and other regions. We performed a genome-wide association study to identify genetic variants and to develop genetic models to predict the risk of AMD development and progression in the Taiwanese population. In total, 4039 patients with AMD and 16,488 non-AMD controls (aged ≥ 65 years) were included. We identified 31 AMD-associated variants (p < 5 × 10-8) on chromosome 10q26, surrounding PLEKHA1-ARMS2-HTRA1. Two genetic models were constructed using the clump and threshold method. Model 1 included the single nucleotide polymorphism rs11200630 and showed a 1.31-fold increase in the risk of AMD per risk allele (95% confidence interval (CI) = 1.20-1.43, p < 0.001). In model 2, 1412 single-nucleotide polymorphisms were selected to construct a polygenic risk score (PRS). Individuals with the top 5% PRS had a 1.40-fold higher AMD risk compared with that of individuals with a PRS in the bottom quartile (95% CI = 1.04-1.89, p = 0.025). Moreover, the PRS in the upper quartile was related to a decreased age at AMD diagnosis by 0.62 years (95% CI = -1.15, -0.09, p = 0.023). Both genetic models provide useful predictive power for populations at high risk of AMD, affording a basis for identifying patients requiring close follow-up and early intervention.

Risk of CKD among patients with DM taking diuretics or SGLT2i: a retrospective cohort study in Taiwan.

BACKGROUND: This study aimed to evaluate the long-term risk of CKD and renal function declines using a combination of diuretics and SGLT2i. METHODS: We selected the data of subjects who had at least two outpatient records or at least one inpatient record for DM treatment as the DM group from the National Health Insurance Research Database (NHIRD). Patients receiving versus not receiving SGLT2i were defined as the SGLT2i and non-SGLT2i cohorts, respectively. The patients in the two groups were matched 1:1 through propensity score matching based on age, sex, year of index date, and comorbidities. RESULTS: The diuretics-only group had a higher risk of CKD (aHR, 2.46; 95% CI, 1.68-3.61) compared to the neither SGLT2i nor diuretics group, while the both SGLT2i and diuretics group and the SGLT2i only group had lower risks (aHR, 0.45, 95% CI, 0.32-0.63; aHR, 0.26, 95% CI, 0.17-0.40) than the diuretics-only group. The SGLT2i-only group had a lower risk (aHR, 0.58, 95% CI, 0.36-0.94) than the both SGLT2i and diuretics group. CONCLUSION: This study indicates that diuretics could raise the risk of CKD in diabetic patients, but when used in combination with SGLT2i, they continue to offer protection against CKD.

Menarche-a journey into womanhood: age at menarche and health-related outcomes in East Asians.

STUDY QUESTION: Are there associations of age at menarche (AAM) with health-related outcomes in East Asians? SUMMARY ANSWER: AAM is associated with osteoporosis, Type 2 diabetes (T2D), glaucoma, and uterine fibroids, as demonstrated through observational studies, polygenic risk scores, genetic correlations, and Mendelian randomization (MR), with additional findings indicating a causal effect of BMI and T2D on earlier AAM. WHAT IS KNOWN ALREADY: Puberty timing is linked to adult disease risk, but research predominantly focuses on European populations, with limited studies in other groups. STUDY DESIGN, SIZE, DURATION: We performed an AAM genome-wide association study (GWAS) with 57 890 Han Taiwanese females and examined the association between AAM and 154 disease outcomes using the Taiwanese database. Additionally, we examined genetic correlations between AAM and 113 diseases and 67 phenotypes using Japanese GWAS summary statistics. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed AAM GWAS and gene-based GWAS studies to obtain summary statistics and identify potential AAM-related genes. We applied phenotype, polygenic risk scores, and genetic correlation analyses of AAM to explore health-related outcomes, using multivariate regression and linkage disequilibrium score regression analyses. We also explored potential bidirectional causal relationships between AAM and related outcomes through univariable and multivariable MR analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen lead single-nucleotide polymorphisms and 24 distinct genes were associated with AAM in Taiwan. AAM was genetically associated with later menarche and menopause, greater height, increased osteoporosis risk, but lower BMI, and reduced risks of T2D, glaucoma, and uterine fibroids in East Asians. Bidirectional MR analyses indicated that higher BMI/T2D causally leads to earlier AAM. LIMITATIONS, REASONS FOR CAUTION: Our findings were specific to Han Taiwanese individuals, with genetic correlation analyses conducted in East Asians. Further research in other ethnic groups is necessary. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides insights into the genetic architecture of AAM and its health-related outcomes in East Asians, highlighting causal links between BMI/T2D and earlier AAM, which may suggest potential prevention strategies for early puberty. STUDY FUNDING/COMPETING INTEREST(S): The work was supported by China Medical University, Taiwan (CMU110-S-17, CMU110-S-24, CMU110-MF-49, CMU111-SR-158, CMU111-MF-105, CMU111-MF-21, CMU111-S-35, CMU112-SR-30, and CMU112-MF-101), the China Medical University Hospital, Taiwan (DMR-111-062, DMR-111-153, DMR-112-042, DMR-113-038, and DMR-113-103), and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-039-063-MY3, MOST 111-2314-B-039-064-MY3, MOST 111-2410-H-039-002-MY3, and NSTC 112-2813-C-039-036-B). The funders had no influence on the data collection, analyses, or conclusions of the study. No conflict of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Comparing the Long-Term Cardiovascular Outcomes of Lumbo-Peritoneal, Ventriculo-Peritoneal, or Non-Shunting Treatment after Idiopathic Normal Pressure Hydrocephalus: A Nationwide Retrospective Cohort Study.

Purpose: With advances in medical technology, the average lifespan has increased, leading to a growing significance of idiopathic normal pressure hydrocephalus (iNPH), particularly in the elderly population. Most patients with iNPH have been treated either with ventriculo-peritoneal shunts (VPS) or conservative measures. However, lumbo-peritoneal shunts (LPS) have emerged as an alternative treatment option for iNPH in recent decades, extensive research still lacks comparing outcomes with LPS to those with VPS or non-surgical treatment. The aim of the resent study is to disclose the long-term therapeutic outcomes of LPS, VPS, and non-shunting in patients with iNPH. Methods: We used the National Health Insurance Research Database in Taiwan to assess the long-term outcomes of these treatment options. We enrolled 5,537 iNPH patients who received shunting surgery, of which 5,254 were VPS and 283 were LPS. To compare the difference between each group, matching was conducted by propensity score matching using a 1:1 ratio based on LPS patients. Primary outcomes included death and major adverse cardiovascular events (MACEs) Results: Our findings show that VPS resulted in significantly more MACEs than non-surgical treatment (Odds ratio: 1.83, 95% confidence interval: 1.16-2.90). In addition, both VPS and LPS groups had significantly lower overall mortality rates than non-shunting group. Moreover, LPS had lower overall mortality but similar MACEs rates to VPS. Conclusions: Based on these findings, we propose that the LPS is preferable to the VPS, and surgical treatment should be considered the primary choice over conservative treatment unless contraindications are present.

Identification of the efficacy of parentage testing based on bi-allelic autosomal single nucleotide polymorphism markers in Taiwanese population.

Parentage testing is crucial for forensic DNA analysis, using short tandem repeats (STRs). Single nucleotide polymorphisms (SNPs) with high minor allele frequency (MAF) are promising for human identification. This study aimed to develop SNP markers for parentage testing in the Taiwanese population and compare their accuracy with STRs. The TPMv1 SNP microarray (714,457 SNPs) was used to screen 180,000 Taiwanese individuals and analyze the SNP data using PLINK. After quality control, allelic distribution, and MAF considerations, a set of SNPs with significant inheritance information was selected. Parentage testing was conducted on 355 single parent-child pairs using both STRs and SNPs, employing three kinship algorithms: identity by descent, kinship-based inference for genome-wide association studies, and the combined paternity index/probability of paternity (CPI/PP). An Affymetrix signature probe for kinship testing (ASP) was also used. Based on the quality control and selection criteria, 176 SNPs with MAF > 0.4995 were selected from the Taiwanese population. The CPI/PP results calculated using SNPs were consistent with the STR results. The accuracy of the SNPs used in the single-parent-child parentage testing was > 99.99%. The set of 176 SNPs had a higher identification rate in the single parent-child parentage test than in the ASP. The CPI/PP value calculated using 176 SNPs was also more accurate than that calculated using ASP. Our findings suggest that these 176 SNPs could be used for single-parent-child parentage identification in the Taiwanese population.

Risk of depression in patients with pneumoconiosis: A population-based retrospective cohort study.

BACKGROUND: Pneumoconiosis is an important occupational disease; the association between pneumoconiosis and depression was largely unknown. This study aimed to investigate the relationship between pneumoconiosis and the risk of subsequent depression. METHODS: A retrospective cohort study was conducted using Taiwan's National Health Insurance database. The study included 16,795 patients diagnosed with pneumoconiosis between 2008 and 2018 and a comparison cohort of 67,180 individuals without pneumoconiosis, propensity score matched in a 1:4 ratio based on age, sex, monthly income, residential urbanization level, and date of pneumoconiosis diagnosis. The development of depression was monitored until the end of 2019. RESULTS: The incidence of depression was 1.68 times higher in the pneumoconiosis cohort than that in the comparison cohort, with an incidence rate of 10.07 versus 5.99 per 1000 person-years (adjusted hazard ratio [aHR] = 1.84, 95 % confidence interval [CI] = 1.70-1.99). The risk of depression increased with an increased mean annual number of emergency department visits for pneumoconiosis, with aHRs of 1.34 (95 % CI = 1.13-1.59) and 2.31 (95 % CI = 1.94-2.76) for 1 ≤ n < 2, and n ≥ 2 compared to n < 1, respectively. LIMITATION: The database lacked detailed socioeconomic history, family history, and clinical variables. CONCLUSION: This study found that patients with pneumoconiosis have a significantly higher risk of depression than those without pneumoconiosis. Furthermore, the risk of depression increases with the frequency of emergency department visits for pneumoconiosis. Healthcare professionals should pay close attention to the mental health of patients with pneumoconiosis.

Genetic susceptibility to prostate cancer in Taiwan: A genome-wide association study.

We conducted the first genome-wide association study (GWAS) of prostate cancer (PCa) in Taiwan with 1844 cases and 80,709 controls. Thirteen independent single-nucleotide polymorphisms (SNPs) reached genome-wide significance (p < 5 × 10-8 ). Among these, three were distinct from previously identified loci: rs76072851 in CORO2B gene (15q23), odds ratio (OR) = 1.54, 95% confidence interval (CI), 1.36-1.76, p = 5.30 × 10-11 ; rs7837051, near two long noncoding RNA (lncRNA) genes, PRNCR1 and PCAT2 (8q24.21), OR = 1.41 (95% CI, 1.31-1.51), p = 8.77 × 10-21 ; and rs56339048, near an lncRNA gene, CASC8 (8q24.21), OR = 1.25 (95% CI, 1.16-1.35), p = 2.14 × 10-8 . We refined the lead SNPs for two previously identified SNPs in Taiwanese: rs13255059 (near CASC8), p = 9.02 × 10-43 , and rs1456315 (inside PRNCR1), p = 4.33 × 10-42 . We confirmed 35 out of 49 GWAS-identified East Asian PCa susceptibility SNPs. In addition, we identified two SNPs more specific to Taiwanese than East Asians: rs34295433 in LAMC1 (1q25.3) and rs6853490 in PDLIM5 (4q22.3). A weighted genetic risk score (GRS) was developed using the 40 validated SNPs and the area under the receiver-operating characteristic curve for the GRS to predict PCa was 0.67 (95% CI, 0.63-0.71). These identified SNPs provide valuable insights into the molecular mechanisms of prostate carcinogenesis in Taiwan and underscore the significant role of genetic susceptibility in regional differences in PCa incidence.

The genome-wide association study of serum IgE levels demonstrated a shared genetic background in allergic diseases.

Immunoglobulin E (IgE) synthessis is highly related to a variety of atopic diseases, and several genome-wide association studies (GWASs) have demonstrated the association between genes and IgE level. In this study, we conducted the largest genome-wide association study of IgE involving a Taiwanese Han population. Eight independent variants exhibited genome-wide significance. Among them, an intronic SNP of CD28, rs1181388, and an intergenic SNP, rs1002957030, on 11q23.2 were identified as novel signals for IgE. Seven of the loci were replicated successfully in a meta-analysis using data on Japanese population. Among all the human leukocyte antigen (HLA) regions, HLA-DQA1*03:02 - HLA-DQB1*03:03 was the most significant haplotype (OR = 1.25, SE = 0.02, FDR = 1.6 × 10-14), corresponding to HLA-DQA1 Asp160 and HLA-DQB1 Leu87 amino acid residues. The genetic correlation showed significance between IgE and allergic diseases including asthma, atopic dermatitis, and pollinosis. IgE PRS was significantly correlated with total IgE levels. Furthermore, the top decile IgE polygenic risk score (PRS) group had the highest risk of asthma for the Taiwan Biobank and Biobank Japan cohorts. IgE PRS may be used to aid in predicting the occurrence of allergic reactions before symptoms occur and biomarkers are detectable. Our study provided a more comprehensive understanding of the impact of genomic variants, including complex HLA alleles, on serum IgE levels.