SLC10A1 rs2296651 variant (S267F mutation) predicts biochemical traits, hepatitis B virus infection susceptibility and the risk of gallstone disease.

Sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter, plays a crucial role in regulating bile acid levels and influencing the risk of HBV infection. Genetic variations in the SLC10A1 gene, which encodes NTCP, affect these functions. However, the impact of SLC10A1 gene variants on the metabolic and biochemical traits remained unclear. We aimed to investigate the association of SLC10A1 gene variants with the clinical and biochemical parameters, and the risk of different HBV infection statuses and gallstone disease in the Taiwanese population. Genotyping data from 117,679 Taiwan Biobank participants were analyzed using the Axiom genome-wide CHB arrays. Regional-plot association analysis demonstrated genome-wide significant association between the SLC10A1 rs2296651 genotypes and lipid profile, gamma glutamyl transferase (γGT) level and anti-HBc-positivity. Genotype-phenotype association analyses revealed significantly lower total cholesterol, low-density lipoprotein (LDL) cholesterol and uric acid levels, a higher γGT level and a higher gallstone incidence in rare rs2296651-A allele carrier. Participants with the rs2296651 AA-genotype exhibited significantly lower rates of anti-HBc-positivity and HBsAg-positivity. Compared to those with the GG-genotype, individuals with non-GG-genotypes had reduced risks for various HBV infection statuses: the AA-genotype showed substantially lower risks, while the GA-genotype demonstrated modestly lower risks. Predictive tools also suggested that the rs2296651 variant potentially induced protein damage and pathogenic effects. In conclusion, our data revealed pleiotropic effects of the SLC10A1 rs2296651 genotypes on the levels of biochemical traits and the risk of HBV infection and gallstone disease. This confirms SLC10A1's versatility and implicates its genotypes in predicting both biochemical traits and disease susceptibility.

The joint effects of physical activity and sleep duration on risk of osteoporosis in Taiwanese adult population: The Taiwan Biobank Study.

Most studies investigating the association between physical activity and osteoporosis prevention only focused on specific types of physical activity. This study's evidence regarding the combined effects or interaction of sleep duration and physical activity. The findings emphasize the role of sleep duration and physical activity in association with osteoporosis. PURPOSE: The associations between physical activity, sleep duration, and prevalent osteoporosis in Taiwanese adults were studied in this cross-sectional study. METHODS: The Taiwan Biobank enrolled a community-based cohort of ~ 120,000 volunteers (as of April 30, 2020) between 30 and 76 years of age with no history of cancer. Amongst, bone mineral density (BMD) measures by dual-energy X-ray absorptiometry (DXA) were available in 22,402 participants. After excluding individuals who had no complete data of BMI (n = 23), MET score (n = 207), T-score (n = 8,826), and sleep duration (n = 16), 13,330 subjects were included as the primary cohort. Univariate and multivariable regression analyses were performed to determine the associations between the presence of osteoporosis, physical activity level, sleep duration, and other variables. RESULTS: The results showed that after adjustment, subjects with physical activity < 20 METs/week and ≥ 20 METs/week (aOR = 1.017 and 0.767, respectively) were associated with risk of osteoporosis than those with zero MET. The odds of osteoporosis were not significantly lower in subjects who slept for ≥ 8 h/day (aOR = 0.934,p=0.266). In addition, compared to short sleepers with no physical activity, adults with increased physical activity ≥ 20 METs/week and sleep ≥ 8 h/day had a significantly lowest likelihood of osteoporosis (aOR = 0.702). Those with medium physical activity (< 20 METs/week) plus average sleep duration (6.5-8 h/day) did not have significant higher odds of osteoporosis (aOR = 1.129,p=0.151). CONCLUSION: The findings emphasize the joint role of sleep duration and physical activity in association with osteoporosis. Adults with high physical activity plus high sleep hours have the highest BMD and lowest risk of osteoporosis.

Sex difference in the associations among risk factors with gastroesophageal reflux disease in a large Taiwanese population study.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common global health issue. Previous studies have revealed a higher prevalence of GERD in females than in males, however few studies have investigated sex differences in the risk factors associated with GERD. Therefore, the aim of this population-based study was to examine sex differences in the risk factors for GERD in a large cohort of over 120,000 Taiwanese participants. METHODS: We enrolled 121,583 participants (male: 43,698; female: 77,885; mean age 49.9 ± 11.0 years) from the Taiwan Biobank. The presence of GERD was ascertained using self-reported questionnaires. Sex differences in the risk factors associated with GERD were examined using multivariable logistic regression analysis. RESULTS: The overall prevalence of GERD was 13.7%, including 13.0% in the male participants and 14.1% in the female participants (p < 0.001). Multivariable analysis showed that older age, hypertension, smoking history, alcohol history, low fasting glucose, and low uric acid were significantly associated with GERD in the male participants. In the female participants, older age, diabetes, hypertension, smoking history, alcohol history, low systolic blood pressure, low fasting glucose, high hemoglobin, high total cholesterol, low high-density lipoprotein cholesterol (HDL-C), low low-density lipoprotein cholesterol, and low uric acid were significantly associated with GERD. Significant interactions were found between sex and age (p < 0.001), diabetes (p < 0.001), smoking history (p < 0.001), fasting glucose (p = 0.002), triglycerides (p = 0.001), HDL-C (p = 0.001), and estimated glomerular filtration rate (p = 0.002) on GERD. CONCLUSIONS: Our results showed a higher prevalence of GERD among females compared to males. Furthermore, sex differences were identified in the risk factors associated with GERD, and older age, diabetes, smoking history, and low HDL-C were more closely related to GERD in females than in males.

Association between HNF4A rs1800961 polymorphisms and gallstones in a Taiwanese population.

BACKGROUND AND AIM: A large genetic effect of a novel gallstone-associated genetic variant, the hepatocyte nuclear factor 4α (HNF4A) rs1800961 polymorphism, has been identified through recent genome-wide association studies. However, this effect has not been validated in Asian populations. We investigated the association between the rs1800961 variant and gallstones among a Taiwanese population. METHODS: A total of 20 405 participants aged between 30 and 70 years voluntarily enrolled in the Taiwan Biobank. Self-report questionnaires, physical examinations, biochemical tests, and genotyping were used for analysis. The association of the HNF4A rs1800961 variant and other metabolic risks with gallstone disease was analyzed using multiple logistic regression models. RESULTS: The minor T allele of HNF4A rs1800961 was associated with an increased risk of gallstone, and the association remained significant even after adjustment for other risk factors including age, body mass index (BMI), diabetes, hyperlipidemia, hypertension, and cigarette smoking (adjusted odds ratio [OR] = 1.90, 95% confidence interval [CI] = 1.31 to 2.75) in male participants. When further stratified by BMI and age, the lithogenic effect was the most significant in male participants with obesity (adjusted OR = 3.55, 95% CI = 1.92 to 6.56) and who were younger (adjusted OR = 2.45, 95% CI = 1.49 to 4.04). CONCLUSION: The novel gallstone-associated HNF4A rs1800961 variant was associated with the risk of gallstone in the Taiwanese men. Screening for the rs1800961 polymorphism may be particularly useful in assessing the risk of gallstone formation in younger or obese men.

Adiposity indices and their higher predictive value for new-onset hypertension in metabolically healthy young women: findings from a population-based prospective cohort study.

BACKGROUND AND AIMS: The present study aimed to investigate the predictive ability of selected adiposity indices, such as body mass index (BMI), waist-to-hip ratio (WHR), waist circumference (WC), and waist-to-height ratio (WHtR), for new-onset hypertension in metabolically healthy Taiwanese adults. The study also sought to establish sex-specific cutoff points for these indices and to analyze the risk of new-onset hypertension, taking into account sex and age. METHODS: This prospective cohort study utilized the Taiwan Biobank database to examine metabolically healthy participants aged between 20 and 65 at baseline. Four adiposity indices, namely BMI, WHR, WC, and WHtR, were calculated and used to predict new-onset hypertension over 4 years. Receiver operating characteristics (ROCs) and areas under the curve (AUCs) were used to evaluate the effectiveness of the parameters in predicting new-onset hypertension over 4 years. Sex-specific cutoff points were identified and used to assess the risk of new-onset hypertension. RESULTS: This study analyzed 13,375 participants over 4.28 years. The incidence of new-onset hypertension was 17.65%. The new-onset rate of hypertension was 34.39% in men and 65.61% in women. Adiposity indices effectively predict new-onset hypertension, with WHtR having the highest predictive value (i.e., AUC) for both sexes. The classification of participants into low and high categories for each adiposity index was based on sex-specific cutoff points, and the risk of new-onset hypertension was assessed according to sex and age. This study found that high adiposity indices predicted a significantly higher risk of new-onset hypertension in metabolically healthy adults. The risk was equal for both sexes. Young women had a higher risk of new-onset hypertension than middle-aged women when they were further categorized. All risk ratios of the indices in young women were over two-fold and significant. CONCLUSION: According to the sex-specific cutoff point, high adiposity indices had a higher predictive value for new-onset hypertension in metabolically healthy Taiwanese young women.

Comparison of Demographic and Clinical Characteristics of Taiwan Biobank Participants with Nonparticipants.

BACKGROUND: This study investigated fundamental demographic variables within the Taiwan Biobank (TWBB) and compared them with national demographic statistics. Additionally, a matched cohort analysis compared TWBB participants with nonparticipants to uncover disparities in sociodemographic and clinical characteristics. METHODS: A total of 128,663 individuals aged 30 to 70 without cancer were recruited within the TWBB, and 514,652 nonparticipants matched by age and sex were randomly selected from the National Health Insurance claims database. Sociodemographic variables, healthcare utilization metrics, underlying medical conditions, and subsequent mortality and cancer risk were analyzed. RESULTS: TWBB participants were more likely to be female, older, married, higher educated, with higher incomes, and urban residency. Healthcare utilization metrics showed minimal differences. Pre-cohort entry, TWBB participants had a higher prevalence of certain medical conditions, such as peptic ulcer disease, osteoarthritis, osteoporosis, and uterine leiomyoma in females. During follow-up periods, elevated mortality rates were observed among TWBB participants but decreased cancer risk. CONCLUSION: The TWBB cohort exhibits disparities in sociodemographic and health-related attributes compared to the general population, comprising older, females, married, higher educated, higher income, and predominantly in urban areas. While mortality rates are slightly elevated within the TWBB cohort, cancer incidence rates are lower. Despite limitations in representativeness, the TWBB's size and exposure measures offer valuable insights into associations between exposures and health conditions.

Sex difference in the associations among secondhand smoke with metabolic syndrome in non-smokers in a large Taiwanese population follow-up study.

Close associations among secondhand smoke (SHS) and metabolic syndrome (MetS) and its components have been demonstrated, however sex differences in these associations remain unclear. We collected 121,364 participants from the Taiwan Biobank, and excluded those with smoking history, the remaining 88,297 participants (male: 18,595; female: 69,702; mean age 50.1 ± 11.0 years) were included. SHS exposure was evaluated based on self-reported questionnaires. SHS was associated with MetS (odds ratio [OR], 1.268, p < 0.001 for males vs. 1.180, p < 0.001 for females), abdominal obesity (OR, 1.234, p < 0.001 for males vs. 1.199, p < 0.001 for females), low high-density lipoprotein cholesterol (OR, 1.183, p = 0.008 for males vs. 1.094, p = 0.011 for females), hyperglycemia (OR, 1.286, p < 0.001 for males vs. 1.234, p < 0.001 for females), but not with hypertriglyceridemia. SHS was associated with high blood pressure (BP) (OR, 1.278, p < 0.001) only in males, but not in females. Furthermore, significant interactions were found between sex x SHS on MetS (p = 0.023), abdominal obesity (p = 0.032), and elevated BP (p < 0.001). Moreover, the participants who were exposed to SHS for ≥1 hour per week were associated with a higher risk (OR = 1.316, p = 0.001 in males vs. OR = 1.220, p < 0.001 in females) of MetS compared to those with no exposure. These results showed an association between SHS and a high OR for MetS in both the males and females. Furthermore, sex differences were identified in the associations between SHS and MetS and its components, and SHS was more closely related to MetS, abdominal obesity, and high BP in males than in females.

Multi-ethnic Imputation System (MI-System): A genotype imputation server for high-dimensional data.

OBJECTIVE: Genotype imputation is a commonly used technique that infers un-typed variants into a study's genotype data, allowing better identification of causal variants in disease studies. However, due to overrepresentation of Caucasian studies, there's a lack of understanding of genetic basis of health-outcomes in other ethnic populations. Therefore, facilitating imputation of missing key-predictor-variants that can potentially improve a risk health-outcome prediction model, specifically for Asian ancestry, is of utmost relevance. METHODS: We aimed to construct an imputation and analysis web-platform, that primarily facilitates, but is not limited to genotype imputation on East-Asians. The goal is to provide a collaborative imputation platform for researchers in the public domain towards rapidly and efficiently conducting accurate genotype imputation. RESULTS: We present an online genotype imputation platform, Multi-ethnic Imputation System (MI-System) (https://misystem.cgm.ntu.edu.tw/), that offers users 3 established pipelines, SHAPEIT2-IMPUTE2, SHAPEIT4-IMPUTE5, and Beagle5.1 for conducting imputation analyses. In addition to 1000 Genomes and Hapmap3, a new customized Taiwan Biobank (TWB) reference panel, specifically created for Taiwanese-Chinese ancestry is provided. MI-System further offers functions to create customized reference panels to be used for imputation, conduct quality control, split whole genome data into chromosomes, and convert genome builds. CONCLUSION: Users can upload their genotype data and perform imputation with minimum effort and resources. The utility functions further can be utilized to preprocess user uploaded data with easy clicks. MI-System potentially contributes to Asian-population genetics research, while eliminating the requirement for high performing computational resources and bioinformatics expertise. It will enable an increased pace of research and provide a knowledge-base for genetic carriers of complex diseases, therefore greatly enhancing patient-driven research. STATEMENT OF SIGNIFICANCE: Multi-ethnic Imputation System (MI-System), primarily facilitates, but is not limited to, imputation on East-Asians, through 3 established prephasing-imputation pipelines, SHAPEIT2-IMPUTE2, SHAPEIT4-IMPUTE5, and Beagle5.1, where users can upload their genotype data and perform imputation and other utility functions with minimum effort and resources. A new customized Taiwan Biobank (TWB) reference panel, specifically created for Taiwanese-Chinese ancestry is provided. Utility functions include (a) create customized reference panels, (b) conduct quality control, (c) split whole genome data into chromosomes, and (d) convert genome builds. Users can also combine 2 reference panels using the system and use combined panels as reference to conduct imputation using MI-System.

The impact of secondhand smoke on the development of kidney stone disease is not inferior to that of smoking: a longitudinal cohort study.

BACKGROUND: Tobacco use and secondhand smoke (SHS) are risk factors of kidney stone disease (KSD). The hypothesis is that tobacco produces chemicals that increase oxidative stress and vasopressin, which leads to decreased urine output, and contributes to stone formation. The aim of this study was to examine the effects of smoking and SHS on the development of KSD. MATERIALS AND METHODS: We analyzed a total of 25,256 volunteers with no history of KSD participated in the Taiwan Biobank. The presence of underlying and follow-up KSD was surveyed by a self-administrated questionnaire. They were classified into three groups on the basis of smoking and SHS exposure, accessed with survey questionnaires; never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups. RESULTS: KSD was noted in 352 (2.0%), 50 (3.3%) and 240 (4.1%) subjects in the never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups, respectively, with a mean follow-up of 4 years. The odds ratio (OR) of KSD was higher in the never-smokers with SHS exposure (OR, 1.622; 95% confidence interval [95% CI], 1.225 to 2.255) and ever-smokers groups (OR, 1.282; 95% CI, 1.044 to 1.574) than in the never-smokers with no SHS exposure group after adjustment of confounders. In addition, never-smokers with SHS exposure had similar effects on the development of KSD than ever-smokers (OR, 1.223; 95% CI, 0.852 to 1.756). CONCLUSION: Our study suggests that both smoking and SHS are a risk factor for developing KSD and that the impact of SHS is not inferior to that of smoking. TRIAL REGISTRATION: The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20,210,058).

Genome-wide causal mediation analysis identifies genetic loci associated with uterine fibroids mediated by age at menarche.

STUDY QUESTION: Could the direct contribution of genetic variants to the pathophysiology of uterine fibroids and the contribution mediated by age at menarche be different? SUMMARY ANSWER: Age at menarche plays a mediation role in the genetic influence on uterine fibroids, and four causal genetic mechanisms underlying the age at menarche-mediated effects of common genetic loci on uterine fibroid development were identified. WHAT IS KNOWN ALREADY: Uterine fibroids are common benign tumors developing from uterine smooth muscle. Genome-wide association studies (GWASs) have identified over 30 genetic loci associated with uterine fibroids in different ethnic populations. Several genetic variations in or nearby these identified loci were also associated with early age at menarche, one of the major risk factors of uterine fibroids. Although the results of GWASs reveal how genetic variations affect uterine fibroids, the genetic mechanism of uterine fibroids mediated by age at menarche remains elusive. STUDY DESIGN, SIZE, DURATION: In this study, we conducted a genome-wide causal mediation analysis in two cohorts covering a total of 69 552 females of Han Chinese descent from the Taiwan Biobank (TWB). TWB is an ongoing community- and hospital-based cohort aiming to enroll 200 000 individuals from the general Taiwanese population between 30 and 70 years old. It has been enrolling Taiwanese study participants since 2012 and has extensive phenotypic data collected from 148 291 individuals as of May 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We recruited individuals in two cohorts, with 13 899 females in TWB1 and 55 653 females in TWB2. The two sets of individuals are almost distinct, with only 730 individuals enrolled in both cohorts. Over 99% of the participants are Han Chinese. Approximately 21% of participants developed uterine fibroids. DNA samples from both cohorts were genotyped using two different customized chips (TWB1 and TWB2 arrays). After quality control and genotype imputation, 646 973 TWB1 single-nucleotide polymorphisms (SNPs) and 686 439 TWB2 SNPs were assessed in our analysis. There were 99 939 SNPs which overlapped between the TWB1 and TWB2 arrays, 547 034 TWB1 array-specific SNPs and 586 500 TWB2 array-specific SNPs. We performed GWASs for screening potential risk SNPs for age at menarche and for uterine fibroids. We subsequently identified causal mediation effects of risk SNPs on uterine fibroids mediated by age at menarche. MAIN RESULTS AND THE ROLE OF CHANCE: In addition to known loci at LIN28B associated with age at menarche and loci at WNT4 associated with uterine fibroids, we identified 162 SNPs in 77 transcripts that were associated with menarche-mediated causal effects on uterine fibroids via four different causal genetic mechanisms: a both-harmful group with 52 SNPs, a both-protective group with 34 SNPs, a mediator-harmful group with 22 SNPs and a mediator-protective group with 54 SNPs. Among these SNPs, rs809302 in SLK significantly increased the risk of developing uterine fibroids by 3.92% through a mechanism other than age at menarche (P < 10-10), and rs371721345 in HLA-DOB was associated with a 2.70% decreased risk (P < 10-10) in the occurrence of uterine fibroids, mediated by age at menarche. These findings provide insights into the mechanism underlying the effect of genetic loci on uterine fibroids mediated by age at menarche. LIMITATIONS, REASONS FOR CAUTION: A potential issue is that the present study relied upon self-reported age at menarche and uterine fibroid information. Due to the experimental design, the consistency between self-reports and medical records for uterine fibroids in Taiwan cannot be checked. Fortunately, the literature support that self-reporting even years later remains a practical means for collecting data on menarche and uterine fibroids. We found that the impact of under-reporting of uterine fibroids is less in our study. In addition, the rate of reporting a diagnosis of uterine fibroids was within the rates of medical diagnosis based on national health insurance data. Future work investigating the consistency between self-reports and medical records in Taiwan can remedy this issue. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to investigate whether and to what extent age at menarche mediates the causal effects of genetic variants on uterine fibroids by using genome-wide causal mediation analysis. By treating age at menarche as a mediator, this report provides an insight into the genetic risk factors for developing uterine fibroids. Thus, this article represents a step forward in deciphering the role of intermediated risk factors in the genetic mechanism of disease. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the China Medical University, Taiwan (CMU110-ASIA-13 and CMU107-Z-04), the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-039-058) and the International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo, Japan (K2104). The authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study.

PCSK9 is a candidate locus for low-density lipoprotein cholesterol (LDL-C) levels. The cause-effect relationship between LDL-C levels and diabetes mellitus (DM) has been suggested to be mechanism-specific. To identify the role of PCSK9 and genome-wide association study (GWAS)-significant variants in LDL-C levels and the risk of DM by using Mendelian randomization (MR) analysis, a total of 75,441 Taiwan Biobank (TWB) participants was enrolled for a GWAS to determine common and rare PCSK9 variants and their associations with LDL-C levels. MR studies were also conducted to determine the association of PCSK9 variants and LDL-C GWAS-associated variants with DM. A regional plot association study with conditional analysis of the PCSK9 locus revealed that PCSK9 rs10788994, rs557211, rs565436, and rs505151 exhibited genome-wide significant associations with serum LDL-C levels. Imputation data revealed that three rare nonsynonymous mutations-namely, rs151193009, rs768846693, and rs757143429-exhibited genome-wide significant association with LDL-C levels. A stepwise regression analysis indicated that seven variants exhibited independent associations with LDL-C levels. On the basis of two-stage least squares regression (2SLS), MR analyses conducted using weighted genetic risk scores (WGRSs) of seven PCSK9 variants or WGRSs of 41 LDL-C GWAS-significant variants revealed significant association with prevalent DM (p = 0.0098 and 5.02 × 10-7, respectively), which became nonsignificant after adjustment for LDL-C levels. A sensitivity analysis indicated no violation of the exclusion restriction assumption regarding the influence of LDL-C-level-determining genotypes on the risk of DM. Common and rare PCSK9 variants are independently associated with LDL-C levels in the Taiwanese population. The results of MR analyses executed using genetic instruments based on WGRSs derived from PCSK9 variants or LDL-C GWAS-associated variants demonstrate an inverse association between LDL-C levels and DM.

Synergistic Effects of Weighted Genetic Risk Scores and Resistin and sST2 Levels on the Prognostication of Long-Term Outcomes in Patients with Coronary Artery Disease.

Resistin and soluble suppression of tumorigenicity 2 (sST2) are useful predictors in patients with coronary artery disease (CAD). Their serum levels are significantly attributed to variations in RETN and IL1RL1 loci. We investigated candidate variants in the RETN locus for resistin levels and those in the IL1RL1 locus for sST2 levels and evaluated the prognostication of these two biomarkers and the corresponding variants for long-term outcomes in the patients with CAD. We included 4652, 557, and 512 Chinese participants from the Taiwan Biobank (TWB), cardiovascular health examination (CH), and CAD cohorts, respectively. Candidate variants in RETN and IL1RL1 were investigated using whole-genome sequence (WGS) and genome-wide association study (GWAS) data in the TWB cohort. The weighted genetic risk scores (WGRS) of RETN and IL1RL1 with resistin and sST2 levels were calculated. Kaplan-Meier curves were used to analyze the prognostication of resistin and sST2 levels, WGRS of RETN and IL1RL1, and their combinations. Three RETN variants (rs3219175, rs370006313, and rs3745368) and two IL1RL1 variants (rs10183388 and rs4142132) were independently associated with resistin and sST2 levels as per the WGS and GWAS data in the TWB cohort and were further validated in the CH and CAD cohorts. In combination, these variants explained 53.7% and 28.0% of the variation in resistin and sST2 levels, respectively. In the CAD cohort, higher resistin and sST2 levels predicted higher rates of all-cause mortality and major adverse cardiac events (MACEs) during long-term follow-up, but WGRS of RETN and IL1RL1 variants had no impact on these outcomes. A synergistic effect of certain combinations of biomarkers with RETN and IL1RL1 variants was found on the prognostication of long-term outcomes: Patients with high resistin levels/low RETN WGRS and those with high sST2 levels/low IL1RL1 WGRS had significantly higher all-cause mortality and MACEs rates, and those with both these combinations had the poorest outcomes. Both higher resistin and sST2 levels, but not RETN and IL1RL1 variants, predict poor long-term outcomes in patients with CAD. Furthermore, combining resistin and sST2 levels with the WGRS of RETN and IL1RL1 genotyping exerts a synergistic effect on the prognostication of CAD outcomes. Future studies including a large sample size of participants with different ethnic populations are needed to verify this finding.

Polygenic approaches to detect gene-environment interactions when external information is unavailable.

The exploration of 'gene-environment interactions' (G × E) is important for disease prediction and prevention. The scientific community usually uses external information to construct a genetic risk score (GRS), and then tests the interaction between this GRS and an environmental factor (E). However, external genome-wide association studies (GWAS) are not always available, especially for non-Caucasian ethnicity. Although GRS is an analysis tool to detect G × E in GWAS, its performance remains unclear when there is no external information. Our 'adaptive combination of Bayes factors method' (ADABF) can aggregate G × E signals and test the significance of G × E by a polygenic test. We here explore a powerful polygenic approach for G × E when external information is unavailable, by comparing our ADABF with the GRS based on marginal effects of SNPs (GRS-M) and GRS based on SNP × E interactions (GRS-I). ADABF is the most powerful method in the absence of SNP main effects, whereas GRS-M is generally the best test when single-nucleotide polymorphisms main effects exist. GRS-I is the least powerful test due to its data-splitting strategy. Furthermore, we apply these methods to Taiwan Biobank data. ADABF and GRS-M identified gene × alcohol and gene × smoking interactions on blood pressure (BP). BP-increasing alleles elevate more BP in drinkers (smokers) than in nondrinkers (nonsmokers). This work provides guidance to choose a polygenic approach to detect G × E when external information is unavailable.

Genetic variants associated with serum alanine aminotransferase levels among patients with hepatitis C virus infection: A genome-wide association study.

Information on genetic variants associated with elevated serum alanine aminotransferase (ALT) levels remains limited. A genome-wide association study was performed to identify single-nucleotide polymorphisms (SNPs) associated with ALT levels. The ALT-associated SNP was further evaluated for hepatocellular carcinoma (HCC) risk. A cohort of 892 anti-HCV seropositive patients was used for genome-wide SNP array to examine the associations with baseline ALT levels. SNPs <10-5 were further tested for associations with serial ALT levels then validated in 486 anti-HCV seropositives. Multinomial logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals of SNPs associated with ALT. The SNP was evaluated for HCC risk by using Cox's proportional hazards models. After quality control, 803 participants with 564,464 SNPs were included in the analysis. Of these, 12 SNPs were associated with ALT (p < 10-5 ). Among the participants, 158 (19.7%) had ALT persistently ≤15 U/L, 327 (40.7%) ever >15 U/L but never >45 U/L, and 318 (39.6%) ever >45 U/L during follow-up. The rs568800 was associated with serial ALT levels, and this was replicated in the external population significantly (p < .05). The A allele (vs C) of rs568800 was associated with ALT >15 U/L but ≤45 U/L and ALT >45 U/L, with the adjusted ORs of 1.41 (1.11-1.78) and 1.86 (1.34-2.60), respectively. The adjusted HRs for HCC were 2.09 (0.90-4.89) for AC and 2.64 (1.13-6.17) for AA (CC as a reference). In conclusion, the rs568800 was associated with serum ALT levels and HCC risk. Clinical utility should be evaluated among patients who have received antivirals.

PM2.5 exposure and DLEC1 promoter methylation in Taiwan Biobank participants.

BACKGROUND: Particulate matter (PM) < 2.5 µm (PM2.5) or fine PM is a serious public health concern. It affects DNA methylation and heightens carcinogenesis. Deleted in lung and esophageal cancer 1 (DLEC1) is a tumor suppressor gene. However, aberrant methylation of the gene is associated with several cancers. We evaluated the association between PM2.5 and DLEC1 promoter methylation in Taiwanese adults based on regular outdoor exercise. METHODS: We obtained DNA methylation and exercise data of 496 participants (aged between 30 and 70 years) from the Taiwan Biobank (TWB) database. We also extracted PM2.5 data from the Air Quality Monitoring Database (AQMD) and estimated participants' exposure using residential addresses. RESULTS: DLEC1 methylation and PM2.5 were positively associated: beta coefficient (ß) = 0.114 × 10-3; p value = 0.046. The test for interaction between exercise and PM2.5 on DLEC1 methylation was significant (p value = 0.036). After stratification by exercise habits, PM2.5 and DLEC1 methylation remained significantly associated only among those who exercised regularly (ß = 0.237 × 10-3; p value = 0.007). PM2.5 quartile-stratified analyses revealed an inverse association between regular exercise and DLEC1 methylation at PM2.5 < 27.37 µg/m3 (ß = - 5.280 × 10-3; p value = 0.009). After combining exercise habits and PM2.5 quartiles, one stratum (i.e., regular exercise and PM2.5 < 27.37 µg/m3) was inversely associated with DLEC1 methylation (ß = -5.160 × 10-3, p value = 0.007). CONCLUSIONS: We found significant positive associations between PM2.5 and DLEC1 promoter methylation. Regular exercise at PM2.5 < 27.37 µg/m3 seemingly regulated DLEC1 promoter methylation.

Trends in age at menarche from 1943 through 1989 in Taiwan: A retrospective population-based analysis.

BACKGROUND: Recent studies have demonstrated a global decline in the age at menarche. Our study aimed to determine the age at menarche of Taiwanese women born between 1943 and 1989. METHODS: Data were obtained from the Taiwan Biobank. To view the trends in age at menarche, we analyzed data from 74,799 women. The mean, standard deviation, and annual percentage change in age at menarche were calculated for birth-year cohorts. RESULTS: The mean age at menarche of Taiwanese women born in 1943 was 14.85 years. The age at menarche decreased to 12.20 years for those born in 1989. The mean age at menarche declined by 2.65 years across the 47-year study period; hence, the reduction rate was 0.56 years per decade. This study demonstrated a downward secular trend in the age at menarche of Taiwanese women born between 1943 and 1989. This trend occurred in three stages of decline: fast (1943-1953), slow (1953-1965), and moderate (1965-1989). CONCLUSION: The age at menarche decreased by 2.65 years among Taiwanese women born in 1943 compared with those born in 1989. This decline occurred in three stages: fast (1943-1953), slow (1953-1965), and moderate (1965-1989). This significant downward secular trend in age at menarche reflects Taiwan's socioeconomic development.

Mendelian randomization analysis on the impacts of age at menarche on adult height: A Taiwanese population study.

BACKGROUNDS: Ample evidence supports potential influence of age at menarche (AM) on adult height (AH), but multiple confounders may affect causal estimates. To address this issue, the Mendelian randomization (MR) analysis was used to explore the causal impacts of AM on AH. METHODS: Using data (n = 57,349) from the publicly accessible Taiwan Biobank and randomly splitting them into 2 equal-size subsets, we identified single nucleotide polymorphisms (SNPs) significantly associated with AM in the exploration subset and used these SNPs as instrumental variables to estimate the effects of instruments on AH in the validation subset based on two stage least squares (2SLS) regression. In addition, three more summary statistics-based approaches, namely inverse variance weighted (IVW), MR-Egger, and weighted median (WM) analyses, were used to verify the findings. We also performed heterogeneity and sensitivity analyses to evaluate the robustness of the results. RESULTS: We identified 4 leading SNPs associated with AM at the genome-wide significant level, whereas rs9409082 may exert some pleiotropic effects on AH. After eliminating rs9409082, the 2SLS analysis indicated that one year delay in genetically determined AM predicted 1.5 cm height gain in adulthood (ß = 1.508, 95% confidence interval [0.852, 2.163]). The causal relationship was also supported by WM (ß = 1.183, [0.329, 2.038]) and IVW (ß = 1.493, [0.523, 2.463]) methods. CONCLUSIONS: Evidence from the present MR study supports a causal relationship between later AM and taller AH.

High Obesity Indices Are Associated with Gastroesophageal Reflux Disease, but Low Obesity Indices Are Associated with Peptic Ulcer Disease in a Large Taiwanese Population Study.

INTRODUCTION: Gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD) are prevalent in Taiwan. Few studies have investigated the associations between obesity indices with GERD and PUD simultaneously. This study aimed to investigate the correlations among obesity indices with GERD and PUD in a large cohort of participants, around 120,000, in the Taiwan Biobank (TWB). METHODS: A total of 121,583 participants (male: 43,698; female: 77,885; mean age 49.9 ± 11.0 years) were included to analyze the associations among obesity indices, including body mass index (BMI), waist-hip ratio (WHR), waist-to-height ratio (WHtR), body roundness index (BRI), abdominal volume index (AVI), lipid accumulation product (LAP), visceral adiposity index (VAI), and triglyceride-glucose index (TyG index), with GERD and PUD. Self-reported GERD and PUD were obtained by questionnaires. Multivariate logistic regression analysis was employed to analyze the relationship between obesity indices with GERD and PUD. RESULTS: The prevalence of GERD and PUD was 13.7% and 14.6%, respectively. After multivariable analysis, high WHR (odds ratio [OR] = 1.009, p < 0.001), WHtR (OR = 1.005, p = 0.003), BRI (OR = 1.022, p = 0.005), AVI (OR = 1.013, p < 0.001), LAP (OR = 1.001, p < 0.001), TyG index (OR = 1.068, p < 0.001), and VAI (OR = 1.013, p = 0.002) were significantly associated with GERD, except BMI (p = 0.384). On the other hand, low BMI (OR = 0.984; p < 0.001) and AVI (OR = 0.994; p = 0.036) were significantly associated with PUD. However, the values of WHR (p = 0.151), WHtR (p = 0.304), BRI (p = 0.452), LAP (p = 0.799), VAI (p = 0.347), and TyG index (p = 0.642) were not. CONCLUSION: This study found that high obesity indices are associated with GERD, but low obesity indices are associated with PUD in a large Taiwanese population study. Our findings may alert physicians to notice that different obesity index may be associated with different gastrointestinal disorder.

Sex difference in the associations among hyperuricemia with self-reported peptic ulcer disease in a large Taiwanese population study.

Background: Hyperuricemia may play a role in various systemic diseases. However, few studies have investigated the relationship between hyperuricemia and the risk of peptic ulcer disease (PUD). Therefore, in this population-based study, we enrolled over 120,000 participants from the Taiwan Biobank (TWB) and examined the risk factors for self-reported PUD. In addition, we investigated sex differences in the association between hyperuricemia and self-reported PUD. Methods: Data of 121,583 participants were obtained from the TWB. Male participants with a serum uric acid level >7 mg/dl and female participants with a serum uric acid level >6 mg/dl were classified as having hyperuricemia. Details of self-reported PUD were obtained by questionnaire. The association between hyperuricemia and self-reported PUD in the male and female participants was examined using multivariable logistic regression analysis. Results: The overall prevalence of self-reported PUD was 14.6%, with a higher incidence in males (16.5%) compared to females (13.5%). After multivariable adjustment, male sex [vs. female sex; odds ratio (OR) = 1.139; 95% confidence interval (CI) = 1.084-1.198; p < 0.001], and hyperuricemia (OR = 0.919; 95% CI = 0.879-0.961; p < 0.001) were significantly associated with self-reported PUD. Further, a significant interaction was found between sex and hyperuricemia on self-reported PUD (p = 0.004). Hyperuricemia was associated with a low risk of self-reported PUD in males (OR = 0.890; 95% CI = 0.837-0.947; p < 0.001) but not in females (p = 0.139). Conclusion: The prevalence of self-reported PUD was higher in the male participants than in the female participants. Hyperuricemia was associated with low prevalence of self-reported PUD in males, but not in females. Further studies are needed to clarify the mechanisms behind these observations and verify the potential protective role of hyperuricemia on the development of self-reported PUD.

Sex differences in the association of long-term exposure to heat stress on kidney function in a large Taiwanese population study.

The incidence and prevalence of dialysis in Taiwan are high compared to other regions. Consequently, mitigating chronic kidney disease (CKD) and the worsening of kidney function have emerged as critical healthcare priorities in Taiwan. Heat stress is known to be a significant risk factor for CKD and kidney function impairment. However, differences in the impact of heat stress between males and females remains unexplored. We conducted this retrospective cross-sectional analysis using data from the Taiwan Biobank (TWB), incorporating records of the wet bulb globe temperature (WBGT) during midday (11 AM-2 PM) and working hours (8 AM-5 PM) periods based on the participants' residential address. Average 1-, 3-, and 5-year WBGT values prior to the survey year were calculated and analyzed using a geospatial artificial intelligence-based ensemble mixed spatial model, covering the period from 2010 to 2020. A total of 114,483 participants from the TWB were included in this study, of whom 35.9% were male and 1053 had impaired kidney function (defined as estimated glomerular filtration rate < 60 ml/min/1.73 m2). Multivariable analysis revealed that in the male participants, during the midday period, the 1-, 3-, and 5-year average WBGT values per 1 â„ƒ increase were significantly positively associated with eGFR < 60 ml/min/1.73 m2 (odds ratio [OR], 1.096, 95% confidence interval [CI] = 1.002-1.199, p = 0.044 for 1 year; OR, 1.093, 95% CI = 1.000-1.196, p = 0.005 for 3 years; OR, 1.094, 95% CI = 1.002-1.195, p = 0.045 for 5 years). However, significant associations were not found for the working hours period. In the female participants, during the midday period, the 1-, 3-, and 5-year average WBGT values per 1 â„ƒ increase were significantly negatively associated with eGFR < 60 ml/min/1.73 m2 (OR, 0.872, 95% CI = 0.778-0.976, p = 0.018 for 1 year; OR, 0.874, 95% CI = 0.780-0.978, p = 0.019 for 3 years; OR, 0.875, 95% CI = 0.784-0.977, p = 0.018 for 5 years). In addition, during the working hours period, the 1-, 3-, and 5-year average WBGT values per 1 â„ƒ increase were also significantly negatively associated with eGFR < 60 ml/min/1.73 m2 (OR, 0.856, 95% CI = 0.774-0.946, p = 0.002 for 1 year; OR, 0.856, 95% CI = 0.774-0.948, p = 0.003 for 3 years; OR, 0.853, 95% CI = 0.772-0.943, p = 0.002 for 5 years). In conclusion, our results revealed that increased WBGT was associated with impaired kidney function in males, whereas increased WBGT was associated with a protective effect against impaired kidney function in females. Further studies are needed to elucidate the exact mechanisms underlying these sex-specific differences.