Lipocalin-2 (LCN2) level, leukocyte count (LC), and renal function are key biomarkers linked to inflammation and metabolism. We aimed to explore the genetic determinants, causal associations, and long-term outcome effects of LCN2 levels. Phenotypic associations, genome-wide association studies (GWASs), linkage disequilibrium score regression (LDSC), and Mendelian randomization (MR) analyses for genetic correlation and causal associations between LCN2, LC, and estimated glomerular filtration rate (eGFR) were performed in 8208, 117,666, and 117,666 Taiwan Biobank participants, respectively. Long-term outcome analyses were performed for LCN2 in 481 patients with coronary artery disease (CAD). Elevated LCN2 levels were associated with older age, male sex, and altered metabolic parameters. GWAS of LCN2 levels identified genome-wide significant loci on LCN2, GSDMA, and MYB. LDSC revealed a limited number of shared loci between LCN2 level, LC and eGFR rather than broad polygenic overlap. MR analyses showed weighted genetic risk scores for LC and eGFR were significantly associated with LCN2 levels, which remain significant even at multivariate analysis (p = 0.0123 and p = 0.0010, respectively). Sensitivity analyses confirmed the robustness of causal estimates. Kaplan–Meier survival and Cox regression analyses further indicated that elevated LCN2 level, especially when combined with C-reactive protein levels, is an independent predictor of all-cause mortality and combined cerebral and cardiovascular event rates in CAD patients. Taken together, these results indicate that circulating LCN2 is largely a downstream marker of immune activation and impaired renal function. Elevated LCN2 levels independently predict poor long-term outcomes of CAD.

We aimed to determine whether the genetically predicted triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, is associated with cardiovascular-kidney-metabolic (CKM) stage severity and whether these associations are consistent with a potential causal role of insulin resistance within the CKM staging framework. The associations between the TyG index and CKM stages were assessed among 107,161 Taiwan Biobank participants using multivariable regression. CKM stages 3 and 4 were combined as the advanced CKM stage group. A genome-wide association study (GWAS) in 104,778 participants identified genetic determinants of the TyG index, followed by Mendelian randomization (MR), weighted genetic risk score (wGRS) analyses, and sample-split MR analyses. CKM stage severity was evaluated using ordinal regression analysis, a sensitivity analysis (CKM stages ≥ 1 vs. stage 0), and a later-stage comparison analysis (CKM stages ≥ 2 vs. stages 0-1). The TyG index increased progressively across CKM stages. GWAS identified 61 genome-wide significant loci associated with the TyG index. MR analyses demonstrated that genetically predicted TyG index was associated with greater CKM stage severity across all models, with consistent findings in the sample-split analyses. Genetic associations were modest for CKM stage 1 versus stage 0 but became substantially stronger for CKM stage 2 and the advanced CKM stages. Genetically predicted TyG index was associated with higher CKM stage severity in a stage-dependent manner, with substantially stronger genetic associations from CKM stage 2 onward. These findings are consistent with a potential causal role of insulin resistance in CKM stage severity and highlight the TyG index as a complementary biomarker for metabolic risk stratification.

Human resistin is a proinflammatory cytokine involving the development and progression of cancer and cardiovascular diseases. However, prediction of long-term outcome using circulating resistin level and its genetic determinants in a population-based study remain to be explored. After genome-wide association study (GWAS), DNA methylation (DNAm) analysis and functional assays of a RETN rs370006313 variant, we tested whether resistin level and its genetic determinants can be used to determine the long-term outcomes of 5678 Taiwan Biobank (TWB) participants. GWAS and DNAm analysis revealed RETN variants, rs3219175, rs370006313, and rs3745368, and DNAm sites, cg21271423 and cg09909011, independently associated with circulating resistin levels. Functional assays showed rs370006313 variant played a key role in affecting RETN promoter activity, whereas genotypes of rs3219175 and rs3745368, but not rs370006313, exhibited genome-wide significant associations with RETN promoter DNAm levels. Using Kaplan-Meier survival and Cox regression analyses, participants with progressively increasing resistin levels had a higher hazard ratio for all-cause mortality and cancer mortality compared to those with lower resistin levels. Participants with all three RETN variants (high mutation burden) also exhibited significantly higher hazard ratios for all-cause mortality and cancer mortality, at 3.99 and 5.55, respectively, compared to those without a high mutation burden. In conclusion, RETN rs370006313 is a functional variant affecting RETN promoter activity. Elevated circulating resistin levels and a high RETN mutation burden predict all-cause and cancer mortality in TWB participants. Both resistin levels and RETN variants may serve as biomarkers of long-term outcomes in the general Taiwanese populations.

BACKGROUND:Circulating PCSK9 concentrations have been linked to various metabolic disorders, with evidence suggesting sex-specific differences-stronger associations in women and inconsistent findings in men. METHODS:This study enrolled 7,950 participants from the Taiwan Biobank. Associations of PCSK9 concentration with insulin resistance (IR), metabolic syndrome (MetS), diabetes mellitus (DM), and long-term outcomes were analyzed. Anthropometric, biochemical, and hematologic parameters were examined in a subgroup of 6,478 participants, and 4,185 participants underwent abdominal sonography for the assessment of metabolic dysfunction-associated steatotic liver disease (MASLD). RESULTS:Increasing PCSK9 concentrations and quartiles were significantly associated with older age, female sex, adverse cardiometabolic traits, and several hematological parameters. Higher hematocrit count, higher triglyceride, low-density lipoprotein cholesterol, fasting plasma glucose, and gamma-glutamyl transferase concentrations, and lower total bilirubin concentrations were independently associated with high PCSK9 concentration, with these associations being more pronounced among female participants. Higher platelet count was independently associated with high PCSK9 concentration only in female participants. Odds ratios for IR, MetS, DM, and MASLD increased progressively across PCSK9 quartiles, with stronger associations in women. Kaplan-Meier survival and Cox regression analyses indicated associations of high PCSK9 concentration with higher all-cause, non-cardiovascular, and cancer mortalities, especially in women. CONCLUSION:High circulating PCSK9 concentration is independently associated with increased risks of IR, MetS, DM, MASLD, and all-cause and cancer mortality, indicating poor metabolic profiles and outcomes in the Taiwanese population. These associations are stronger in women, highlighting the importance of sex-specific risk evaluation in metabolic diseases and long-term outcomes.

YKL-40, an obesity-related inflammatory biomarker, has inconsistently been associated with insulin resistance, and its relationship with metabolic syndrome is not well established. This study investigated the associations of YKL-40 levels with insulin resistance and metabolic syndrome independently of obesity. We analyzed data from 4303 participants without diabetes in the Taiwan Biobank. Insulin resistance was defined by the highest quartile of triglyceride-glucose body mass index (TyG-BMI). Metabolic syndrome was defined per AHA/NLHBI criteria. Both univariate and multivariate analyses demonstrated significant correlations between YKL-40 levels and TyG-BMI. Participants with higher YKL-40 quartiles exhibited increased odds of TyG-BMI-estimated insulin resistance even after adjusting for established predictors of TyG-BMI, including waist circumference. Similarly, higher YKL-40 quartiles significantly correlated with increased metabolic syndrome prevalence, and this relationship persisted after stratifying participants by weight status (normal weight vs. overweight/obese). Interaction analysis indicated that overweight/obesity individuals consistently had higher metabolic syndrome prevalence than normal-weight counterparts within identical YKL-40 quartiles, though the impact of overweight/obese diminished across rising YKL-40 quartiles (p for interaction = 0.008). Increased YKL-40 levels are significantly associated with TyG-BMI-estimated insulin resistance and metabolic syndrome, independent of obesity. There is a significant interaction between overweight/obese and YKL-40 levels in determining metabolic syndrome prevalence.

Objectives:3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is a rate-limiting enzyme involved in cholesterol synthesis. The common HMGCR variants are associated with low-density lipoprotein cholesterol (LDL-C) levels. We aimed to identify novel HMGCR variants influencing the lipid profiles of Taiwanese and assess the causal links between LDL-C levels and diabetic risk based on HMGCR genotypes. Materials and Methods:Genome-wide genotyping of 108,880 participants from Taiwan Biobank was used for the association studies and Mendelian randomization (MR) analysis. Results:Regional association and stepwise linear regression analyses showed HMGCR rs3064191, rs150454634, and rs13354746 variants were independently associated with total cholesterol (TC), LDL-C, and non-high-density lipoprotein cholesterol (non-HDL-C) levels with the former two variants in strong linkage disequilibrium with HMGCR rs3846662, a variant influencing exonal alternative splicing, and HMGCR rs191835914 (p.Y311S), an Asian-specific nonsynonymous mutation, respectively. Multivariate MR analyses showed significant associations between weighted genetic risk scores using LDL-C-determining HMGCR variants and using genome-wide association study identifying LDL-C-determining 47 variants and the prevalence of diabetes mellitus (DM) (P = 0.0011 and P = 1.66 × 10-8, respectively). Conclusion:The HMGCR variants exhibited significant associations with TC, LDL-C, and non-HDL-C levels as well as causally with DM risk in our Taiwanese population. HMGCR genotypes may play an important role and serve as a reference for the prevention and treatment of cardiovascular diseases in the clinical settings.

BACKGROUND:Physical inactivity contributes to systemic disease burden and premature mortality worldwide. Leisure-time physical activity (LTPA) improves health outcomes; however, its genetic determinants, particularly in Asian populations, remain unclear. This study aimed to identify genetic loci associated with LTPA in the Taiwanese population. METHODS:We conducted genome-wide association studies in 122,258 Taiwan Biobank participants. LTPA was assessed both as a binary trait (regular exerciser vs non-exerciser) and an ordinal trait (categorized by MET-hours per week into low, moderate, and high physical activity levels). Logistic and ordinal logistic regression models were used under an additive genetic model, adjusting for age, age 2 , sex, body mass index, smoking, and the first 10 genetic principal components. Candidate nonsynonymous mutations were further examined in 1494 whole-genome sequenced participants. RESULTS:Binary trait genome-wide association studies identified genome-wide significant (GWS) loci at ATXN2 (12q24.12), FTO (16q12.2), and NOTCH4 (6p21.32), with associations for FTO and NOTCH4 only observed in body mass index (BMI)-adjusted models. Ordinal trait analysis (<10, 10-<20, ≥20 MET·h·wk -1 ) identified a single GWS locus at BRAP (12q24.12). Fine-mapping of 12q24.12 revealed multiple GWS single-nucleotide polymorphisms (SNPs) in strong linkage disequilibrium with lead variants; these signals largely disappeared after conditional analysis, consistent with a single underlying association. Whole-genome sequencing and linkage disequilibrium analysis identified three GWS nonsynonymous mutations, with ALDH2 rs671 emerging as the most likely causal variant. CONCLUSIONS:ATXN2-ALDH2 region on chromosome 12q24.12 was identified as a key locus for LTPA in Taiwanese individuals. These findings enhance our understanding of the genetic basis of physical activity and may inform future precision medicine and public health strategies.

Background: Despite the widespread use of lipid-lowering agents, the risk of atherosclerotic cardiovascular disease (ASCVD) remains; this residual risk has been attributed to remnant cholesterol (RC) levels. However, the causal associations between RC levels and various atherosclerosis-related cardiometabolic and vascular risk factors for ASCVD remain unclear. Methods: Using genetic and biochemical data of 108,876 Taiwan Biobank study participants, follow-up data of 31,790 participants, and follow-up imaging data of 18,614 participants, we conducted a genome-wide association study, a Functional Mapping and Annotation analysis, and bidirectional Mendelian randomization analyses to identify the genetic determinants of RC levels and the causal associations between RC levels and various cardiometabolic and vascular risk factors. Results: We found that higher RC levels were associated with higher prevalence or incidence of the analyzed risk factors. The genome-wide association study unveiled 61 lead genetic variants determining RC levels. The Functional Mapping and Annotation analysis revealed 21 gene sets exhibiting strong enrichment signals associated with lipid metabolism. Standard Mendelian randomization models adjusted for nonlipid variables and low-density lipoprotein cholesterol levels unraveled forward causal associations of RC levels with the prevalence of diabetes mellitus, hypertension, microalbuminuria, and metabolic liver disease. Reverse Mendelian randomization analysis revealed the causal association of diabetes mellitus with RC levels. Conclusions: RC levels, mainly influenced by genes associated with lipid metabolism, exhibit causal associations with various cardiometabolic risk factors, including diabetes mellitus, hypertension, microalbuminuria, and metabolic liver disease. This study provides further insights into the role of RC levels in predicting the residual risk of ASCVD.

The structure and function of high-density lipoprotein (HDL), rather than its concentration, are more important factors in determining HDL activity. HDL particles (HDL-P) are heterogeneous in their composition, size, and antioxidative function. We investigated the levels of HDL subfractions and oxidized high-density lipoprotein (Ox-HDL) and validated their correlation with genetic determinants underlying peripheral artery disease (PAD). We recruited a PAD population stratified by claudication severity (group I) and critical limb ischemia (group II) according to the Rutherford classification. We found that the level of Ox-HDL was significantly increased with Rutherford classification (group II; p = 0.001). Conversely, the levels of high-density lipoprotein cholesterol (HDL-C), HDL-P, and small high-density lipoprotein particles (S-HDL-P) were significantly reduced in group II. Three single nucleotide polymorphisms (SNPs) were differentially associated with HDL particles and Ox-HDL. Briefly, rs117685211 and rs7934858 showed opposing effects, with rs117685211 and rs148877054 being associated with low levels of HDL subfractions; rs148877054 was significantly associated with M and S-HDL-P. Our study indicated the significance of HDL subfractions and Ox-HDL in the pathogenesis of PAD.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid metabolism. The rare PCSK9 C378W (rs776752113) mutation influences the level of low-density lipoprotein cholesterol (LDL-C); however, its association with PCSK9 levels remain unclear. Methods: This study investigates the frequency of the C378W mutation and its effects on PCSK9 levels and lipid profiles in 5901 Taiwan Biobank participants, including 1486 individuals with available whole-genome sequencing data. The C378W mutations were detected using a TaqMan genotyping assay and confirmed using direct DNA sequencing. Results: Whole-genome sequencing data revealed a single carrier of the C378W mutation. The TaqMan assay identified seven carriers of the 378W allele (7/5901 [0.119%]). After the exclusion of an individual with a history of hyperlipidemia, six carriers exhibited significantly lower levels of LDL-C (−30.5%) and PCSK9 (−56.4%) than noncarriers (LDL-C: 81.17 ± 21.79 vs. 116.70 ± 30.70 mg/dL [p = 0.0005]; PCSK9: 67.20 ± 14.83 vs. 154.02 ± 45.52 ng/mL [p = 3.59 × 10−12]. Moreover, carriers exhibited significantly lower levels of total cholesterol (−18.6%) and non-high-density lipoprotein cholesterol (non-HDL-C; −28.4%) than noncarriers (total cholesterol: 157.17 ± 19.30 vs. 193.18 ± 35.22 mg/dL [p = 0.0035]; non-HDL-C: 99.50 ± 20.22 vs. 138.91 ± 34.97 mg/dL [p = 0.0005]). Mediation analysis suggests that the association between the C378W mutation and LDL-C levels persisted even after adjustment for PCSK9 levels. Functional characterization indicates that the C378W mutation impairs protein stability and function. Conclusion: In conclusion, the rare C378W mutation represents a loss-of-function mutation in the Taiwanese population. This variant is independently associated with reduced PCSK9 levels and improved lipid profiles, highlighting its potential cardioprotective role.

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.

YKL-40 is significantly associated with the prevalence and severity of coronary artery disease (CAD). YKL-40 levels are significantly associated with variations in the CHI3L1 and TRIB1 genes. We investigated candidate genes for YKL-40 levels and evaluated the prognostic value of this biomarker and corresponding variants for long-term outcomes in patients with CAD. We included 4664 and 521 participants from the Taiwan Biobank (TWB) and CAD cohorts, respectively. Candidate variants for circulating YKL-40 levels were investigated using genome-wide association study (GWAS) data from the TWB cohort, and the results were validated in the CAD cohort. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiac events (MACEs), which included the composite endpoints of all-cause mortality, nonfatal acute coronary syndrome, hospitalization for heart failure, and nonfatal stroke. According to the GWAS data from the TWB cohort, three CHI3L1 variants (rs4950928, rs10399931, and rs872129) and one TRIB1 variant (rs6982502) were independently associated with YKL-40 levels. These findings were validated in the CAD cohort. The combined CHI3L1 and TRIB1 weighted genetic risk scores (WGRSs) were not associated with the long-term outcomes (median follow-up period of 3.7 years) in patients with CAD. Conversely, patients with YKL-40 levels in the upper tertile had the highest rates of all-cause mortality and MACEs (log-rank p = 9.58 x 10-8 for all-cause mortality and 1.34 x 10-7 for MACEs). Furthermore, YKL-40 levels predicted poor clinical outcomes only in patients with multivessel CAD (log-rank p = 3.0 x 10-6 for all-cause mortality and 1.10 x 10-5 for MACEs) and not in patients with single-vessel CAD. This study revealed that YKL-40 levels but not the combined CHI3L1 and TRIB1 WGRSs were found to be independent predictors of poor clinical outcomes in patients with multivessel CAD.

Our study aimed to investigate if genetic variants around 16p13.3's HBA1 locus, associated with erythrocyte indices and HbA1c levels, predict α-thalassemia-related erythrocyte indices, cardiometabolic traits, and diabetes risk in Taiwanese individuals. We analyzed Taiwan Biobank data, including whole-genome sequencing from 1,493 participants and genotyping arrays from 129,542 individuals. First, we performed regional association analysis using whole-genome sequencing data to identify genetic variants significantly associated with erythrocyte indices, confirming their linkage disequilibrium with the α0 thalassemia --SEA deletion mutation, a common cause of α-thalassemia in Southeast Asian populations. Deletion mutation sequencing further validated these variants' association with α-thalassemia. Subsequently, we analyzed genotyping array data, revealing associations between specific genetic variants and cardiometabolic traits, including lipid profiles, HbA1c levels, bilirubin levels, and diabetes risk. Using Mendelian randomization, we established causal relationships between α-thalassemia-related erythrocyte indices and cardiometabolic traits, elucidating their role in diabetes susceptibility. Our findings highlight genetic variants around the α-globin genes as surrogate markers for common α-thalassemia mutations in Taiwan, emphasizing the causal links between α-thalassemia-related erythrocyte indices, cardiometabolic traits, and heightened diabetes risk.

Background:A recent meta-analysis reported late excess mortality in patients treated with paclitaxel-coated devices (PCDs) for symptomatic femoropopliteal disease. However, this finding is controversial. Objectives:To investigate the impact on mortality and predictors of repeat exposure to PCDs in patients with lower extremity peripheral arterial disease (LE-PAD). Methods:We analyzed registry patient-level data from two centers. A total of 214 patients were enrolled, and stratified based on terciles of cumulative dose of paclitaxel. We treated 134 patients with a single PCD exposure and 80 with multiple PCD exposures. We used the follow-up index (FUI) in Kaplan-Meier survival estimates to minimize potential selection bias. We used Cox proportional hazard and splines models to determine the predictors of mortality and assess their relationships with mortality. Results:The mean cumulative dose of paclitaxel was significantly different among groups (6.40 mg vs. 15.06 mg vs. 38.57 mg, p < 0.001). The 5-year FUI (0.93 ± 0.19 vs. 0.94 ± 0.18 vs. 0.95 ± 0.15, p = 0.836) and survival rates were not different (65.4% vs. 51.9% vs. 72.0%, p = 0.148). There was no dose-response association between paclitaxel dosage and death (p = 0.297). The predictors of death were congestive heart failure, stroke, dialysis dependence, neutrophil-lymphocyte ratio (NLR) > 3, age > 71 years, and body mass index (BMI) < 20 kg/m2. Spline model analysis validated the non-linear associations between mortality, age, BMI, and NLR. Conclusions:Repeated PCD exposure for LE-PAD did not result in excess late mortality. Predictors of mortality might change over time, and continuous variables had non-linear relationships with death.

ABCG5 and ABCG8 are two key adenosine triphosphate-binding cassette (ABC) proteins that regulate whole-body sterol trafficking. This study aimed to elucidate the association between ABCG5/G8 gene region variants and lipid profile, cardiometabolic traits, and gallstone disease history in Taiwan. A total of 1494 Taiwan Biobank participants with whole-genome sequencing data and 117,679 participants with Axiom Genome-Wide CHB Array data were enrolled for analysis. Using genotype-phenotype and stepwise linear regression analyses, we found independent associations of four Asian-specific ABCG5 variants, rs119480069, rs199984328, rs560839317, and rs748096191, with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (HDL) cholesterol levels (all p ≤ 0.0002). Four other variants, which were in nearly complete linkage disequilibrium, exhibited genome-wide significant associations with gallstone disease history, and the ABCG8 rs11887534 variant showed a trend of superiority for gallstone disease history in a nested logistic regression model (p = 0.074). Through regional association analysis of various other cardiometabolic traits, two variants of the PLEKHH2, approximately 50 kb from the ABCG5/G8 region, exhibited significant associations with blood pressure status (p < 10-6). In conclusion, differential effects of ABCG5/G8 region variants were noted for lipid profile, blood pressure status, and gallstone disease history in Taiwan. These results indicate the crucial role of individualized assessment of ABCG5/G8 variants for different cardiometabolic phenotypes.

Previous investigations have suggested an association between the PCSK9 common polymorphism E670G and Lipoprotein(a) (Lp(a)) levels, as well as a link between plasma PCSK9 levels and Lp(a) concentrations. However, the causal relationship between plasma PCSK9 and Lp(a) levels remains uncertain. In this study, we explored the association between PCSK9 E670G polymorphism and Lp(a) levels in 614 healthy Taiwanese individuals. Employing a two-sample Mendelian randomization (MR) analysis using openly accessible PCSK9 and Lp(a) summary statistics from the genome-wide association studies (GWAS) and UK Biobank, we aimed to determine if a causal link exists between plasma PCSK9 levels and Lp(a) concentrations. Our findings reveal that the E670G G allele is independently associated with a decreased likelihood of developing elevated Lp(a) levels. This association persists even after adjusting for common cardiovascular risk factors and irrespective of lipid profile variations. The MR analysis, utilizing six PCSK9 GWAS-associated variants as instrumental variables to predict plasma PCSK9 levels, provides compelling evidence of a causal relationship between plasma PCSK9 levels and Lp(a) concentration. In conclusion, our study not only replicates the association between the PCSK9 E670G polymorphism and Lp(a) levels but also confirms a causative relationship between PCSK9 levels and Lp(a) concentrations through MR analysis.

Several apolipoprotein genes are located at the APOE locus on chromosome 19q13.32. This study explored the genetic determinants of cardiometabolic traits and metabolic syndrome at the APOE locus in a Taiwanese population. A total of 81,387 Taiwan Biobank (TWB) participants were enrolled to undergo genotype–phenotype analysis using data from the Axiom Genome-Wide CHB arrays. Regional association analysis with conditional analysis revealed lead single-nucleotide variations (SNVs) at the APOE locus: APOE rs7412 and rs429358 for total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol levels; CLPTM1 rs3786505 and rs11672748 for LDL and HDL cholesterol levels; and APOC1 rs438811 and APOE-APOC1 rs439401 for serum triglyceride levels. Genotype–phenotype association analysis revealed a significant association of rs429358 and rs438811 with metabolic syndrome and of rs7412, rs438811, and rs439401 with serum albumin levels (p < 0.0015). Stepwise regression analysis indicated that CLPTM1 variants were independently associated with LDL and HDL cholesterol levels (p = 3.10 × 10−15 for rs3786505 and p = 1.48 × 10−15 for rs11672748, respectively). APOE rs429358 and APOC1 rs438811 were also independently associated with metabolic syndrome (p = 2.29 × 10−14) and serum albumin levels (p = 3.80 × 10−6), respectively. In conclusion, in addition to APOE variants, CLPTM1 is a novel candidate locus for LDL and HDL cholesterol levels at the APOE gene region in Taiwan. Our data also indicated that APOE and APOC1 variants were independently associated with metabolic syndrome and serum albumin levels, respectively. These results revealed the crucial role of genetic variants at the APOE locus in predicting cardiometabolic traits and metabolic syndrome.

Background: The common non-synonymous mutation of the glucokinase regulator (GCKR) gene, namely rs1260326, is widely reported to have pleiotropic effects on cardio-metabolic traits and hematological parameters. Objective: This study aimed to identify whether other GCKR variants may have pleiotropic effects independent of the rs1260326 genotypes. Methods: In total, 81,097 Taiwan Biobank participants were enrolled for the regional plot association studies and candidate variant analysis of the region around the GCKR gene. Results: The initial candidate variant approach showed the significant association of the rs1260326 genotypes with multiple phenotypes. Regional plot association analysis of the GCKR gene region further revealed genome-wide significant associations between GCKR variants and serum total and low-density lipoprotein cholesterol; triglyceride, uric acid, creatinine, aspartate aminotransferase, γ-Glutamyl transferase, albumin, and fasting plasma glucose levels; estimated glomerular filtration rate; leukocyte and platelet counts; microalbuminuria, and metabolic syndrome, with rs1260326 being the most common lead polymorphism. Serial conditional analysis identified genome-wide significant associations of two low-frequency exonic mutations, rs143881585 and rs8179206, with high serum triglyceride and albumin levels. In five rare GCKR exonic non-synonymous or nonsense mutations available for analysis, GCKR rs146175795 showed an independent association with serum triglyceride and albumin levels and rs150673460 showed an independent association with serum triglyceride levels. Weighted genetic risk scores from the combination of GCKR rs143881585 and rs146175795 revealed a significant association with metabolic syndrome. Conclusion: In addition to the rs1260326 variant, low-frequency and rare GCKR exonic mutations exhibit pleiotropic effects on serum triglyceride and albumin levels and the risk of metabolic syndrome. These results provide evidence that both common and rare GCKR variants may play a critical role in predicting the risk of cardiometabolic disorders.

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.

Objectives: Circulating serum amyloid A (SAA) levels are strongly associated with atherosclerotic cardiovascular disease risk and severity. The association between SAA1 genetic variants, SAA levels, inflammatory marker levels, and coronary artery disease (CAD) prognosis has not been fully understood. Materials and Methods: In total, 2199 Taiwan Biobank (TWB) participants were enrolled for a genome-wide association study (GWAS), and the long-term outcomes in 481 patients with CAD were analyzed. The primary endpoint was all-cause mortality, and the secondary endpoint was the combination of all-cause death, myocardial infarction, stroke, and hospitalization for heart failure. Results: Through GWAS, SAA1 rs11024600 and rs7112278 were independently associated with SAA levels (P = 3.84 × 10−145 and P = 1.05 × 10−29, respectively). SAA levels were positively associated with leukocyte counts and multiple inflammatory marker levels in CAD patients and with body mass index, hemoglobin, high-density lipoprotein cholesterol, and alanine aminotransferase levels in TWB participants. By stepwise linear regression analysis, SAA1 gene variants contributed to 27.53% and 8.07% of the variation of the SAA levels in TWB and CAD populations, respectively, revealing a stronger influence of these two variants in TWB participants compared to CAD patients. Kaplan–Meier survival analysis revealed that SAA levels, but not SAA1 gene variants, were associated with long-term outcomes in patients with CAD. Cox regression analysis also indicated that high circulating SAA levels were an independent predictor of both the primary and secondary endpoints. Conclusion: SAA1 genotypes contributed significantly to SAA levels in the general population and in patients with CAD. Circulating SAA levels but not SAA1 genetic variants could predict long-term outcomes in patients with angiographically confirmed CAD.