Polygenic risk score predicting susceptibility and outcome of benign prostatic hyperplasia in the Han Chinese.

BACKGROUND: Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. METHODS: A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. RESULTS: Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274-1.783, p < 0.0001), after adjusting for PSA level. The Q4 group exhibited larger prostate volumes and a smaller volume reduction after 5ARI treatment. The Q1 group had a lower cumulative TURP probability at 3, 5, and 10 years compared to the Q4 group. PRS Q4 was an independent risk factor for TURP. CONCLUSIONS: In this Han Chinese cohort, higher PRS was associated with an increased susceptibility to BPH, larger prostate volumes, poorer response to 5ARI treatment, and a higher risk of TURP. Larger prospective studies with longer follow-up are warranted to further validate these findings.

Polymorphisms of HLA genes and hypersensitivity to penicillin among patients in a Taiwanese population.

Penicillin allergy is a potentially life-threatening condition that is common among patients. However, the genetic associations with penicillin allergy are not yet recognized for prevention or diagnosis, particularly in East Asian populations. We conducted a retrospective case-control study using data from the Taiwan Precision Medicine Initiative and analysing DNA samples to identify eight major MHC Class I and Class II loci. We employed imputation methods for accurate HLA typing and enrolled 17,827 individuals who received penicillin. Logistic regression analyses were utilized to explore associations between HLA genotypes, comorbidities and allergy risk, while simultaneously conducting a subgroup analysis to explore the association between HLA genotypes, comorbidities and the severity of allergic reactions. Our study assigned 496 cases to the penicillin allergy group and 4960 controls to a matched group. The risk of penicillin allergy was significantly higher with HLA-DPB1*05:01 (OR = 1.36, p = .004) and HLA-DQB1*05:01 (OR = 1.54, p = .03), with adjusted p-values of .032 and .24, respectively. Urticaria was identified as a separate risk factor (OR = 1.73, p < .001). However, neither the HLA alleles nor the comorbidities had a significant relationship with the risk of severe penicillin-induced allergy. HLA-DPB1*05:01 was found to be significantly associated with penicillin allergy reactions among the Taiwanese population.

Sex-specific genetic variants associated with adult-onset inguinal hernia in a Taiwanese population.

Introduction: Inguinal hernia repair is one of the most common surgeries worldwide. However, there is limited information on its underlying genetic mechanism. Studies on the genetic factors related to inguinal hernia in Han Chinese are lacking. Therefore, we aimed to conduct a hospital-based study to assess the genetic factors and comorbidities underlying inguinal hernia in Taiwan. Materials and Methods: This was a retrospective case-control study. Utilizing data from the Taiwan Precision Medicine Initiative, we identified 1000 patients with inguinal hernia and 10,021 matched controls without inguinal hernia between June 2019 and June 2020. Four susceptibility loci (rs2009262, rs13091322, rs6991952, and rs3809060) associated with inguinal hernia were genotyped by the Taiwan Biobank version 2 (TWBv2) array. Inguinal hernia, surgery types, and comorbidities were obtained from the electronic health records of Taichung Veterans General Hospital. Results: Adult-onset inguinal hernia was associated with WT1 rs3809060 GT/TT genotype in males and EFEMP1 rs2009262 TC/CC genotype in females. In addition, we identified sex-specific risk factors associated with inguinal hernia; benign prostatic hyperplasia in males (OR: 3.19, 95% CI: 2.73 - 3.73, p< 0.001), chronic obstructive pulmonary disease in females (OR: 2.34, 95% CI: 1.33 - 4.11, p = 0.003) and overweight, defined by body mass index ≧24 kg/m2 (OR: 0.75, 95% CI: 0.65 - 0.86, p<0.001 in males, and OR: 0.60, 95% CI:0.37 - 0.98, p = 0.042 in females), were inversely associated with inguinal hernia. After stratifying BMI, overweight males with EFEMP1 rs2009262 TC/CC genotype exhibited a higher risk of inguinal hernia (OR: 1.31, 95% CI: 1.07 - 1.61, p = 0.01). Additionally, rs3809060 was specifically associated with male patients with direct-type inguinal hernia (OR: 1.62, 95% CI: 1.19 - 2.22, p = 0.002). Conclusion: Genetic susceptibility appears to participate in the pathogenesis of inguinal hernia in the Taiwanese population in a sex-specific manner. Future studies are needed to illuminate the complex interplay between heredity and comorbidities.

Identification of GTF2I Polymorphisms as Potential Biomarkers for Chronic Kidney Disease in the Han Chinese Population: Multicentric Collaborative Cross-Sectional Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) poses a global health challenge, but its molecular mechanisms are poorly understood. Genetic factors play a critical role, and phenome-wide association studies (PheWAS) and genome-wide association studies (GWAS) shed light on CKD's genetic architecture, shared variants, and biological pathways. METHODS: Using data from the multicenter collaborative precision medicine cohort, we conducted a retrospective prospectively maintained cross-sectional study. Participants with comprehensive information and genotyping data were selected, and GWAS and PheWAS analyses were performed using the curated Taiwan Biobank version 2 array to identify CKD-associated genetic variants and explore their phenotypic associations. RESULTS: Among 58,091 volunteers, 8,420 participants were enrolled. Individuals with CKD exhibited higher prevalence of metabolic, cardiovascular, autoimmune, and nephritic disorders. Genetic analysis unveiled two closely linked SNPs, rs117026326 and rs73366469, both associated with GTF2I and CKD (r2=0.64). Further examination revealed significant associations between these SNPs and various kidney-related diseases. The CKD group showed a higher proportion of individuals with specific genotypes (CT/TT for rs117026326 and CT/CC for rs73366469), suggesting potential associations with CKD susceptibility(p<0.001). Furthermore, individuals with these genotypes developed CKD at an earlier age. Multiple logistic regression confirmed the independent association of these genetic variants with CKD. Subgroup analysis based on estimated glomerular filtration rate (eGFR) demonstrated an increased risk of CKD among carriers of the rs117026326 CT/TT genotypes (OR=1.15, 95% CI: 1.07-1.24, p<0.001; OR=1.32; 95% CI: 1.04-1.66, p=0.02, respectively) and carriers of the rs73366469 CT/CC genotypes (OR=1.13, 95% CI=1.05-1.21, p<0.001; OR=1.31, 95% CI: 1.08-1.58, p=0.0049, respectively). Additionally, men had a higher CKD risk than women at lower eGFR levels (OR=1.35, 95%: 1.13-1.61, p<0.001). CONCLUSIONS: Our study reveals important links between genetic variants GTF2I and susceptibility to CKD, advancing our understanding of CKD development in the Taiwanese population and suggesting potential for personalized prevention and management strategies. More research is needed to validate and explore these variants in diverse populations.

Association of HLA alleles with cephalosporin allergy in the Taiwanese population.

Cephalosporin antibiotics are widely used in clinical settings, but they can cause hypersensitivity reactions, which may be influenced by genetic factors such as the expression of Human leukocyte antigen (HLA) molecules. This study aimed to investigate whether specific HLA alleles were associated with an increased risk of adverse reactions to cephalosporins among individuals in the Taiwanese population. This retrospective case-control study analyzed data from the Taiwan Precision Medicine Initiative (TPMI) on 27,933 individuals who received cephalosporin exposure and had HLA allele genotyping information available. Using logistic regression analyses, we examined the associations between HLA genotypes, comorbidities, allergy risk, and severity. Among the study population, 278 individuals had cephalosporin allergy and 2780 were in the control group. Our results indicated that certain HLA alleles, including HLA-B*55:02 (OR = 1.76, 95% CI 1.18-2.61, p = 0.005), HLA-C*01:02 (OR = 1.36, 95% CI 1.05-1.77, p = 0.018), and HLA-DQB1*06:09 (OR = 2.58, 95% CI 1.62-4.12, p < 0.001), were significantly associated with an increased risk of cephalosporin allergy reactions. Additionally, the HLA-C*01:02 allele genotype was significantly associated with a higher risk of severe allergy (OR = 2.33, 95% CI 1.05-5.15, p = 0.04). This study identified significant associations between HLA alleles and an increased risk of cephalosporin allergy, which can aid in early detection and prediction of adverse drug reactions to cephalosporins. Furthermore, our study highlights the importance of HLA typing in drug safety and expanding our knowledge of drug hypersensitivity syndromes.

Coarctation-induced degenerative abdominal aortic aneurysm in a porcine model.

OBJECTIVE: Hemodynamic stress participates in the initiation and progression of aneurysmal degeneration. Coarctation increases flow-mediated stress on the aortic wall. We tested the hypothesis that prolonged coarctation of an infrarenal abdominal aorta (AA) segment leads to abdominal aortic aneurysm (AAA) formation in mini pigs. METHODS: An asymmetric, funnel-shaped flow path was created by constricting the infrarenal AA segment of Taiwanese Lanyu mini pigs (age, 7-10 months; male and female) wrapped with an 8-mm-wide expanded polytetrafluoroethylene Teflon strip for 4 weeks (4w), 8 weeks (8w), and 12 weeks (12w) (seven pigs per group). This mimics the tortuous aneurysm neck in human AAA, which increases downstream flow-mediated stress. Significant flow disturbance resulting from moderate coarctation was indicated by a pulsatility index reduced to one third the inherent levels. Sham control pigs received Teflon wrapping without coarctation. RESULTS: Aneurysm characterized by progressive medial degeneration occurred at the terminal AA after 12w coarctation. The outer dimension enlargement of the distal AA exceeded 50% compared with that of the proximal AA at 4w, 8w, and 12w postcoarctation (sham, 1.0; 4w, 1.7 ± 0.08; 8w, 1.5 ± 0.09; 12w, 1.7 ± 0.01). Lumen ratio of the distal-to-suprarenal AA increased time dependently, with 12w postcoarctation exhibiting significant increase (sham, 1.0 ± 0.05; 4w, 1.1 ± 0.11; 8w, 1.4 ± 0.20; 12w, 1.5 ± 0.09). In the distal AA, elastic lamellae exhibited fragmentation at 4w and more pronounced fragmentation with decreased density at 8w and 12w postcoarctation. Medial collagen density exhibited the trend to increase at 4w and 8w but was reversed at 12w postcoarctation. Smooth muscle exhibited disarray and nuclear density decrease at 8w and 12w postcoarctation (sham, 6966 ± 888/mm; 4w, 5747 ± 1340/mm; 8w, 4153 ± 323/mm; 12w, 4083 ± 465/mm). Gelatin zymography revealed that matrix metalloproteinase-9 activity markedly increased at 4w postcoarctation. CONCLUSIONS: Prolonged moderate coarctation caused regional hemodynamic stress and thereby induced degenerative AAA in the terminal AA.

Genetic Susceptibility of HLA Alleles to Non-Steroidal Anti-Inflammatory Drug Hypersensitivity in the Taiwanese Population.

BACKGROUND: Human leukocyte antigen (HLA) genes are important in many immune processes and contribute to many adverse drug reactions. Whether genetic variations in the HLA region are associated with non-steroid anti-inflammatory drug (NSAID) hypersensitivity remains uncertain. Therefore, the aim of our study was to identify HLA genetic variations in patients with NSAID hypersensitivity in the Taiwanese population. METHODS: This hospital-based, retrospective case-control study enrolled 37,156 participants with NSAID exposure from the Taiwan Precision Medicine Initiative (TPMI), who were all genotyped and imputed to fine map HLA typing. Our study assigned 1217 cases to the NSAID allergy group and 12,170 controls to a matched group. Logistic regression analyses were utilized to explore associations between HLA alleles and NSAID hypersensitivity. RESULTS: Overall, 13,387 patients were genotyped for eight major HLA alleles. Allele frequencies were different between the two groups. In the NSAID allergy group, the genotype frequencies of HLA-A*02:01, HLA-A*34:01, and HLA-DQA1*06:01 were found to be markedly elevated compared to the control group, a significance that persisted even after applying the Bonferroni correction. Furthermore, the risk of NSAID allergy demonstrated a significant association with HLA-A*02:01 (OR = 1.29, p < 0.001) and HLA-A*34:01 (OR = 9.90, p = 0.001), in comparison to their respective counterparts. Notably, the genotype frequency of HLA-B*46:01 exhibited a significant increase in the severe allergy group when compared with the mild allergy group. CONCLUSIONS: We identified HLA genotypes linked to the onset and severity of NSAID hypersensitivity. Our findings establish a basis for precision prescription in future clinical applications.

Applying Apriori algorithm to explore long-term care services usage status-Variables based on the combination of patients with dementia and their caregivers.

Purpose: The aim of this study was to identify the combination of patients with dementia and their caregivers' characteristics associated with long-term care (LTC) services usage. Patients and methods: A cross-sectional study was conducted with 475 patients with mild, moderate, and severe dementia at Changhua Christian Hospital, Taiwan. Eleven types of variables from patients with dementia, nine types of variables from patients' caregivers, and 15 types of LTC services were used for this study. The Apriori algorithm was employed to identify the attributes from the patients and their caregivers who used a particular LTC service from a comprehensive viewpoint. Results: A total of 75 rules were generated by the Apriori algorithm with support of 2%, confidence of 80%, and lift >1. Among these rules, 25 rules belonged to home personal care services which were summarized further into four general rules for home personal care services. On the other hand, 50 rules belonged to assistive devices that were summarized further into 21 general rules based on their similarities. Patient's walking ability, patient's emotional liability, unemployed or retired caregivers, caregivers' feelings with either helplessness or hopelessness, and caregivers who cared for patients with dementia solely were found to be the critical variables to use home personal care services. In contrast, patient's walking ability, age, and severity as well as caregivers' age, mood, marital status, caregiving burden, and the patient being cared for mainly by a foreign care helper were found to be the critical variables to use assistive devices. Conclusion: This study showed preliminary results on the LTC service usage from patients with dementia and their caregivers residing in the community. Understanding the patient-caregiver dyad's profile leads the service providers, policymakers, and the referral team to tailor service provisions better to meet the needs and identify the potential target groups. The findings in this study serve as references to reduce caregivers' burden as well as to improve the quality of care for patients with dementia.

Dengue and Zika Virus Domain III-Flagellin Fusion and Glycan-Masking E Antigen for Prime-Boost Immunization.

The viral E proteins of dengue virus (DENV) and Zika virus (ZIKV) are the major viral proteins involved in receptor binding and fusion, and for the induction of protective antibodies against viral infections. DIII of the E proteins is an independent domain and stretches out on the virion surface that can elicit type-specific neutralizing antibodies. For recombinant DIII vaccine development, prime-boost immunizations can provide an advantage of eliciting more type-specific neutralizing antibodies by recalling DIII antigens after DIII booster to improve protection. Methods: The DIII of the E genes of DENV and ZIKV were fused with bacterial fliC gene for the expression of flagellin-DIII (FliC-DIII) fusion proteins. Prime-boost immunization strategies by the second-dose booster of four DENV serotype or ZIKV FliC-DIII fusion proteins were used to investigate the induction of neutralizing antibodies and protection against viral infections. Cross-reactive non-neutralizing antibodies in each group of antisera were also examined using in vitro antibody-dependent enhancement (ADE) assay. A series of glycan-masking E antigens were finally constructed for prime-boost immunizations to abolish the elicitation of cross-reactive non-neutralizing antibodies for ADE activity. Results: We showed that inclusion of a bivalent live-attenuated vaccine with a FliC-DIII booster is superior in eliciting neutralization titers and protection in vivo against all four-serotype DENVs. We also demonstrated that recombinant adenovirus vectors encoding four-serotype DENV prMEs with a FliC-DIII prime-boost scheme is capable of eliciting good antibody responses. In contract, recombinant adenovirus vector of ZIKV prME gene priming, followed by ZIKV FliC-DIII booster did not improve vaccine efficacy. The glycan-masking mutation on the ZIKV E protein ij loop (E-248NHT), but not on DENV2 E protein ij loop (E-242NHT), resulted in abolishing the elicitation of cross-reactive antibodies for DENV and ZIKV infection enhancements. Conclusions: Our findings can provide useful information for designing novel immunogens and vaccination strategies in an attempt to develop a safe and efficacious DENV or ZIKV vaccine.