Han Chinese Population In Taiwan Research Articles

Phenomic landscape and pharmacogenomic implications for HLA region in a Taiwan Han Chinese population

BackgroundThe human leukocyte antigen (HLA) genes, exhibiting significant genetic diversity, are associated with susceptibility to various clinical diseases and diverse in drug responses. High costs of HLA sequencing and the population-specific architecture of this genetic region necessitate the establishment of a population-specific HLA imputation reference panel. Moreover, there is a lack of understanding about the genetic and phenotypic landscape of HLA variations within the Taiwanese population.MethodsWe created models for a Taiwanese-specific HLA imputation reference panel. These models were trained with the array genotype data and HLA sequencing data from 845 Taiwanese subjects. HLA imputation was applied for 59,448 Taiwanese subjects to characterize the HLA allele and haplotype frequencies. Additionally, a phenome-wide association study (PheWAS) was conducted to identify the phenotypes associated with HLA variations. The association of the biallelic HLA variants with the binary and quantitative traits were evaluated with additive logistic and linear regression models, respectively. Furthermore, an omnibus test with likelihood-ratio test was applied for each HLA amino acid position in the multiallelic HLA amino acid polymorphisms to compare the difference between a fitted model and a null model following a χ2 distribution of n-1 degree of freedom at a position with n residues. Finally, we estimated the prevalence of adverse drug reactions (ADR)-related HLA alleles in the Taiwanese population.ResultsIn this study, the reference panel models displayed remarkable accuracy, with averages of 99.3%, 98.9%, and 99.1% for 2-, 4-, 6-digit alleles of the eight classical HLA genes, respectively. For PheWAS, a total of 18,136 significant associations with HLA variants across 26 phenotypes are identified (p < 5×10-8), highlighting the pleiotropy feature of the HLA region. Among the independent signals, 15 are novel, including the association of HLA-B pos 138 variation with ankylosing spondylitis (AS), and rs9266290 and rs9266292 with allergy. Through an analysis spanning the entire HLA region, we identified clusters of phenotype correlations. Finally, the carriers of pharmacogenomic related HLA alleles, including HLA-C*01:02 (35.86%), HLA-B*58:01 (20.9%), and HLA-B*15:02 (8.38%), were characterized in the Taiwanese general population.ConclusionsWe successfully delivered the HLA imputation for 59,448 Taiwanese subjects and characterized the genetic and phenotypic landscapes of the HLA variations. In addition, we quantified the estimated prevalence of the ADR-related HLA alleles in the Taiwanese population. The developed HLA imputation reference panel could be used for estimation of population HLA allele frequencies, which can facilitate further studies in the role of HLA variants in a wider range of phenotypes in the population.

Association of IL-18 gene polymorphisms with clinical aspects of hyperlipidemia in middle-aged and early people in the community.

Hyperlipidemia is notorious for causing coronary artery disease (CAD). IL-18 is a proinflammtory cytokine that contributes to the pathogenesis of CAD. Previous reports have revealed that genetic polymorphism of IL-18 is associated with its expression level as well as the susceptibility to CAD. In the present study, we aim to investigate the relationship between IL-18 single nucleotide polymorphisms (SNPs) and hyperlipidemia in the Han Chinese population in Taiwan. A total of 580 participants older than 30 were recruited from the community. We collected the demographics, self-reported disease histories, and lifestyles. We also assessed the levels of lipid profiles including total cholesterol (CHOL), triglyceride, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol. Two SNPs, rs3882891C/A (intron 5) and rs1946518A/C (promoter -607) of IL-18 were elucidated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Our results revealed that rs3882891 AA was associated with lower risk of hypercholesterolemia, higher CHOL and LDL-C in subjects (p=0.003, p=0.000 and p=0.005 separately), and rs1946518 CC was associated with hypercholesterolemia, higher CHOL and LDL-C as well (p=0.021, p=0.003 and p=0.001 separately) Furthermore, both SNPs were associated with IL-18 expression level, which was examined by Genotype-Tissue Expression (GTEx) Portal (p=0.042 and 0.016 separately). Finally, the haplotype of IL-18 was subsequently arranged in the order of rs3882891 and rs1946518. The result revealed that the AC haplotype of 2 IL-18 SNPs was also associated with lower risk of hypercholesterolemia, lower levels of CHOL and LDL-C (p=0.01, p=0.001 and 0.003). The current study is the first to report the association between IL-18 SNPs and hyperlipidemia in the Chinese Han population.

Gender Differences in Subclinical Coronary Atherosclerosis in the Asian Population With a Coronary Artery Calcium Score of Zero

There is little evidence on whether gender difference influences the incidence of subclinical coronary atherosclerosis in Asian populations with a 0 score. In this study, we investigated the influence of age and gender on the extent of subclinical coronary atherosclerotic burden within a healthy Asian population with a 0 coronary artery calcium (CAC) score. A total of 934 participants (320 women and 614 men) from Taiwan's Han Chinese population with an initial CAC score of 0 were included in this study. They underwent 2 consecutive cardiac computed tomography scans over a clinical follow-up period of 4.35 ± 2.37years. Clinical information and laboratory measurements were collected for analysis. Compared with the female group, the male group demonstrated significantly higher rates of subclinical CAC progression (27.4% vs 13.8%, p <0.001). Across the age group deciles (≤40, 41 to 50, 51 to 60, ≥61years), the male group had a higher prevalence of subclinical CAC progression than the female group. For the subclinical CAC progression, the logistic regression model demonstrated that age, gender (male gender), cholesterol level, and follow-up period were statistically significant parameters. In conclusion, these findings support that a gender difference impacts the long-term natural course of subclinical coronary calcification conversion in women compared with men, suggesting that the gender-based effect on coronary CAC conversion plays an important role in subclinical coronary atherosclerosis risk stratification in personalized preventive medicine.

The Endophenotypic Effect of the SORL1 Variant rs2298813 on Regional Brain Volume in Patients with Alzheimer’s Disease

AbstractBackgroundTwo common variants of sortilin‐related receptor 1 gene (SORL1), rs2298813 and rs1784933, have been associated with late‐onset Alzheimer’s disease (AD) in the Han Chinese population in Taiwan. However, neuroimaging correlates of these two SORL1 variants remain unknown. We aimed to determine whether the two SORL1 polymorphisms were associated with any volumetric differences in brain regions in AD patients.MethodsWe recruited 200 patients with late‐onset AD from Taipei Veterans General Hospital. All patients received a structural magnetic resonance imaging brain scan and completed a battery of neurocognitive tests at enrollment. We followed up to assess changes in Mini‐Mental State Examination (MMSE) scores in 155 patients (77.5%) at an interval of 2 years. Volumetric measures and cortical thickness of various brain regions were performed using FreeSurfer. Regression analysis controlled for apolipoprotein E status. Multiple comparisons were corrected for using the false discovery rate.ResultThe rs2298813 and rs1783933 genotypes were not associated with cognitive test performance or clinical progression. The homozygous major allele of rs2298813 was associated with larger volumes in the right putamen (p = 0.0442) and right pallidum (p = 0.0346). There was no link of the rs1784933 genotypes with any of the imaging measures. In the rs2298813 homozygous major allele carriers, the right putaminal volume was associated with verbal fluency (p = 0.008) and clinical progression (p = 0.020). In the minor allele carriers, the right putaminal and right pallidal volumes were not significantly related to cognitive test scores or clinical progression.ConclusionThe major and minor alleles of rs2298813 had differential effects on the right lentiform nucleus volume and distinctively modulated the association between the regional volume and cognitive function.

Identification of genetic risk loci for depression and migraine comorbidity in Han Chinese residing in Taiwan.

The genetic association between depression and migraine has not been well investigated in Asian populations. Furthermore, the genetic basis of depression and comorbid migraine subtypes remains nebulous. Hence, in the current study we investigate the susceptibility loci associated with depression and migraine comorbidity in the Han Chinese population in Taiwan. We perform a genome-wide association study involving 966 migraine patients, with or without comorbid depression. Genotyping is performed using participant genomic DNA. Association analyses are performed for the entire migraine cohort (subgroups: episodic migraine, chronic migraine, and migraine with or without aura). Results show that the single nucleotide polymorphism variants of the CDH4 intron region (rs78063755), NTRK3-AS1 downstream region (rs57729223), and between LINC01918 and GPR45 (rs2679891) are suggestively associated with depression. Twenty additional susceptibility loci occur within the subgroups. A multivariate association study demonstrated that a variant in the intron region of CDH4 rs78063755 was associated with Beck Depression Inventory and Migraine Disability Assessment scores. The findings of this study identify several genetic loci suggestively associated with depression among migraine patients in the Han Chinese population. Moreover, a potential genetic basis has been characterized for depression and migraine comorbidity, thus providing genetic candidates for further investigation.

Prognostic Comparison between Oncotype DX® and a 23-Gene Classifier, RecurIndex®, on the Taiwan Breast Cancer Population.

The applicability of the Oncotype DX® (Genomic Health, Inc., Redwood City, CA, USA) recurrence score (RS) in Asian populations is unclear. A 23-gene classifier, RecurIndex® (Amwise Diagnostics, Pte. Ltd., Singapore), has been developed based on the gene expression profiles of early-stage breast cancer patients of ethnic Han Chinese population in Taiwan. This study aimed to compare the performance of the Oncotype DX® RS with the RecurIndex® recurrence index (RI) for predicting relapse-free survival. Therefore, we calculated both the RI and RS for 110 early stage breast cancer patients, with the cut-off value for high-risk recurrence set at 26 and 29 for the RS and the RI, respectively. With relapse-free interval (RFI) as the primary endpoint, the concordance between RS and RI was 78.2% (Kappa value = 0.297). For a median follow-up interval of 27 months, there was a statistically significant difference in RFI between the high- and low-risk groups defined by the RI (p = 0.04) but not between risk groups defined by the RS (p = 0.66). In conclusion, whereas there was high concordance between the RecurIndex® RI and the Oncotype DX RS, the current data showed that the RI had a better discrimination for recurrence risk than the RS. Subsequent studies with larger sample sizes will be needed to confirm the superiority of the RI over the RS in the Asian population.

Endophenotypic effects of the SORL1 variant rs2298813 on regional brain volume in patients with late-onset Alzheimer's disease.

Introduction: Two common variants of sortilin-related receptor 1 gene (SORL1), rs2298813 and rs1784933, have been associated with late-onset Alzheimer’s disease (AD) in the Han Chinese population in Taiwan. However, neuroimaging correlates of these two SORL1 variants remain unknown. We aimed to determine whether the two SORL1 polymorphisms were associated with any volumetric differences in brain regions in late-onset AD patients.Methods: We recruited 200 patients with late-onset AD from Taipei Veterans General Hospital. All patients received a structural magnetic resonance (MR) imaging brain scan and completed a battery of neurocognitive tests at enrollment. We followed up to assess changes in Mini-Mental State Examination (MMSE) scores in 155 patients (77.5%) at an interval of 2 years. Volumetric measures and cortical thickness of various brain regions were performed using FreeSurfer. Regression analysis controlled for apolipoprotein E status. Multiple comparisons were corrected for using the false discovery rate.Results: The homozygous major allele of rs2298813 was associated with larger volumes in the right putamen (p = 0.0442) and right pallidum (p = 0.0346). There was no link between the rs1784933 genotypes with any regional volume or thickness of the brain. In the rs2298813 homozygous major allele carriers, the right putaminal volume was associated with verbal fluency (p = 0.008), and both the right putaminal and pallidal volumes were predictive of clinical progression at follow-up (p = 0.020). In the minor allele carriers, neither of the nuclei was related to cognitive test performance or clinical progression.Conclusion: The major and minor alleles of rs2298813 had differential effects on the right lentiform nucleus volume and distinctively modulated the association between the regional volume and cognitive function in patients with AD.

Identification of Novel Genetic Variants Associated with Insomnia and Migraine Comorbidity.

PurposeAlthough insomnia and migraine are often comorbid, the genetic association between insomnia and migraine remains unclear. This study aimed to identify susceptibility loci associated with insomnia and migraine comorbidity.Patients and MethodsWe performed a genome-wide association study (GWAS) involving 1063 clinical outpatients at a tertiary hospital in Taiwan. Migraineurs with and without insomnia were genotyped using the Affymetrix Axiom Genome-Wide TWB 2.0. We performed association analyses for the entire cohort and stratified patients into the following subgroups: episodic migraine (EM), chronic migraine (CM), migraine with aura (MA), and migraine without aura (MoA). Potential correlations between SNPs and clinical indices in migraine patients with insomnia were examined using multivariate regression analysis.ResultsThe SNP rs1178326 in the gene HDAC9 was significantly associated with insomnia. In the EM, CM, MA, and MoA subgroups, we identified 30 additional susceptibility loci. Multivariate regression analysis showed that SNP rs1178326 also correlated with higher migraine frequency and the Migraine Disability Assessment (MIDAS) questionnaire score. Finally, two SNPs that had been previously reported in a major insomnia GWAS were also significant in our migraineurs, showing a concordant effect.ConclusionIn this GWAS, we identified several novel loci associated with insomnia in migraineurs in a Han Chinese population in Taiwan. These results provide insights into the possible genetic basis of insomnia and migraine comorbidity.

Identifying genetic variants for age of migraine onset in a Han Chinese population in Taiwan

BackgroundConsidering the involvement of genetics in migraine pathogenesis in diverse ethnic populations, genome-wide association studies (GWAS) are being conducted to identify migraine-susceptibility genes. However, limited surveys have focused on the onset age of migraine (AoM) in Asians. Therefore, in this study, we aimed to identify the susceptibility loci of migraine considering the AoM in an Asian population.MethodsWe conducted a GWAS in 715 patients with migraine of Han Chinese ethnicity, residing in Taiwan, to identify the susceptibility genes associated with AoM. Based on our standard demographic questionnaire, the population was grouped into different subsets. Single-nucleotide polymorphism (SNP) associations were examined using PLINK in different AoM onset groups.ResultsWe discovered eight novel susceptibility loci correlated with AoM that reached the GWAS significance level in the Han Chinese population. First, rs146094041 in ESRRG was associated with AoM le 12 years. The other SNPs including rs77630941 in CUX1, rs146778855 in CDH18, rs117608715 in NOL3, rs150592309 in PRAP1, and rs181024055 in NRAP were associated with the later AoM.ConclusionsTo our knowledge, this is the first GWAS to investigate the AoM in an Asian Han Chinese population. Our newly discovered susceptibility genes may have prospective associations with migraine pathogenesis.

Rare variants discovery by extensive whole-genome sequencing of the Han Chinese population in Taiwan: Applications to cardiovascular medicine

IntroductionA population-specific genomic reference is important for research and clinical practice, yet it remains unavailable for Han Chinese (HC) in Taiwan. ObjectivesWe report the first whole genome sequencing (WGS) database of HC (1000 Taiwanese genome (1KTW-WGS)) and demonstrate several applications to cardiovascular medicine. MethodsWhole genomes of 997 HC were sequenced to at least 30X depth. A total of 20,117 relatively healthy HC individuals were genotyped using a customized Axiom GWAS array. We performed a genome-wide genotype imputation technique using IMPUTE2. ResultsWe identified 26.7 million single-nucleotide variants (SNVs) and 4.2 million insertions-deletions. Of the SNVs, 16.1% were novel relative to dbSNP (build 152), and 34.2% were novel relative to gnomAD. A total of 18,450 healthy HC individuals were genotyped using a customized Genome-Wide Association Study (GWAS) array. We identified hypertension-associated variants and developed a hypertension prediction model based on the correlation between the WGS data and GWAS data (combined clinical and genetic models, AUC 0.887), and also identified 3 novel hyperlipidemia-associated variants. Each individual carried an average of 16.42 (SD = 3.72) disease-causing variants. Additionally, we established an online SCN5A (an important cardiac gene) database that can be used to explore racial differences. Finally, pharmacogenetics studies identified HC population-specific SNVs in genes (CYP2C9 and VKORC1) involved in drug metabolism and blood clotting. ConclusionThis research demonstrates the benefits of constructing a population-specific genomic reference database for precision medicine.

299 The prevalence and role of SCN10A variants in Han Chinese patients with Brugada syndrome: the SADS-TW BrS registry

Abstract On Behalf SADS-TW BrS registry Background Brugada syndrome (BrS) is an inheritable arrhythmic disease responsible for sudden cardiac death. Information on the prevalence and role of SCN10A variants in BrS is limited and equivocal. Purpose We aimed to investigate the prevalence and role of SCN10A variants in BrS in Han Chinese. Methods From 2000 to 2017, we prospectively and consecutively enrolled 176 unrelated BrS patients from the Han Chinese population in Taiwan (the SADS-TW BrS registry). Thirty-four BrS-related genes were screened by next-generation sequencing, using Taiwan Biobank as the population reference. The pathogenicity was evaluated by literature review and in silico analyses, including the SKAT-O algorithm. Results The SKAT-O algorithm showed that rare variants of SCN10A, but not common variants, were significantly different between BrS patients and healthy controls in the additive and dominant models (p-value &amp;lt;0.001), suggesting that rare SCN10A variants may play a role in BrS. Six likely pathogenic SCN10A variants were found in 6 patients and were compared to 25 pathogenic or likely pathogenic SCN5A variants found in 29 patients. The patients with likely pathogenic SCN10A variants tended to exhibit sudden death in older age and have a shorter QRS interval than those carrying pathogenic or likely pathogenic SCN5A variants or no variants in either gene (p = 0.06, 0.07, respectively). Collectively, the prevalence of likely pathogenic SCN10A variants was 3.4% in Han Chinese patients with BrS in Taiwan. Conclusions SCN10A likely pathogenic variants were present in 3.4% of Han Chinese BrS patients. Rare SCN10A variants may play a role in BrS, and may have impact on clinical and electrocardiographic manifestations. Table 1. Patient Nucleotide Amino acid TWB gnomAD_EA REVEL CADD PHRED SIFT Polyphen-2 GERP++ 1 c.5789A &amp;gt; T p.D1930V 0.001318 0.0008700 0.479 24.5 Damaging Possibly damaging 4.22 2 c.2341G &amp;gt; A p.G781R 0 0.00005301 0.866 33 Damaging Probably damaging 4.83 3 c.5587C &amp;gt; T p.R1863W 0.000502 0 0.832 27.8 Damaging Probably damaging 1.97 4 c.2161C &amp;gt; T p.P721S 0.000989 0.0009016 0.933 28.5 Damaging Probably damaging 4.19 5 c.3749G &amp;gt; A p.R1250Q 0 0 0.907 31 Damaging Probably damaging 4.23 6 c.1825A &amp;gt; T p.R609W 0.000659 0.0001591 0.811 32 Damaging Probably damaging 4.28 Clinical and predicted functional characteristics of 6 likely pathogenic SCN10A variants. EA = East Asian; GERP = Genomic Evolutionary Rate Profiling; TWB = Taiwan Biobank. Transcript: NM_006514.3. Abstract 299 Figure. Location of the SCN10A variants

P1604Validating previously reported Brugada syndrome-associated common variants identified in caucasian population in the Han Chinese BrS cohort in Taiwan: SADS-BrS registry

Abstract Background Brugada syndrome (BrS) is a sudden arrhythmic death. The prevalence of BrS is higher in the Southeast Asian populations than that in Caucasian patients. A previous genome-wide association study (GWAS) has reported 13 SNPs significantly associated with BrS. However, no study was performed to validate whether these SNPs are enriched in BrS patients in Han Chinese (HC). Purpose Evaluating the common variants previously reported in Caucasian BrS patients could be generalized to HC BrS patients in Taiwan Methods We genotyped 200 unrelated BrS patients using Affymetrix TWB Array (N=653,291 SNPs, a customized array for HC in Taiwan). The controls are obtained from the Taiwan Biobank (N ≈ 16,000) using the same array. An imputation workflow was shown in Figure 1. To confirm the accuracy of the imputed genotype of each variant, Sanger sequencing was performed in 10% of randomly selected cases. Results Among the 3 most important common variants (rs11708996 in SCN5A, rs10428132 in SCN10A and rs9388451 in HEY2/NCOA7) reported in the previous GWAS mainly conducted in Caucasian BrS patients, 2 of them (rs10428132 and rs9388451) were successfully replicated in the HC population in Taiwan (P&lt;0.01). We also found that the differences of minor allele frequency (dMAF: the MAF of cases minus the MAF of controls) of the two variants were relatively smaller between the BrS cases and healthy controls in HC population compared with that in Caucasian populations (dMAF, rs9388451: 0.15 (Caucasian) vs −0.07 (HC); rs10428132: 0.28 (Caucasian) vs 0.11 (HC)). For the remaining 10 common variants reaching genome-wide significance (P=5×10–8) in Caucasian BrS patients, 9 of them were also significantly enriched in the HC BrS patients after the Bonferroni correction (P&lt;0.05/12=0.0042). We next analyzed the variants identified in the previous GWAS on ECG traits (PR interval, QRS duration, QTc interval, and heart rate) in the Caucasian population. Among the reported 75 variants associated with ECG traits, 5 common variants (rs6798015 (PR), rs1760876 (QRS), rs6795970 (PR/QRS), rs2074238 (QTc) and rs314370 (heart rate)) were significant after Bonferroni correction (P&lt;0.05/75=0.00066). Figure 1 Conclusions The preliminary results indicated that 85% of common variants of SCN10A and HEY2/NCOA7 previously reported in Caucasian BrS patients are replicated in BrS patients in the HC population but not the common variant of SCN5A (rs11708996). Furthermore, the common variants of SCN10A and HEY2/NCOA7 related to cardiac depolarization or repolarization may also contribute to the development of BrS. Acknowledgement/Funding NTUH 106-S3469, NTUH106-S3458 and NTUH 106-018

Association of apolipoprotein A1 and A5 polymorphisms with stroke subtypes in Han Chinese people in Taiwan

Background and purposesStroke is a leading cause of death and serious disability worldwide. Now, evidences indicate that dyslipidemia may play an important role in stroke. APOA1 and APOA5 involve in lipid metabolism. In this study, we investigated the association of APOA1 rs670 and APOA5 rs662799 with different stroke subtypes in the Han Chinese population of Taiwan. MethodsA total of 1751 participants, including 459 control subjects, 606 large artery atherosclerosis (LAA), 339 small vessel occlusion (SVO), and 347 hypertensive intracranial hemorrhage (HICH), were enrolled. The presence of rs670 and rs662799 was analyzed through polymerase chain react ion and matrix-assisted laser desorption/ionization–time-of-flight–mass spectrometry. ResultsNotably, the frequency of the rs662799 C allele was significantly lower in the SVO patients than in the controls (24.36% vs. 29.74%, P = 0.024). The frequencies of heterozygote TC [odd ratio (OR) = 0.732, 95% confidence interval (CI) = 0.544–0.984, P = 0.038] and TC + CC (OR = 0.719, 95% CI = 0.542–0.953, P = 0.022) genotypes were significantly lower in the SVO patients than in the controls. In addition, triglyceride levels in individuals carrying the rs662799 TC + CC genotype were significantly higher than in those carrying the TT genotype, especially in older age, female, and body mass index (BMI) ≥ 25 groups. On the contrary, the low-density lipoprotein-cholesterol (LDL-C) was significantly lower in rs662799 TC + CC genotype than TT genotype. The BMI was significantly lower in subjects with rs662799 TC + CC genotype than those with TT genotype, especially in older age and female. High-density lipoprotein-cholesterol (HDL-C) levels were higher in individuals carrying the rs670 GG genotype than in those carrying the AG + AA genotype, especially in BMI < 25 group. Logistic regression analysis showed that the rs662799 C allele (TC + CC) was an independent protective factor for SVO after adjustment for conventional risk factors (OR = 0.709, 95% CI = 0.526–0.956; P = 0.024). ConclusionGG genotype of rs670 is correlated with high serum HDL-C levels, whereas TC + CC genotype of rs662799 is associated with high serum triglyceride and low LDL and BMI levels. In addition, the rs662799 C allele (TC + CC) is an independent protective factor for SVO in the Han Chinese population in Taiwan.

Multilocus genetic risk score for diabetic retinopathy in the Han Chinese population of Taiwan

The aim of this study is to explore the effect of genetic variation on diabetic retinopathy (DR) risk in a Taiwanese population. The logistic regression model was used to evaluate the relationship between DR status and risk factors, including the conventional parameters and genetic risk score (GRS). Candidate single nucleotide polymorphisms (SNPs) in GRS were selected based on previous reports with a combined P < 10−4 (genome-wide association) and P < 0.05 (meta-analysis). In total, 58 SNPs in 44 susceptibility loci were selected, and four were used to calculate GRS. After adjustment for age, systolic blood pressure, diabetes duration, and HbA1c, the DR risk was 4.95 times higher for patients in the top GRS third tile than for those in the bottom third tile (95% CI = 2.99–8.18; P < 0.001). The addition of genetic information improved DR prediction, increasing the area under the curve (AUC) from 0.72 to 0.77 (P = 0.0024) and improving the sensitivity of the model such that 40 more subjects were reclassified into DR status. The developed multivariate logistic regression model combining conventional risk factors and the multilocus GRS can predict DR, thus enabling timely treatment to reduce blindness in T2D patients.

Hematopoietically expressed homeobox gene is associated with type 2 diabetes in KK Cg-Ay/J mice and a Taiwanese Han Chinese population.

Diabetes mellitus (DM) is a chronic disease. The KK Cg-Ay/J (KK-Ay) mouse is an animal model to study type 2 diabetes mellitus (T2D) disease. The present study assessed the expression of hematopoietically expressed homeobox (HHEX) protein in liver tissues of different age groups of mice (6, 16 and 42 weeks) by immunohistochemistry (IHC). The results demonstrated a significant decrease in the percentage of HHEX-positive cells in KK-Ay mice as compared with that in KK-α/α control mice. Furthermore, in Taiwan's Han Chinese population, genotypic and allelic frequency distributions of the rs61862780 single-nucleotide polymorphism (SNP) in the HHEX gene were investigated. The results demonstrated that in the rs61862780 SNP of the 3′-untranslated region (UTR) of HHEX, the frequency of the CC genotype was higher in patients (6.0%) than in controls (2.7%), while the TT genotype frequency was about equal. In the same SNP, the frequency of the C allele was higher in patients (21.0%) than in controls (17.3%), while the T allele frequency was about equal. These results may pave the road for exploring the KK-Ay mouse model and the HHEX SNP rs61862780, which was correlated with the susceptibility to T2D in a Chinese population. Based on these findings, an association of HHEX gene expression with pathological features of T2D was indicated.

A Two-Stage Whole-Genome Gene Expression Association Study of Young-Onset Hypertension in Han Chinese Population of Taiwan

Hypertension is an important public health problem in the world. Since the intermediate position of the gene expression between genotype and phenotype makes it suitable to link genotype to phenotype, we carried out a two-stage whole-genome gene expression association study to find differentially expressed genes and pathways for hypertension. In the first stage, 126 cases and 149 controls were used to find out the differentially expressed genes. In the second stage, an independent set of samples (127 cases and 150 controls) was used to validate the results. Additionally, we conducted a gene set enrichment analysis (GSEA) to search for differentially affected pathways. A total of nine genes were implicated in the first stage (Bonferroni-corrected p-value < 0.05). Among these genes, ZRANB1, FAM110A, PREP, ANKRD9 and LAMB2 were also differentially expressed in an existing database of hypertensive mouse model (GSE19817). A total of 16 pathways were identified by the GSEA. ZRANB1 and six pathways identified are related to TNF-α. Three pathways are related to interleukin, one to metabolic syndrome, and one to Hedgehog signaling. Identification of these genes and pathways suggest the importance of 1. inflammation, 2. visceral fat metabolism, and 3. adipocytes and osteocytes homeostasis in hypertension mechanisms and complications.

Genome-wide copy number variation analysis identified deletions in SFMBT1 associated with fasting plasma glucose in a Han Chinese population

BackgroundFasting glucose and fasting insulin are glycemic traits closely related to diabetes, and understanding the role of genetic factors in these traits can help reveal the etiology of type 2 diabetes. Although single nucleotide polymorphisms (SNPs) in several candidate genes have been found to be associated with fasting glucose and fasting insulin, copy number variations (CNVs), which have been reported to be associated with several complex traits, have not been reported for association with these two traits. We aimed to identify CNVs associated with fasting glucose and fasting insulin.ResultsWe conducted a genome-wide CNV association analysis for fasting plasma glucose (FPG) and fasting plasma insulin (FPI) using a family-based genome-wide association study sample from a Han Chinese population in Taiwan. A family-based CNV association test was developed in this study to identify common CNVs (i.e., CNVs with frequencies ≥ 5%), and a generalized estimating equation approach was used to test the associations between the traits and counts of global rare CNVs (i.e., CNVs with frequencies <5%). We found a significant genome-wide association for common deletions with a frequency of 5.2% in the Scm-like with four mbt domains 1 (SFMBT1) gene with FPG (association p-value = 2×10−4 and an adjusted p-value = 0.0478 for multiple testing). No significant association was observed between global rare CNVs and FPG or FPI. The deletions in 20 individuals with DNA samples available were successfully validated using PCR-based amplification. The association of the deletions in SFMBT1 with FPG was further evaluated using an independent population-based replication sample obtained from the Taiwan Biobank. An association p-value of 0.065, which was close to the significance level of 0.05, for FPG was obtained by testing 9 individuals with CNVs in the SFMBT1 gene region and 11,692 individuals with normal copies in the replication cohort.ConclusionsPrevious studies have found that SNPs in SFMBT1 are associated with blood pressure and serum urate concentration, suggesting that SFMBT1 may have functional implications in some metabolic-related traits.

Comparisons of clinical impacts on individuals with Brugada electrocardiographic patterns defined by ISHNE criteria or EHRA/HRS/APHRS criteria: a nationwide community-based study

Introduction: Identifying Brugada electrocardiographic pattern (BrP) early is crucial to prevent sudden cardiac death. Two different diagnostic criteria proposed by International Society for Holter and Noninvasive Electrocardiography (ISHNE) and Heart Rhythm Society/European Heart Rhythm Association/Asia-Pacific Heart Rhythm Society (HRS/EHRA/APHRS) were widely used in clinical practice. The difference in prevalence and prognosis of BrP by applying the two different criteria was never studied before.Methods: This study was prospectively conducted in a nationwide large-scale stratified random sampling community-based cohort (HALST) from Han Chinese population in Taiwan from December 2008 to December 2012. We compared the prevalence and prognosis of BrP defined by the two diagnostic criteria.Results: A total of 5214 adults were enrolled (2530 men) with mean age of 69.3 years. Four had spontaneous type 1 BrP (0.077%). By the HRS/EHRA/APHRS criteria, 68 individuals have type 2 BrP (1.30%) and 101 have type 3 BrP (1.94%) whereas by the ISHNE criteria, 46 individuals exhibited type 2 BrP (0.88%). When applying the ISHNE criteria, the number of individuals with BrP decreased by 71%. However, all-cause mortality and cardiovascular mortality were not different between individuals with or without BrP, irrespective of the criteria used.Conclusions: The two different criteria may impact the diagnostic yield of individuals with BrP, but do not affect the prognosis of the individuals with BrP.Key messagesComparing with the use of HRS/EHRA/APHRS criteria, the number of individuals with Brugada ECG patterns was decreased by 71% when applying the ISHNE criteria.The prognosis of individuals with Brugada ECG patterns defined by 2012 ISHNE or 2013 HRS/EHRA/APHRS criteria were not different.

SORL1 gene, plasma biomarkers, and the risk of Alzheimer's disease for the Han Chinese population in Taiwan.

BackgroundThe sortilin-related receptor 1 (SORL1) gene, regulating the trafficking and recycling of amyloid precursor protein, has been related to Alzheimer’s disease (AD) and mild cognitive impairment (MCI). The aim of the present study was to investigate the relationship between SORL1 polymorphisms, plasma concentrations of amyloid-beta (Aβ) isoforms, and AD and MCI susceptibility for a Han Chinese population in Taiwan.MethodsEight single-nucleotide polymorphisms (SNPs) in SORL1 and the apolipoprotein E gene (APOE) ε4 alleles were genotyped in 798 patients with AD, 157 patients with MCI, and 401 control subjects. Plasma concentrations of Aβ42, Aβ40, and neuropsychiatric tests for six different cognitive domains were examined.ResultsAmong the eight tested SNPs, SORL1 rs1784933 was most significantly associated with AD and MCI in our population. The G allele of rs1784933 exerted a protective effect and was associated with a reduced risk of AD (odds ratio [OR] = 0.75, p = 0.004) and MCI (OR = 0.69, p = 0.013). The significance remained after we adjusted for age, sex, and APOE ε4 alleles. For the overall participants, the plasma concentrations of Aβ42 were nominally significant for subjects carrying the rs1784933 G allele having a lower level than those without the G allele (p = 0.046). There was a similar trend for the G allele carriers to have a lower plasma Aβ40 level than noncarriers, but this was not significant. The nonsynonymous SNP rs2298813 was also related to a lower disease risk when AD and MCI were combined as a group (OR = 0.76, p = 0.035). However, there was no association between SORL1 genotypes and any of the six cognitive tests.ConclusionsFindings from our study provide support for the effect of SORL1 gene on the disease risks and pathognomonic surrogates of AD/MCI. The interaction between SORL1 polymorphisms and Aβ formation requires further study.

TPH1 and 5-HTTLPR Genes Specifically Interact in Opiate Dependence but Not in Alcohol Dependence

Background: Different drug dependencies may have unique genetic vulnerabilities. Changes in serotonin availability and function have been linked to addiction. We investigated whether 2 serotonergic polymorphisms, TPH1 A218C (rs1800532) and 5-HTT-linked promoter region (5-HTTLPR) (rs25531), are differently associated with alcohol or opiate dependence. Methods: Alcohol-dependent patients (n = 292), opiate-dependent patients (n = 309), and healthy controls (n = 301) were recruited from the Han Chinese population in Taiwan. Genotypes of TPH1 A218C and 5-HTTLPR polymorphisms were analyzed using a polymerase chain reaction with restriction fragment length polymorphism. Results: The genotype frequencies of the TPH1 A218C polymorphisms were not significantly different in the 3 groups. The genotype frequencies of the 5-HTTLPR S+ (S/S, S/L_G, L_G/L_G) polymorphisms were significantly higher in opiate-dependent patients (χ² = 8.77, p = 0.01), but not after controlling for the covariates of age, gender, and interaction effect in logistic regression analysis. Moreover, there was a significant interaction between the TPH1 A218C A/C and 5-HTTLPR S+ gene polymorphisms in opiate-dependent (OR 2.72, p = 0.01), but not in alcohol-dependent patients. Conclusions: Our data suggested that there may be a differential genetic vulnerability in serotonergic genes for alcohol and opiate addiction. However, replications of our findings are still needed.