Residual risk of cardiovascular complications in statin-using patients with type 2 diabetes: the Taiwan Diabetes Registry Study.

BACKGROUND: The residual risks of atherosclerotic cardiovascular disease in statin-treated patients with diabetes remain unclear. This study was conducted to identify factors associated with these residual risks in patients with no prior vascular event. METHODS: Data on 683 statin-using patients with type 2 diabetes mellitus (T2DM) from the Taiwan Diabetes Registry were used in this study. Patients aged < 25 or > 65 years at the time of diabetes diagnosis and those with diabetes durations ≥ 20 years were excluded. The United Kingdom Prospective Diabetes Study risk engine (version 2.01; https://www.dtu.ox.ac.uk/riskengine/ ) was used to calculate 10-year residual nonfatal and fatal coronary heart disease (CHD) and stroke risks. Associations of these risks with physical and biochemical variables, including medication use and comorbidity, were examined. RESULTS: The 10-year risks of nonfatal CHD in oral anti-diabetic drug (OAD), insulin and OAD plus insulin groups were 11.8%, 16.0%, and 16.8%, respectively. The 10-year risks of nonfatal stroke in OAD, insulin and OAD plus insulin groups were 3.0%, 3.4%, and 4.3%, respectively. In the multivariate model, chronic kidney disease (CKD), neuropathy, insulin use, calcium-channel blocker (CCB) use, higher body mass indices (BMI), low-density lipoprotein (LDL), fasting glucose, log-triglyceride (TG), and log-alanine transaminase (ALT) levels were associated with an increased CHD risk. The residual risk of stroke was associated with CKD, neuropathy, CCB use, and lower LDL cholesterol levels, higher BMI and diastolic blood pressure. CONCLUSION: This study indicated that insulin was probably a residual risk factor of CHD but not stroke, and that there was a possible presence of obesity paradox in patients with T2DM on statin therapy. In addition to lowering TG and normalizing fasting glucose levels, lower LDL cholesterol level is better for reduction of risk of CHD on statin therapy. On the other hand, lower LDL cholesterol level could potentially be related to higher risk of stroke among populations receiving statin therapy. These findings suggest potential therapeutic targets for residual cardiovascular risk reduction in patients with T2DM on statin therapy.

Genetic risk score constructed from common genetic variants is associated with cardiovascular disease risk in type 2 diabetes mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) experience a two-fold increased risk of cardiovascular diseases. Genome-wide association studies (GWAS) have identified T2DM susceptibility genetic variants. Interestingly, the genetic variants associated with cardiovascular disease risk in T2DM Han Chinese remain to be elucidated. The present study aimed to investigate the genetic variants associated with cardiovascular disease risk in T2DM. METHODS: We performed bootstrapping, GWAS and an investigation of genetic variants associated with cardiovascular disease risk in a discovery T2DM cohort and in a replication cohort. The discovery cohort included 326 cardiovascular disease patients and 1209 noncardiovascular disease patients. The replication cohort included 68 cardiovascular disease patients and 317 noncardiovascular disease patients. The main outcome measures were genetic variants for genetic risk score (GRS) in cardiovascular disease risk in T2DM. RESULTS: In total, 35 genetic variants were associated with cardiovascular disease risk. A GRS was generated by combining risk alleles from these variants weighted by their estimated effect sizes (log odds ratio [OR]). T2DM patients with weighted GRS ≥ 12.63 had an approximately 15-fold increase in cardiovascular disease risk (odds ratio = 15.67, 95% confidence interval [CI] = 10.33-24.00) compared to patients with weighted GRS < 10.39. With the addition of weighted GRS, receiver-operating characteristic curves showed that area under the curve with conventional risk factors was improved from 0.719 (95% CI = 0.689-0.750) to 0.888 (95% CI = 0.866-0.910). CONCLUSIONS: These 35 genetic variants are associated with cardiovascular disease risk in T2DM, alone and cumulatively. T2DM patients with higher levels of weighted genetic risk score have higher cardiovascular disease risks.

Effect of mean HbA1c on the association of HbA1c variability and all-cause mortality in patients with type 2 diabetes.

AIM: To evaluate the effect of mean HbA1c on the correlation between HbA1c variability and all-cause mortality, and the risks associated with different levels of HbA1c and glycaemic control status in patients with type 2 diabetes. MATERIALS AND METHODS: Patients with type 2 diabetes and at least three HbA1c measurements within 12-24 months were included. HbA1c variability score, coefficient of variation (CV) and standard deviation (SD) were used to evaluate variability. A variability score of 50 was set as a cutoff to define low and high variability. RESULTS: A total of 4216 patients were included, of whom 1196 died during the observation period (11.1 ± 3.2 years). All-cause mortality increased with HbA1c variability score and the quartiles of HbA1c CV and SD. The strength of this association was attenuated after adjustment for mean HbA1c, and the risks associated with HbA1c variability and glycaemic control status were similar. The highest associated risk was observed with an HbA1c variability score of >50 and mean HbA1c of ≥7.5%. Mortality risk was significantly higher with a mean HbA1c of ≤6.0% and >8.5% and of ≤6.0% and >8.0% for low and high HbA1c variability, respectively. CONCLUSIONS: Mean HbA1c contributed to the correlation between HbA1c variability and all-cause mortality. The risks associated with HbA1c variability and glycaemic control status were similar. The relationship between mean HbA1c and mortality presented a J-shaped distribution for both low and high HbA1c variability.

KCNQ1 variants associate with hypertension in type 2 diabetes and affect smooth muscle contractility in vitro.

KCNQ1 encodes a potassium voltage-gated channel and represents a susceptibility locus for type 2 diabetes mellitus (T2DM). Here, we explored the association between KCNQ1 polymorphisms and hypertension risk in individuals with T2DM, as well as the role of KCNQ1 in vascular smooth muscle cell contraction in vitro. To investigate the relationship between KCNQ1 and the risk of developing hypertension in patients with T2DM, we divided the T2DM cohort into hypertension (n = 452) and non-hypertension (n = 541) groups. The Mann-Whitney U test, chi-square test, and multivariate regression analyses were used to assess the clinical characteristics and genotypic frequencies. In vitro studies utilized the rat aortic smooth muscle A10 cell line. Patients in the hypertension group were significantly older at the time of enrollment and had higher levels of body mass index, waist-to-hip ratio, and triglyceride than those in the non-hypertension group. The KCNQ1 rs3864884 and rs12576239 genetic variants were associated with hypertension in T2DM. KCNQ1 expression was lower in the individuals with the CC versus the CT and TT genotypes. Smooth muscle cell contractility was inhibited by treatment with a KCNQ1 inhibitor. These results suggest that KCNQ1 might be associated with hypertension in individuals with T2DM.

Levels of high-mobility group box-1 in gingival crevicular fluid in nonsmokers and smokers with chronic periodontitis.

BACKGROUND/PURPOSE: High-mobility group box-1 (HMGB1), a proinflammatory cytokine, plays a role in inflammatory disorders. Smoking is a well-established risk factor for periodontal disease. The aim of this study was to compare the levels of HMGB1 in the gingival crevicular fluid from periodontally healthy nonsmokers, chronic periodontitis nonsmokers, and chronic periodontitis smokers. Furthermore, the relationship between levels of HMGB1 and periodontal parameters was examined. METHODS: Periodontal parameters of 17 nonsmokers with chronic periodontitis, nine smokers with chronic periodontitis, and nine periodontally healthy nonsmokers were examined. Gingival crevicular fluid samples were collected, and the levels of HMGB1 were analyzed using the enzyme-linked immunosorbent assay. RESULTS: The median level of HMGB1 was statistically significantly higher in chronic periodontitis nonsmokers (37.5 ng/mL) than in chronic periodontitis smokers (9.5 ng/mL) and periodontally healthy nonsmokers (3.7 ng/mL). There was no significant difference in the levels of HMGB1 between chronic periodontitis smokers and periodontally healthy nonsmokers. Levels of HMGB1 were positively correlated with plaque index, gingival index, probing depth, and clinical attachment level of nonsmokers. However, no significant correlations were found between levels of HMGB1 and all periodontal parameters examined in chronic periodontitis smokers. CONCLUSION: Chronic periodontitis nonsmokers had elevated levels of HMGB1 in gingival crevicular fluid. Moreover, the levels of HMGB1 were correlated with severity of periodontitis. Chronic periodontitis smokers exhibited lower levels of HMGB1 than chronic periodontitis nonsmokers. Further research is needed for understanding the role of HMGB1 in smoking and pathogenesis of periodontitis.

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.

Andrographolide inhibits adipogenesis of 3T3-L1 cells by suppressing C/EBPß expression and activation.

Andrographolide, a diterpenoid, is the most abundant terpenoid in Andrographis paniculata, a popular Chinese herbal medicine. Andrographolide displays diverse biological activities including hypoglycemia, hypolipidemia, anti-inflammation, and anti-tumorigenesis. Recent evidence indicates that andrographolide displays anti-obesity property by inhibiting lipogenic gene expression, however, the underlying mechanisms remain to be elucidated. In this study, the effects of andrographolide on transcription factor cascade and mitotic clonal expansion in 3T3-L1 preadipocyte differentiation into adipocyte were determined. Andrographolide dose-dependently (0-15µM) inhibited CCAAT/enhancer-binding protein α (C/EBPα) and C/EBPß mRNA and protein expression as well as peroxisome proliferator-activated receptor γ (PPARγ) protein level during the adipogenesis of 3T3-L1 cells. Concomitantly, fatty acid synthase and stearoyl-CoA desaturase expression and lipid accumulation were attenuated by andrographolide. Oil-red O staining further showed that the first 48h after the initiation of differentiation was critical for andrographolide inhibition of adipocyte formation. Andrographolide inhibited the phosphorylation of PKA and the activation of cAMP response element-binding protein (CREB) in response to a differentiation cocktail, which led to attenuated C/EBPß expression. In addition, ERK and GSK3ß-dependent C/EBPß phosphorylation was attenuated by andrographolide. Moreover, andrographolide suppressed cyclin A, cyclin E, and CDK2 expression and impaired the progression of mitotic clonal expansion (MCE) by arresting the cell cycle at the Go/G1 phase. Taken together, these results indicate that andrographolide has a potent anti-obesity action by inhibiting PKA-CREB-mediated C/EBPß expression as well as C/EBPß transcriptional activity, which halts MCE progression and attenuates C/EBPα and PPARγ expression.

Susceptible gene of stasis-stagnation constitution from genome-wide association study related to cardiovascular disturbance and possible regulated traditional Chinese medicine.

BACKGROUND: This study identified susceptible loci related to the Yu-Zhi (YZ) constitution, which indicates stasis-stagnation, found in a genome-wide association study (GWAS) in patients with type 2 diabetes and possible regulated traditional Chinese medicine (TCM) using docking and molecular dynamics (MD) simulation. METHODS: Non-aboriginal Taiwanese with type 2 diabetes were recruited. Components of the YZ constitution were assessed by a self-reported questionnaire. Genome-wide SNP genotypes were obtained using the Illumina HumanHap550 platform. The world's largest TCM database ( http://tcm.cmu.edu.tw/ ) was employed to investigate potential compounds for PON2 interactions. RESULTS: The study involved 1,021 unrelated individuals with type 2 diabetes. Genotyping data were obtained from 947 of the 1,021 participants. The GWAS identified 22 susceptible single nucleotide polymorphisms on 13 regions of 11 chromosomes for the YZ constitution. Genotypic distribution showed that PON2 on chromosome 7 was most significantly associated with the risk of the YZ constitution. Docking and MD simulation indicated 13-hydroxy-(9E_11E)-octadecadienoic acid was the most stable TCM ligand. CONCLUSIONS: Risk loci occurred in PON2, which has antioxidant properties that might protect against atherosclerosis and hyperglycemia, showing it is a susceptible gene for the YZ constitution and possible regulation by 13-hydroxy-(9E_11E)-octadecadienoic acid.

Genetic variation in the peroxisome proliferator-activated receptor (PPAR) and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) gene families and type 2 diabetes.

We used a two-stage study design to evaluate whether variations in the peroxisome proliferator-activated receptors (PPAR) and the PPAR gamma co-activator 1 (PGC1) gene families (PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B) are associated with type 2 diabetes (T2D) risk. Stage I used data from a genome-wide association study (GWAS) from Shanghai, China (1019 T2D cases and 1709 controls) and from a meta-analysis of data from the Asian Genetic Epidemiology Network for T2D (AGEN-T2D). Criteria for selection of single nucleotide polymorphisms (SNPs) for stage II were: (1) P < 0.05 in single marker analysis in Shanghai GWAS and P < 0.05 in the meta-analysis or (2) P < 10(-3) in the meta-analysis alone and (3) minor allele frequency ≥ 0.10. Nine SNPs from the PGC1 family were assessed in stage II (an independent set of middle-aged men and women from Shanghai with 1700 T2D cases and 1647 controls). One SNP in PPARGC1B, rs251464, was replicated in stage II (OR = 0.87; 95% CI: 0.77-0.99). Gene-body mass index (BMI) and gene-exercise interactions and T2D risk were evaluated in a combined dataset (Shanghai GWAS and stage II data: 2719 cases and 3356 controls). One SNP in PPARGC1A, rs12640088, had a significant interaction with BMI. No interactions between the PPARGC1B gene and BMI or exercise were observed.

Visit-to-visit variability of fasting plasma glucose as predictor of ischemic stroke: competing risk analysis in a national cohort of Taiwan Diabetes Study.

BACKGROUND: Glycemic variation as an independent predictor of ischemic stroke in type 2 diabetic patients remains unclear. This study examined visit-to-visit variations in fasting plasma glucose (FPG), as represented by the coefficient of variation (CV), for predicting ischemic stroke independently, regardless of glycated hemoglobin (HbA1c) and other conventional risk factors in such patients. METHODS: Type 2 diabetic patients enrolled in the National Diabetes Care Management Program, ≥30 years old and free of ischemic stroke (n = 28,354) in 2002 to 2004 were included, and related factors were analyzed with extended Cox proportional hazards regression models of competing risk data on stroke incidence. RESULTS: After an average 7.5 years of follow-up, there were 2,250 incident cases of ischemic stroke, giving a crude incidence rate of 10.56/1,000 person-years (11.64 for men, 9.63 for women). After multivariate adjustment, hazard ratios for the second, third and fourth versus first FPG-CV quartile were 1.11 (0.98, 1.25), 1.22 (1.08, 1.38) and 1.27 (1.12, 1.43), respectively, without considering HbA1c, and 1.09 (0.96, 1.23), 1.16 (1.03, 1.31) and 1.17 (1.03, 1.32), respectively, after considering HbA1c. CONCLUSIONS: Besides HbA1c, FPG-CV was a potent predictor of ischemic stroke in type 2 diabetic patients, suggesting that different therapeutic strategies now in use be rated for their potential to (1) minimize glucose fluctuations and (2) reduce HbA1c level in type 2 diabetic patients to prevent ischemic stroke.

Identified single-nucleotide polymorphisms and haplotypes at 16q22.1 increase diabetic nephropathy risk in Han Chinese population.

BACKGROUND: Diabetic nephropathy (DN) has become one of the most common causes of end-stage renal disease (ESRD) in many countries, such as 44.5% in Taiwan. Previous studies have shown that there is a genetic component to ESRD. Studies attempting to determine which genetic variants are related to DN in Han Chinese are limited. A case-control study was conducted to identify DN susceptibility variants in Han Chinese patients with type 2 diabetes. RESULTS: We included 574 unrelated type 2 diabetes patients (217 DN cases and 357 controls), who were genotyped using Illumina HumanHap550-Duo BeadChip. In single-SNP association tests, the SNPs rs11647932, rs11645214, and rs6499323 located at 16q22.1 under the additive-effect disease model were significantly associated with an approximately 2-fold increased risk of DN. In haplotype association tests, identified haplotypes located in the chromosome 16q22.1 region (containing ST3GAL2, COG4, SF3B3, and IL34 genes) raised DN risk. The strongest association was found with haplotype rs2288491-rs4985534-rs11645214 (C-C-G) (adjusted odds ratio [AOR] 1.93, 95% confidence interval [CI] 1.83-2.03, p = 6.25 × 10⁻7), followed by haplotype rs8052125-rs2288491-rs4985534-rs11645214 (G-C-C-G) (AOR 1.92, 95% CI 1.82-2.02, p = 6.56 × 10⁻7), and haplotype rs2303792-rs8052125-rs2288491-rs4985534-rs11645214 (A-G-C-C-G) (AOR 1.91, 95% CI 1.81-2.01, p = 1.15 × 10⁻6). CONCLUSIONS: Our results demonstrate that the novel SNPs and haplotypes located at the 16q22.1 region may involve in the biological pathways of DN in Han Chinese patients with type 2 diabetes. This study can provide new insights into the etiology of DN.

Association of TLR7 and TSHR copy number variation with Graves' disease and Graves' ophthalmopathy in Chinese population in Taiwan.

BACKGROUND: Graves' disease (GD) and Graves' ophthalmopathy (GO) are autoimmune disorders, which might be influenced by genetic factors. Copy number variation (CNV) is an important source of genomic diversity in humans, and influences disease susceptibility. This study investigated the association between CNV in the TSHR and TLR7 genes and the development of GD and GO in a Chinese population in Taiwan. METHODS: For this case-control study, sample from 196 healthy controls and 484 GD patients, including 203 patients with GO were studied. CNV was detected by real-time polymerase chain reaction (PCR) using TaqMan™ probes and the relative copy number (CN) was estimated by using the comparative Ct method. RESULTS: The differences in the distribution of TSHR CNV in healthy controls and GD patients were statistically significant (p value = 0.01). However, the difference in the distribution of TSHR CNV in the control group and the GO group was not statistically significant (p value = 0.06). For TLR7 CNV, the results were not significantly different when we compared the distribution in healthy controls and GD patients and in healthy controls and GO patients (p values for Fisher's exact test were 0.13 and 0.09, respectively). However, a lower than normal CNV for TLR7 (CNV < 2 for female and CNV < 1 for male) was found to have a protective effect against the development of GD (odds ratio (OR) = 0.24; 95% confidence interval (CI), 0.07-0.75) after adjusting for age and gender. CONCLUSIONS: These results suggested that TSHR and TLR7 CNV might be associated with susceptibility to GD.

HbA1c and systolic blood pressure variation to predict all-cause mortality in patients with type 2 diabetes mellitus.

BACKGROUND: Glycated hemoglobin A1c (HbA1c) variation or blood pressure (BP) variation was known to be an independent predictor of all-cause mortality in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the combined effect of HbA1c and systolic blood pressure (SBP) variation on all-cause mortality and if there was a gender difference in patients with T2DM. METHODS: Patients with T2DM who had at least three HbA1c, SBP measurements within 12-24 months during 2001-2007 were included. Coefficient of variation (CV) was used to evaluate variation. The 75th percentile of HbA1c-CV and SBP-CV were set as a cutoff to define high and low variation. Hazard ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazard models. RESULTS: A total of 2744 patients were included, of whom 769 died during the 11.7 observation years. The associated risk of all-cause mortality was 1.22 [1.01- 1.48], P = 0.044, for low HbA1c-CV & high SBP-CV; 1.28 [1.04-1.57], P = 0.020, for high HbA1c-CV & low SBP-CV; and 1.68 [1.31-2.17], P < 0.001, for high HbA1c-CV & high SBP-CV. The associated risk remained unchanged in either males or females older than 50 years old, although there is only numerically higher for high HbA1c-CV & low SBP-CV in females older than 50 years old. CONCLUSIONS: Both HbA1c and SBP variation were significant predictors of all-cause mortality in patients with T2DM. The combined effect was higher than either alone and no gender difference in patients older than 50 years old.

The expert consensus on care and education for patients with diabetic kidney disease in Taiwan.

Increasing prevalence of type 2 DM (T2DM) and diabetic kidney disease (DKD) has posed a great impact in Taiwan. However, guidelines focusing on multidisciplinary patient care and patient education remain scarce. By literature review and expert discussion, we propose a consensus on care and education for patients with DKD, including general principles, specifics for different stages of chronic kidney disease (CKD), and special populations. (i.e. young ages, patients with atherosclerotic cardiovascular disease or heart failure, patients after acute kidney injury, and kidney transplant recipients). Generally, we suggest performing multidisciplinary patient care and education in alignment with the government-led Diabetes Shared Care Network to improve the patients' outcomes for all patients with DKD. Also, close monitoring of renal function with early intervention, control of comorbidities in early stages of CKD, and nutrition adjustment in advanced CKD should be emphasized.

Optimizing lipid control in Taiwanese diabetic patients: A collaborative consensus by the Diabetes Association of the Republic of China (Taiwan) and the Taiwanese Association of Diabetes Educators.

We present an in-depth analysis of dyslipidemia management strategies for patients with diabetes mellitus in Taiwan. It critically examines the disparity between established guideline recommendations and actual clinical practices, particularly in the context of evolving policies affecting statin prescriptions. The focus is on synthesizing the most recent findings concerning lipid management in patients with diabetes mellitus, with a special emphasis on establishing consensus regarding low-density lipoprotein cholesterol treatment targets. The article culminates in providing comprehensive, evidence-based recommendations tailored to the unique needs of those living with diabetes mellitus in Taiwan. It underscores the criticality of personalized care approaches, which incorporate multifaceted factors, and the integration of novel therapeutic options to enhance cardiovascular health outcomes.

Oral hypoglycaemic agents and the development of non-fatal cardiovascular events in patients with type 2 diabetes mellitus.

AIMS: This study aimed to assess the risk of non-fatal cardiovascular events among patients with type 2 diabetes mellitus (T2DM) who are taking metformin, glimepiride or glyburide. MATERIALS AND METHODS: Using the National Health Insurance Research database in Taiwan, this retrospective cohort study identified 1159 patients with newly diagnosed T2DM from 1998 to 2007, 30 years and older and without a history of cardiovascular disease at baseline. Patients with cancer, liver cirrhosis or chronic kidney disease were excluded. On the basis of prescription, patients were grouped into three medication subcohorts: metformin (N = 595), glimepiride (N = 234) or glyburide (N = 330) monotherapy for 100% of the follow-up period without any oral anti-diabetic agents added or changed, by the end of 2009. Incidence and hazard ratios of non-fatal cardiovascular events including coronary artery disease, peripheral artery disease, stroke and heart failure among these three subcohorts were compared. RESULTS: The overall incidence of non-fatal cardiovascular events was the highest for patients taking glyburide (169.1 per 1000 person-years), followed by for those taking glimepiride and metformin (95.2 and 49.1 per 1000 person-years, respectively). Compared with the adjusted hazard ratio for patients taking glyburide, the adjusted hazard ratio for those taking glimepiride was 0.52 (95% CI 0.40-0.69) and for those taking metformin was 0.31 (95% CI 0.24-0.40). CONCLUSIONS: T2DM patients taking metformin and glimepiride are at lower risk of non-fatal cardiovascular events than those taking glyburide.

A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese.

To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54x10(-10); odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36-1.82), and serine racemase (SRR) (P = 3.06x10(-9); OR = 1.28; 95% CI = 1.18-1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65x10(-10); OR = 1.29, 95% CI = 1.19-1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations.

Maternal autoimmune disease and risk of offspring autism spectrum disorder - a nationwide population-based cohort study.

Introduction: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which cause long term social and behavior impairment, and its prevalence is on the rise. Studies about the association between maternal autoimmune diseases and offspring ASD have controversial results. The aim of this study was to investigate whether maternal autoimmune diseases increase the risk of ASD in offspring from a population-based perspective. Methods: The data sources were Taiwan's National Health Insurance Research Database (NHIRD) and Taiwan's Maternal and Child Health Database (MCHD), which were integrated and used to identify newborns whose mothers were diagnosed with autoimmune disease. Newborns were matched by maternal age, neonatal gender, and date of birth with controls whose mothers were without autoimmune disease using a ratio of 1:4 between 2004 and 2019. Data on diagnoses of autoimmune disease and autism spectrum disorders were retrieved from NHIRD. Patients who had at least 3 outpatient visits or at least 1 admission with a diagnosis of autoimmune disease and autism spectrum disorders were defined as incidence cases. The risks of ASD in offspring were compared between mothers with or without autoimmune disorders. Results: We identified 20,865 newborns whose mothers had been diagnosed with autoimmune disease before pregnancy and matched them at a ratio of 1:4 with a total of 83,460 newborn whose mothers were without autoimmune disease, by maternal age, neonatal gender, and date of birth. They were randomly selected as the control group. The cumulative incidence rates of autism spectrum disorders (ASD) were significantly higher among the offspring of mothers with autoimmune diseases. After adjusting for cofactors, the risk of ASD remained significantly higher in children whose mother had autoimmune diseases. Regarding to specific maternal autoimmune disease, Sjögren's syndrome and rheumatoid arthritis were both associated with elevated risks of ASD in offspring. Conclusion: Mother with autoimmune disease might be associated with increasing the risk of autism spectrum disorder in offspring.

Joint relationship between renal function and proteinuria on mortality of patients with type 2 diabetes: the Taichung Diabetes Study.

BACKGROUND: Estimated glomerular filtration rate (eGFR) is a powerful predictor of mortality in diabetic patients with limited proteinuria data. In this study, we tested whether concomitant proteinuria increases the risk of mortality among patients with type 2 diabetes. METHODS: Participants included 6523 patients > 30 years with type 2 diabetes who were enrolled in a management program of a medical center before 2007. Renal function was assessed by eGFR according to the Modification of Diet in Renal Disease Study equation for Chinese. Proteinuria was assessed by urine dipstick. RESULTS: A total of 573 patients (8.8%) died over a median follow-up time of 4.91 years (ranging from 0.01 year to 6.42 years). The adjusted expanded cardiovascular disease (CVD)-related mortality rates among patients with proteinuria were more than three folds higher for those with an eGFR of 60 mL/min/1.73 m2 or less compared with those with an eGFR of 90 mL/min/1.73 m2 or greater [hazard ratio, HR, 3.15 (95% confidence interval, CI, 2.0-5.1)]. The magnitude of adjusted HR was smaller in patients without proteinuria [1.98 (95% CI, 1.1-3.7)]. An eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 significantly affected all-cause mortality and mortality from expanded CVD-related causes only in patients with proteinuria. Similarly, proteinuria affected all outcomes only in patients with an eGFR of <60 mL/min/1.73 m2. CONCLUSION: The risks of all-cause mortality, as well as expanded and non-expanded mortality from CVD-related causes associated with proteinuria or an eGFR of 90 mL/min/1.73 m2 or greater are independently increased. Therefore, the use of proteinuria measurements with eGFR increases the precision of risk stratification for mortality.

Association of IL12B polymorphisms with susceptibility to Graves ophthalmopathy in a Taiwan Chinese population.

BACKGROUND: Interleukin 12B (IL12B) gene polymorphisms have been linked to several inflammatory diseases, but their role in the development of Graves ophthalmopathy (GO) in Graves disease (GD) patients is unclear. The purpose of this study was to investigate the disease association of IL12B single nucleotide polymorphisms (SNPs). METHODS: A Taiwan Chinese population comprising 200 GD patients with GO and 271 GD patients without GO was genotyped using an allele-specific extension and ligation method. Hardy-Weinberg equilibrium was estimated using the chi-square test. Allele and genotype frequencies were compared between GD patients with and without GO using the chi-square test. RESULTS: The genotype and allele frequencies of examined SNPs did not differ between GD patients with and without GO. Although the genotype distribution remained nonsignificant in the sex-stratified analyses, the frequency of the T allele at SNP rs1003199 was significantly higher in patients with GO in the male cohort (P = 6.00 × 10(-3)). In addition, haplotypes of IL12B may be used to predict the risk of GO (P = 1.70 × 10(-2)); however, we could not prove the statistical significance of analysis after applying the Bonferroni correction. CONCLUSIONS: Our results provide new information that the examined IL12B gene polymorphisms may be associated with susceptibility to GO in the Taiwan Chinese population in a sex-specific manner. This conclusion requires further investigation.