Associations of comorbid depression with cardiovascular-renal events and all-cause mortality accounting for patient reported outcomes in individuals with type 2 diabetes: a 6-year prospective analysis of the Hong Kong Diabetes Register.

Background: Psychosocial status and patient reported outcomes (PRO) [depression and health-related quality-of-life (HRQoL)] are major health determinants. We investigated the association between depression and clinical outcomes in Chinese patients with type 2 diabetes (T2D), adjusted for PRO. Methods: Using prospective data from Hong Kong Diabetes Register (2013-2019), we estimated the hazard-ratio (HR, 95%CI) of depression (validated Patient Health Questionnaire 9 (PHQ-9) score≥7) with incident cardiovascular disease (CVD), ischemic heart disease (IHD), chronic kidney disease (CKD: eGFR<60 ml/min/1.73m2) and all-cause mortality in 4525 Chinese patients with T2D adjusted for patient characteristics, renal function, medications, self-care and HRQoL domains (mobility, self-care, usual activities, pain/discomfort, anxiety/depression measured by EQ-5D-3L) in linear-regression models. Results: In this cohort without prior events [mean ± SD age:55.7 ± 10.6, 43.7% women, median (IQR) disease duration of 7.0 (2.0-13.0) years, HbA1c, 7.2% (6.6%-8.20%), 26.4% insulin-treated], 537(11.9%) patients had depressive symptoms and 1923 (42.5%) patients had some problems with HRQoL at baseline. After 5.6(IQR: 4.4-6.2) years, 141 patients (3.1%) died, 533(11.8%) developed CKD and 164(3.6%) developed CVD. In a fully-adjusted model (model 4) including self-care and HRQoL, the aHR of depression was 1.99 (95% confidence interval CI):1.25-3.18) for CVD, 2.29 (1.25-4.21) for IHD. Depression was associated with all-cause mortality in models 1-3 adjusted for demographics, clinical characteristics and self-care, but was attenuated after adjusting for HRQoL (model 4- 1.54; 95%CI: 0.91-2.60), though HR still indicated same direction with important magnitude. Patients who reported having regular exercise (3-4 times per week) had reduced aHR of CKD [0.61 (0.41-0.89)]. Item 4 of PHQ-9 (feeling tired, little energy) was independently associated with all-cause mortality with aHR of 1.66 (1.30-2.12). Conclusion: Depression exhibits significant association with CVD, IHD, and all-cause mortality in patients with diabetes, adjusting for their HRQoL and health behaviors. Despite the association between depression and all-cause mortality attenuated after adjusting for HRQoL, the effect size remains substantial. The feeling of tiredness or having little energy, as assessed by item Q4 of the PHQ-9 questionnaire, was found to be significantly associated with an increased risk of all-cause mortality after covariate adjustments. Our findings emphasize the importance of incorporating psychiatric evaluations into holistic diabetes management.

Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation study.

Background: Current labelling advises discontinuation of metformin when estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 due to increased risk of lactic acidosis. However, in real-world practice, the risk-benefit ratios remain uncertain. We examined the risk associations of discontinued-metformin use with cardiorenal and clinical outcomes in patients with type 2 diabetes (T2D) and advanced chronic kidney disease. Methods: In this territory-wide, retrospective cohort and target trial emulation study, we included Chinese patients attending the Hong Kong Hospital Authority (HA) and enrolled in the Risk-Assessment-and-Management-Programme-for-Diabetes-Mellitus (RAMP-DM) from 2002 to 2019. Patients were stratified by discontinuation of metformin within six months after reaching eGFR < 30 ml/min/1.73 m2 from January 1, 2002 to December 31, 2018, and followed up until December 31 2019. We excluded patients who had observational time <6 months from eGFR < 30 ml/min/1.73 m2, and had their eGFR measured during a hospitalisation episode due to acute kidney injury, or missing diagnosis date of diabetes. We compared the risk associations of metformin discontinuation with clinical outcomes. The primary outcomes were major adverse cardiovascular events (MACE), end-stage kidney disease (ESKD), cancer, and all-cause mortality. A Cox-model with time-dependent exposure and covariates was used to estimate the hazard ratio (HR) of outcomes in a propensity-score overlap-weighted cohort. The risk of occurrence of lactic acidosis (serum lactate > 5.0 mmol/L with a concomitant blood pH < 7.35 or ICD-9 codes of 276.2) in discontinued-metformin versus continued-metformin users was assessed in a separate register-based cohort. Findings: A total of 33,586 metformin users with new-onset eGFR < 30 ml/min/1.73 m2 were included in the study, 7500 (22.3%) of whom discontinued metformin within 6 months whereas 26,086 (77.7%) continued use of metformin. During a median follow-up of 3.8 (IQR: 2.2-6.1) years, 16.4% (5505/33,586), 30.1% (10,113/33,586), and 7.1% (2171/30,682) had incident MACE, ESKD, and cancer respectively, and 44.4% (14,917/33,586) died. Compared to continued-metformin use, discontinuation was associated with higher risk of MACE (weighted and adjusted HR = 1.40, 95% CI: 1.29-1.52), ESKD (HR = 1.52, 1.42-1.62), and death (HR = 1.22, 1.18-1.27). No association was observed for cancer (HR = 0.93, 0.85-1.01). Discontinued-metformin users had higher change in HbA1c change at 6-month of follow-up versus continued-metformin users (weighted mean HbA1c level change: 0.5% [0.4-0.6%] versus 0.2% [0.1-0.2]). In the separate register-based cohort (n = 3235), null association was observed between metformin use and risk of lactic acidosis (weighted HR = 0.94 [0.53-1.64]). Interpretation: Our results suggest that discontinuation of metformin in patients with T2D and chronic kidney disease may be associated with increased risk of cardiovascular-renal events. Use of metformin below eGFR of 30 ml/min/1.73 m2 may be associated with cardiovascular, renal, and mortality benefits that need to be weighed against the risk of lactic acidosis, but further research is needed to validate these findings. Funding: CUHK Impact Research Fellowship Scheme.

Health impacts of new-onset diabetes in women post-gestational diabetes mellitus: Insights from Hong Kong's territory-wide data.

AIMS/INTRODUCTION: To determine the population health burden attributable to the development of diabetes among women with a history of gestational diabetes mellitus (GDM). MATERIALS AND METHODS: We conducted a retrospective analysis of women with a history of GDM attending the Hong Kong Hospital Authority between 2000 and 2019. The time-varying population attributable fraction was calculated. RESULTS: A total of 76,181 women with a history of gestational diabetes mellitus were included, 6,606 of them developed diabetes during a median follow-up of 8.6 years. The respective hazard ratios (95% confidence interval) among women with GDM who developed diabetes vs those with GDM only were 2.8 (2.2, 3.7) for cardiovascular disease (CVD), 4.8 (3.0, 7.7) for end-stage kidney disease (ESKD), 2.2 (1.9, 2.6) for infection-related hospitalization, and 1.8 (1.3, 2.4) for all-cause mortality. The development of diabetes was associated with 1.3 (0.8, 1.7), 0.6 (0.3, 0.8), 3.2 (2.4, 4.0), and 0.5 (0.2, 0.9) additional incident cases per 1,000 person-years, accounting for 24.0% (13.2%, 35.9%), 42.0% (22.5%, 58.8%), 10.8% (7.1%, 14.9%), and 6.0% (-3.1%, 16.1%) of absolute number of CVD, ESKD, infection-related hospitalization, and all-cause mortality over 20 years after GDM, respectively. CONCLUSIONS: Diabetes is a significant contributor to the population health burden of some clinical outcomes in women with a history of gestational diabetes mellitus, but other risk factors need to be considered.

Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes.

Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome-wide methylation patterns are poorly defined. While methylation is known to alter gene expression, the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n = 39) that was subsequently replicated in a larger validation cohort (n = 296). Gene body-related regions made up more than 60% of the methylation differences and emphasized the importance of methylation sequencing. We observed differentially methylated genes associated with DN in 3 independent T1D registries originating from Denmark (n = 445), Hong Kong (n = 107), and Thailand (n = 130). Reduced DNA methylation at CTCF and Pol2B sites was tightly connected with DN pathways that include insulin signaling, lipid metabolism, and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubule cells. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding, and the activation of insulin-signaling phosphoproteins in hyperglycemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophages and vascular endothelial cells.

A diet high in FODMAPs as a novel dietary strategy in diabetes?

Dietary patterns have a profound effect on shaping the gut microbiota. Diverse populations of intestinal bacteria mediate their health-related effects through fermentation of short-chain carbohydrates to produce short-chain fatty acids (SCFAs) which have both pro-inflammatory and anti-inflammatory effects. Type 2 diabetes (T2D) is a disease characterized by chronic inflammation and both microbiota and SCFA have been implicated. Dietary intervention is a cornerstone for controlling body weight, insulin secretion, and postprandial glycemic response. The term FODMAPs stands for poorly-absorbed fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. The health benefits of FODMAPS mainly came from research on gastrointestinal disease where the reduced intake of poorly absorbed FODMAP alleviated symptoms of irritable bowel syndrome albeit with an alteration in gut microbiota. Despite a large amount of literature on dietary intervention in T2D, the health-related effects of FODMAPs have not been explored in this high-risk population. Thus, apart from reducing quantity, modulating the quality of different carbohydrates may reduce glucose absorption and alter the balance of health-related gut microbiota in our pursuit of prevention and treatment of type 2 diabetes. In this review, we summarize the evidence of individual FODMAP contents which influence the pathogenic processes of T2D, especially in the diverse populations of intestinal bacteria. Individual FODMAPs can increase health-promoting bacteria, such as Akkermansia muciniphila and Bifidobacterium. It can mediate the host health-related effects through fermentation of short-chain carbohydrates to produce SCFAs and other metabolic pathways in the management and prevention of T2D.

Time-varying risk associations of renin angiotensin system inhibitors with pneumonia and related deaths in a cohort of 252,616 patients with diabetes (2002-2019).

AIMS: To evaluate the time-varying and cumulative risk associations of renin-angiotensin-system-inhibitors (RASi) with pneumonia and related deaths in people with diabetes. METHODS: This was a prospective analysis with propensity-score overlap-weighting of a territory-wide cohort (n = 252,616, 1.7 million person-years) and a register-based cohort (n = 13,017, 0.1 million person-years) of patients with diabetes in Hong Kong. We compared risk of pneumonia and related death in new-users of angiotensin-converting-enzyme-inhibitor (ACEi) and angiotensin-receptor-blocker (ARBs) with non-RASi users and new-users of calcium-channel-blockers as active comparator. RESULTS: Amongst 252,616 people with diabetes (99.3% type 2 diabetes) in the population-based cohort with a mean follow-up of 6.7 years, 73,161 were new-ACEi-only users; 20,907 new-ARBs-only users; 38,778 ACEi/ARBs users; and 119,770 never-ACEi/ARBs. Time-varying RASi exposure was associated with reduced risk of pneumonia (HR = 0.78, 95% CI: 0.75-0.82) and pneumonia-related death (HR = 0.49, 0.46-0.53). The respective HRs for ARBs-only were 0.70 (0.62-0.78) and 0.41 (0.33-0.52) and that of ACEi-only were 0.98 (0.91-1.05) and 0.77 (0.68-86). The attenuated risk association of RASi use was time-invariant for pneumonia (P = 0.340) and time-varying for related-death (P < 0.001) with prevention of 0.6 (0.2-0.9) and 1.4 (1.0-1.6) per-1000-person-years events and deaths, respectively. CONCLUSIONS: Long-term use of RASi, notably ARBs, was associated with reduced risk of pneumonia and related deaths in Chinese people with diabetes.

Skin autofluorescence is associated with progression of kidney disease in type 2 diabetes: A prospective cohort study from the Hong Kong diabetes biobank.

BACKGROUND AND AIMS: Skin autofluorescence (SAF) can non-invasively assess the accumulation of tissue AGEs. We investigated the association between SAF and kidney dysfunction in participants with T2D. METHODS: Of 4030 participants consecutively measured SAF at baseline, 3725 participants free of end-stage kidney disease (ESKD) were included in the analyses. The association of SAF with incident ESKD or ≥30% reduction in estimated glomerular filtration rate (eGFR) was examined with Cox regression, linear mixed-effects model for the association with annual eGFR decline, and mediation analyses for the mediating roles of renal markers. RESULTS: During a median (IQR) 1.8 (1.1-3.1) years of follow-up, 411 participants developed the outcome. SAF was associated with progression of kidney disease (hazard ratio 1.15 per SD, 95% confidence interval [CI] [1.04, 1.28]) and annual decline in eGFR (ß -0.39 per SD, 95% CI [-0.71, -0.07]) after adjustment for risk factors, including baseline eGFR and urinary albumin-creatinine ratio (UACR). Decreased eGFR (12.9%) and increased UACR (25.8%) accounted for 38.7% of the effect of SAF on renal outcome. CONCLUSIONS: SAF is independently associated with progression of kidney disease. More than half of its effect is independent of renal markers. SAF is of potential to be a prognostic marker for kidney dysfunction.

Investigating the role of dachshund b in the development of the pancreatic islet in zebrafish.

AIMS/INTRODUCTION: ß-Cell dysfunction is a hallmark of type 2 diabetes. In a previous pilot study, we identified an association between genetic variants within the human DACH1 gene and young-onset type 2 diabetes. Here, we characterized the function of dachb, the only dach homologue to be expressed in the pancreas, in developing zebrafish embryos. MATERIALS AND METHODS: We injected one-cell stage embryos with a dachb-morpholino (MO) or with the dachb-MO and dachb messenger ribonucleic acid, and determined the effect on the development of the pancreatic islet. We also carried out quantitative polymerase chain reaction and ribonucleic acid sequencing on the dachb-MO group to determine the effect of dachb knockdown on gene expression. RESULTS: MO-mediated dachb knockdown resulted in impaired islet cell development, with a significant decrease in both the ß-cell and islet cell numbers. This islet developmental defect was rescued when embryos were co-injected with dachb-MO and dachb messenger ribonucleic acid. Knockdown of dachb was associated with a significant downregulation of the ß-cell specific marker gene, insa, and the somatostatin cell marker, sst2, as well as regulators of pancreas development, ptf1a, neuroD, pax6a and nkx6.1, and the cell cycle gene, insm1a. Furthermore, ribonucleic sequencing analysis showed an upregulation of genes enriched in the forkhead box O and mitogen-activated protein kinase signaling pathways in the dachb-MO group, when compared with the control groups. CONCLUSIONS: Together, our results suggest the possible role of dachb in islet development in zebrafish.

Machine learning risk score for prediction of gestational diabetes in early pregnancy in Tianjin, China.

AIMS: This study aimed to develop a machine learning-based prediction model for gestational diabetes mellitus (GDM) in early pregnancy in Chinese women. MATERIALS AND METHODS: We used an established population-based prospective cohort of 19,331 pregnant women registered as pregnant before the 15th gestational week in Tianjin, China, from October 2010 to August 2012. The dataset was randomly divided into a training set (70%) and a test set (30%). Risk factors collected at registration were examined and used to construct the prediction model in the training dataset. Machine learning, that is, the extreme gradient boosting (XGBoost) method, was employed to develop the model, while a traditional logistic model was also developed for comparison purposes. In the test dataset, the performance of the developed prediction model was assessed by calibration plots for calibration and area under the receiver operating characteristic curve (AUR) for discrimination. RESULTS: In total, 1484 (7.6%) women developed GDM. Pre-pregnancy body mass index, maternal age, fasting plasma glucose at registration, and alanine aminotransferase were selected as risk factors. The machine learning XGBoost model-predicted probability of GDM was similar to the observed probability in the test data set, while the logistic model tended to overestimate the risk at the highest risk level (Hosmer-Lemeshow test p value: 0.243 vs. 0.099). The XGBoost model achieved a higher AUR than the logistic model (0.742 vs. 0.663, p < 0.001). This XGBoost model was deployed through a free, publicly available software interface (https://liuhongwei.shinyapps.io/gdm_risk_calculator/). CONCLUSION: The XGBoost model achieved better performance than the logistic model.

Impact of age at type 2 diabetes mellitus diagnosis on mortality and vascular complications: systematic review and meta-analyses.

AIMS/HYPOTHESIS: Few studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes. METHODS: Data were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593). RESULTS: Data from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p < 0.001). Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The effects were consistent for the individual components of the composite outcomes (all p < 0.001). CONCLUSIONS/INTERPRETATION: Younger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality. Graphical abstract.

Long-term maternal cardiometabolic outcomes 22 years after gestational diabetes mellitus.

AIMS/INTRODUCTION: Women with gestational diabetes mellitus are at increased risk for type 2 diabetes. We characterized the association between maternal glycemia during pregnancy with long-term outcomes. METHODS AND METHODS: In this prospective nested case-cohort study, participants were recalled for follow up with detailed evaluation including oral glucose tolerance test at 8, 15 and 22 years. Logistic regression was used to estimate the risk of developing impaired glucose tolerance/type 2 diabetes and metabolic syndrome at follow up. The association between maternal glycemia at pregnancy and follow up was evaluated by linear regression. We also charted trajectory of ß-cell function during follow up. RESULTS: The analysis included 121 women with a mean follow-up period of 22.5 years, and a mean age of 50.3 years. Gestational diabetes was associated with an adjusted odds ratio of 2.48 (95% confidence interval 1.03-5.99) for combined diabetes/impaired glucose tolerance at follow up (P = 0.04). Women with a pre-pregnancy body mass index ≥23 had an odds ratio of 5.43 (95% confidence interval 1.87-15.72) for metabolic syndrome at follow up, compared with those with body mass index <23 (P = 0.002). Both fasting and 2-h glucose during pregnancy were strongly associated with glycemic indices at follow up (P-value <0.001-0.016). Gestational diabetes was associated with impaired ß-cell function that remained relatively stable after the index pregnancy. CONCLUSIONS: Chinese women with a history of gestational diabetes have a high prevalence of impaired glucose tolerance/type 2 diabetes at 22-year follow up. Glucose levels during mid-pregnancy are strongly associated with those of middle age.

CYP2C19*2 Polymorphism Is Associated with Impaired Oral Clearance of Gliclazide in Healthy Chinese.

BACKGROUND: Previous studies suggest gliclazide is metabolised primarily by CYP2C19 rather than CYP2C9, unlike other sulphonylureas. CYP2C19 *2 and *3 polymorphisms are more common in Asians. METHODS: We investigated the effect of CYP2C19 polymorphisms on gliclazide pharmacokinetics in 15 healthy male Chinese subjects after a single 80mg oral dose. RESULTS: In CYP2C19 poor metabolisers (*2/*2, n=4), plasma area-under-the-curve was higher by nearly two-fold compared with intermediate metabolisers (*2 and *3 heterozygotes, n=7) and extensive metabolisers (*1/*1, n=4) (p<0.001). Apparent oral clearance was mean (SD) 0.70 (0.12), 1.22 (0.22) and 1.52 (0.47) mL/min/kg in poor, intermediate and extensive metabolisers, respectively (p = 0.005). CONCLUSION: CYP2C19*2 polymorphism is associated with increased total gliclazide concentration and reduced oral clearance. Pharmacogenetic studies are warranted on the impact of CYP2C19 polymorphisms on treatment response and hypoglycaemia.

Association between educational level and cardiovascular disease and all-cause mortality in patients with type 2 diabetes: a prospective study in the Joint Asia Diabetes Evaluation Program.

PURPOSE: The aim of this study was to describe the association between educational level and incident cardiovascular disease (CVD) and all-cause mortality in Hong Kong Chinese patients with type 2 diabetes. PATIENTS AND METHODS: We included 12,634 patients with type 2 diabetes who were enrolled into the Joint Asia Diabetes Evaluation Program between June 1, 2007, and June 30, 2017. We classified patients' educational level into the following three groups: ≤6 years, 6-13 years, and >13 years. Incident CVD events were identified using hospital discharge diagnoses. Death was identified from Hong Kong Death Register. We estimated HRs for incident CVD and all-cause mortality using Cox regression models. RESULTS: Patients with the highest educational level were younger and had shorter diabetes duration and better glycemic control at enrollment than those with the lowest educational level. During the median follow-up of 6.2 years for CVD and 6.4 years for all-cause mortality, 954 CVD events and 833 deaths were recorded. HRs for CVD and all-cause mortality were 0.73 (95% CI: 0.57, 0.94) and 0.71 (95% CI: 0.54, 0.94) for the highest educational level compared to the lowest educational level, after adjustment for age, sex, diabetes duration, and family history of diabetes. CONCLUSION: Educational level is inversely associated with the risk of CVD and all-cause mortality among Hong Kong Chinese patients with type 2 diabetes. Hong Kong Chinese patients with type 2 diabetes and low educational level should be given special attention for the prevention of key complications of diabetes.

Precision medicine in diabetes prevention, classification and management.

Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment failure and development of diabetic complications. Recent advances in our understanding of the genomic architecture of diabetes and its complications have provided the framework for development of precision medicine to personalize diabetes prevention and management. In the present review, we summarized recent advances in the understanding of the genetic basis of diabetes and its complications. From a clinician's perspective, we attempted to provide a balanced perspective on the utility of genomic medicine in the field of diabetes. Using genetic information to guide management of monogenic forms of diabetes represents the best-known examples of genomic medicine for diabetes. Although major strides have been made in genetic research for diabetes, its complications and pharmacogenetics, ongoing efforts are required to translate these findings into practice by incorporating genetic information into a risk prediction model for prioritization of treatment strategies, as well as using multi-omic analyses to discover novel drug targets with companion diagnostics. Further research is also required to ensure the appropriate use of this information to empower individuals and healthcare professionals to make personalized decisions for achieving the optimal outcome.

Plasma Levels of Alanine Aminotransferase in the First Trimester Identify High Risk Chinese Women for Gestational Diabetes.

Alanine aminotransferase (ALT) predicts type 2 diabetes but it is uncertain whether it also predicts gestational diabetes mellitus (GDM). We recruited 17359 Chinese women with ALT measured in their first trimester. At 24-28 weeks of gestation, all women underwent a 50-gram 1-hour glucose challenge test (GCT) followed by a 75-gram 2-hour oral glucose tolerance test if GCT result was ≥7.8 mmol/L. Restricted cubic spline analysis was used to examine full-range risk associations of ALT levels with GDM. Relative excess risk due to interaction, attributable proportion due to interaction and synergy index were used to estimate additive interaction between high ALT and overweight/obesity for GDM. Finally, 1332 (7.7%) women had GDM. ALT levels were positively associated with GDM risk without a clear threshold. Using ALT levels <22 U/L as the referent, the middle ALT levels (≥22 to <40 U/L) [odds ratio (OR) (95% confidence intervals): 1.41(1.21-1.65)] and high ALT levels (≥40 U/L) [1.62 (1.31-2.00)] were associated with increased GDM risk. Maternal overweight/obesity greatly enhanced the OR of ALT ≥22 U/L from 1.44 (1.23-1.69) to 3.46 (2.79-4.29) with significant additive interactions. In conclusion, elevated ALT levels in the first trimester even within normal range predicted GDM risk, further enhanced by overweight/obesity.

Management of Familial Hypercholesterolemia in Hong Kong.

Familial hypercholesterolemia (FH) is an autosomal-dominant genetic disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic coronary heart disease (CHD). Patients with FH in Hong Kong were found by the identification of potential probands with primary hypercholesterolemia manifesting total cholesterol levels greater than 7.5 mmol/L or LDL-C levels greater than 4.9 mmol/L and undertaking cascade screening of available relatives in the Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong since the early 1990s. Our previous study in a group of 252 subjects from 87 pedigrees clinically diagnosed as having heterozygous FH reported the mean plasma LDL-C level as 7.2±1.5 mmol/L. Xanthomata were present in 40.6% of males and 54.8% of females. The prevalence of known CHD was relatively low at 9.9% in males and 8.5% in females. All FH patients were offered treatment with statins and many of them reached the LDL-C goal with a moderate or high dose of potent statin alone. Ezetimibe is usually added for patients who have not achieved target LDL-C levels on statin alone, particularly in patients with established CHD. Some FH patients who have not achieved the LDL-C targets with this combination have entered into clinical trials with new cholesterol-modifying agents such as the monoclonal antibodies to proprotein convertase subtilisin-kexin type 9. Increased awareness, early identification, and optimal treatment are essential to reduce the risk of CHD, increase life expectancy, and improve the quality of life of patients with FH.

Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes.

There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.

Childhood asthma is associated with polymorphic markers of PROC on 2q14 in addition to 17q21 locus.

BACKGROUND: Childhood asthma is caused by both genetic and environmental factors. The first genomewide association study (GWAS) for asthma revealed putative candidates on nine chromosomal regions in Caucasians, with 17q21 locus being the most widely replicated one. However, there was no replication study for the other loci. This study investigated genetic associations between childhood asthma and autosomal single nucleotide polymorphisms (SNPs) on eight loci reported in the first GWAS among Hong Kong Chinese. METHODS: 510 asthmatic children and 510 non-allergic controls were recruited. 110 tagging SNPs selected based on r(2 ) ≥ 0.80 and minor allele frequency ≥0.05 for Han Chinese among all SNPs located 50-kb upstream and downstream of significant autosomal SNPs were genotyped by TaqMan allelic discrimination assays. Transcription factor binding of SNPs was determined by electrophoretic mobility shift assay (EMSA). RESULTS: Asthma was significantly associated with SNPs on 17q21 and 2q14 loci. Twelve SNPs on 17q21 were associated with asthma, with rs6503527 being the most significant SNP. Five SNPs of protein C gene (PROC) on 2q14 were associated with asthma, with rs6755028 being the most significant SNP. Plasma protein C concentrations were higher in asthmatic patients than controls, and five PROC SNPs were associated with plasma protein C concentrations. EMSA showed specific differential binding of rs878461 to nuclear extracts from bronchial epithelial and hepatocarcinoma cell lines. CONCLUSIONS: Our findings identify PROC on 2q14 as a novel candidate for childhood asthma and replicate the genetic association for 17q21 locus. Rs878461 of PROC may increase asthma susceptibility by altering transcription factor binding.

Depression in Chinese patients with type 2 diabetes: associations with hyperglycemia, hypoglycemia, and poor treatment adherence.

BACKGROUND: We hypothesize that depression in type 2 diabetes might be associated with poor glycemic control, in part due to suboptimal self-care. We tested this hypothesis by examining the associations of depression with clinical and laboratory findings in a multicenter survey of Chinese type 2 diabetic patients. METHOD: 2538 patients aged 18-75 years attending hospital-based clinics in four cities in China underwent detailed clinical-psychological-behavioral assessment during a 12-month period between 2011 and 2012. Depression was diagnosed if Patient Health Questionnaire-9 (PHQ-9) score ≥10. Diabetes self-care and medication adherence were assessed using the Summary of Diabetes Self-care Activities and the 4-item Morisky medication adherence scale respectively. RESULTS: In this cross-sectional study (mean age: 56.4 ± 10.5[SD] years, 53% men), 6.1% (n = 155) had depression. After controlling for study sites, patients with depression had higher HbA(1c) (7.9 ± 2.0 vs. 7.7 ± 2.0%, P = 0.008) and were less likely to achieve HbA(1c) goal of <7.0% (36.2% vs 45.6%, P = 0.004) than those without depression. They were more likely to report hypoglycemia and to have fewer days of being adherent to their recommended diet, exercise, foot care and medication. In logistic regression, apart from young age, poor education, long disease duration, tobacco use, high body mass index, use of insulin, depression was independently associated with failure to attain HbA(1c) target (Odds Ratio [OR] = 1.56, 95%CI:1.05-2.32, P = 0.028). The association between depression and glycemic control became non-significant after inclusion of adherence to diet, exercise and medication (OR = 1.48, 95% CI 0.99-2.21, P = 0.058). CONCLUSION: Depression in type 2 diabetes was closely associated with hyperglycemia and hypoglycemia, which might be partly mediated through poor treatment adherence.