Development and validation of the CHIME simulation model to assess lifetime health outcomes of prediabetes and type 2 diabetes in Chinese populations: A modeling study.

BACKGROUND: Existing predictive outcomes models for type 2 diabetes developed and validated in historical European populations may not be applicable for East Asian populations due to differences in the epidemiology and complications. Despite the continuum of risk across the spectrum of risk factor values, existing models are typically limited to diabetes alone and ignore the progression from prediabetes to diabetes. The objective of this study is to develop and externally validate a patient-level simulation model for prediabetes and type 2 diabetes in the East Asian population for predicting lifetime health outcomes. METHODS AND FINDINGS: We developed a health outcomes model from a population-based cohort of individuals with prediabetes or type 2 diabetes: Hong Kong Clinical Management System (CMS, 97,628 participants) from 2006 to 2017. The Chinese Hong Kong Integrated Modeling and Evaluation (CHIME) simulation model comprises of 13 risk equations to predict mortality, micro- and macrovascular complications, and development of diabetes. Risk equations were derived using parametric proportional hazard models. External validation of the CHIME model was assessed in the China Health and Retirement Longitudinal Study (CHARLS, 4,567 participants) from 2011 to 2018 for mortality, ischemic heart disease, cerebrovascular disease, renal failure, cataract, and development of diabetes; and against 80 observed endpoints from 9 published trials using 100,000 simulated individuals per trial. The CHIME model was compared to United Kingdom Prospective Diabetes Study Outcomes Model 2 (UKPDS-OM2) and Risk Equations for Complications Of type 2 Diabetes (RECODe) by assessing model discrimination (C-statistics), calibration slope/intercept, root mean square percentage error (RMSPE), and R2. CHIME risk equations had C-statistics for discrimination from 0.636 to 0.813 internally and 0.702 to 0.770 externally for diabetes participants. Calibration slopes between deciles of expected and observed risk in CMS ranged from 0.680 to 1.333 for mortality, myocardial infarction, ischemic heart disease, retinopathy, neuropathy, ulcer of the skin, cataract, renal failure, and heart failure; 0.591 for peripheral vascular disease; 1.599 for cerebrovascular disease; and 2.247 for amputation; and in CHARLS outcomes from 0.709 to 1.035. CHIME had better discrimination and calibration than UKPDS-OM2 in CMS (C-statistics 0.548 to 0.772, slopes 0.130 to 3.846) and CHARLS (C-statistics 0.514 to 0.750, slopes -0.589 to 11.411); and small improvements in discrimination and better calibration than RECODe in CMS (C-statistics 0.615 to 0.793, slopes 0.138 to 1.514). Predictive error was smaller for CHIME in CMS (RSMPE 3.53% versus 10.82% for UKPDS-OM2 and 11.16% for RECODe) and CHARLS (RSMPE 4.49% versus 14.80% for UKPDS-OM2). Calibration performance of CHIME was generally better for trials with Asian participants (RMSPE 0.48% to 3.66%) than for non-Asian trials (RMPSE 0.81% to 8.50%). Main limitations include the limited number of outcomes recorded in the CHARLS cohort, and the generalizability of simulated cohorts derived from trial participants. CONCLUSIONS: Our study shows that the CHIME model is a new validated tool for predicting progression of diabetes and its outcomes, particularly among Chinese and East Asian populations that has been lacking thus far. The CHIME model can be used by health service planners and policy makers to develop population-level strategies, for example, setting HbA1c and lipid targets, to optimize health outcomes.

Plasma concentration of pigment epithelium-derived factor is closely associated with blood pressure and predicts incident hypertension in Chinese: a 10-year prospective study.

OBJECTIVES: Pigment epithelium-derived factor (PEDF) is secreted from the adipose tissue. It circulates at high concentrations, and was reported to play a causal role in obesity-induced insulin resistance and metabolic dysfunctions in mice. Previous cross-sectional studies also demonstrated plasma PEDF concentration correlated positively with systolic blood pressure (BP) and pulse pressure, and inversely with small artery elasticity. Here we investigated the relationship of plasma PEDF concentration with BP and incident hypertension in a 10-year prospective study. METHODS: Baseline plasma PEDF concentrations were measured by ELISA in 520 Chinese subjects, aged 51 ± 12 years, followed up long-term from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study. The association between plasma PEDF concentration and BP was investigated in both cross-sectional and prospective studies, using multiple linear regression and path analyses. Cox proportional hazards analysis was used to determine whether baseline PEDF concentration was independently related to the subsequent development of hypertension over 10 years. RESULTS: Baseline plasma concentrations of PEDF were higher in men (P < 0·001), and were directly related to systolic BP at 2 and 5 years, and to diastolic BP at 2 years, after adjustment for covariates. Of the 386 normotensive subjects at baseline, high baseline PEDF concentration was predictive of incident hypertension, independent of the effects of age, sex, baseline BP and obesity parameters (hazard ratio: 1·135; 95% CI: 1·039-1·241; P = 0·005). CONCLUSION: Our data suggest that plasma PEDF concentration is significantly associated with BP, and incident hypertension. PEDF may be involved in the pathogenesis of hypertension in humans.

High density lipoprotein-cholesterol levels increase with age in American women but not in Hong Kong Chinese women.

OBJECTIVES: High-density lipoprotein (HDL) cholesterol is a powerful cardiovascular risk factor. Important gender and ethnic differences in plasma HDL levels exist and warrant investigation. DESIGN: Cross-sectional survey in two different general populations. Patients 7700 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2002 and 1944 participants of the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2) 2000-2004. MEASUREMENTS: Plasma HDL levels. RESULTS: Plasma HDL levels were higher in women than in men in both populations. In the United States women, it increased with age, whereas in Chinese women, it declined with age and converged with male HDL levels. In the United States, 37.1 +/- 1.2% men and 38.9 +/- 1.1% women had low HDL levels. In Hong Kong, 34.3 +/- 1.6% men and 34.5 +/- 1.5% women had low HDL levels. In Americans, the independent predictors of low HDL levels were lower age, being non-Mexican Hispanic, waist circumference, triglycerides and not drinking alcohol in men, and lower age, being Hispanic, waist circumference, triglycerides, current smoking and not drinking alcohol in women. In Hong Kong Chinese, the independent predictors of low HDL levels were body mass index, triglycerides, current smoking and not drinking alcohol in men, and lower age, waist circumference, triglycerides, diabetes and former smoking in women. CONCLUSIONS: The decline in plasma HDL with age in Chinese women is opposite to that seen in American women. The increased cardiovascular risk in elderly Chinese women requires further study.

Epidermal fatty-acid-binding protein: a new circulating biomarker associated with cardio-metabolic risk factors and carotid atherosclerosis.

AIMS: Epidermal fatty-acid-binding protein (E-FABP) is highly homologous to adipocyte FABP (A-FABP), which mediates obesity-related metabolic syndrome (MetS), diabetes and atherosclerosis in animals. Combined deficiency of E-FABP and A-FABP protects against the MetS and atherosclerosis in mice. This study investigated the association of serum E-FABP with cardio-metabolic risk factors and carotid atherosclerosis in humans. METHODS AND RESULTS: The presence of E-FABP in human plasma was detected by tandem mass spectrometry. Serum E-FABP levels, determined by an enzyme-linked immunosorbent assay in 479 Chinese subjects (age: 55.4 ± 13.5 years; M/F: 232/247), correlated positively (P < 0.05 to <0.001, age-adjusted) with parameters of adiposity, adverse lipid profiles, serum insulin, A-FABP, and C-reactive protein levels and were higher in subjects with the MetS (P < 0.001 vs. no MetS). The association of E-FABP with the MetS was independent of A-FABP. Furthermore, serum E-FABP correlated with carotid intima-media thickness (IMT; P < 0.001) and was independently associated with carotid IMT in men (adjusted P = 0.03). CONCLUSION: E-FABP is a new circulating biomarker associated with increased cardio-metabolic risk. It may contribute to the development of the MetS and carotid atherosclerosis in humans, independent of the effect of A-FABP.

Risk Prediction Scores for Mortality, Cerebrovascular, and Heart Disease Among Chinese People With Type 2 Diabetes.

CONTEXT: Risk scores for cardiovascular and mortality outcomes have not been commonly applied in Chinese populations. OBJECTIVE: To develop and externally validate a set of parsimonious risk scores [University of Hong Kong-Singapore (HKU-SG)] to predict the risk of mortality, cerebrovascular disease, and ischemic heart disease among Chinese people with type 2 diabetes and compare HKU-SG risk scores to other existing ones. DESIGN: Retrospective population-based cohorts drawn from Hong Kong Hospital Authority health records from 2006 to 2014 for development and Singapore Ministry of Health records from 2008 to 2016 for validation. Separate five-year risk scores were derived using Cox proportional hazards models for each outcome. SETTING: Study participants were adults with type 2 diabetes aged 20 years or over, consisting of 678,750 participants from Hong Kong and 386,425 participants from Singapore. MAIN OUTCOME MEASURES: Performance was evaluated by discrimination (Harrell C-index), and calibration plots comparing predicted against observed risks. RESULTS: All models had fair external discrimination. Among the risk scores for the diabetes population, ethnic-specific risk scores (HKU-SG and Joint Asia Diabetes Evaluation) performed better than UK Prospective Diabetes Study and Risk Equations for Complications Of type 2 Diabetes models. External validation of the HKU-SG risk scores for mortality, cerebrovascular disease, and ischemic heart disease had corresponding C-indices of 0.778, 0.695, and 0.644. The HKU-SG models appeared well calibrated on visual plots, with predicted risks closely matching observed risks. CONCLUSIONS: The HKU-SG risk scores were developed and externally validated in two large Chinese population-based cohorts. The parsimonious use of clinical predictors compared with previous risk scores could allow wider implementation of risk estimation in diverse Chinese settings.

Circulating adipocyte-fatty acid binding protein levels predict the development of the metabolic syndrome: a 5-year prospective study.

BACKGROUND: Adipocyte-fatty acid binding protein (A-FABP), a major cytoplasmic protein in adipocytes, plays a central role in the development of diabetes and atherosclerotic cardiovascular disease in experimental animals. We have previously shown that A-FABP is present in the bloodstream and that its circulating levels correlate with metabolic risk factors in a cross-sectional study. In the present study, we further evaluated the prospective association of A-FABP with the metabolic syndrome (MetS) as defined by the updated National Cholesterol Education Program criteria. METHODS AND RESULTS: In the present study, 495 nondiabetic adults from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study were prospectively followed up for 5 years. The relationship of serum A-FABP with the MetS and its components was investigated. At baseline, high A-FABP levels were associated with the MetS (odds ratio, 4.0; 95% CI, 1.5 to 10.4; highest versus lowest sex-specific tertile, adjusted for age, body mass index, the homeostasis model assessment index for insulin resistance, C-reactive protein, and adiponectin, P=0.005). On long-term follow-up, subjects with higher baseline A-FABP levels had progressively worse cardiometabolic risk profile and increasing risk of the MetS. Among 376 subjects without the MetS at baseline, 50 had developed it at 5 years. Apart from the homeostasis model assessment index for insulin resistance (P=0.001), baseline A-FABP was the only independent predictor of the development of the MetS during the 5-year follow-up (odds ratio, 4.7; 95% CI, 1.8 to 11.9; highest versus lowest sex-specific tertile, P=0.001, adjusted for the homeostasis model assessment index for insulin resistance and body mass index). A-FABP was predictive of the MetS even after adjustment for each of its individual components. CONCLUSIONS: Circulating A-FABP predicts the development of the MetS independently of adiposity and insulin resistance.

Prevalence, treatment, and control of diagnosed diabetes in the U.S. National Health and Nutrition Examination Survey 1999-2004.

PURPOSE: This study aimed to examine the trends in prevalence, treatment, and control of diagnosed diabetes in United States adults 20 years of age or older. METHODS: Data from the National Health and Nutrition Examination Survey 1999-2004 were used. Glycemic, blood pressure, and total cholesterol target levels were defined as having glycosylated hemoglobin <7.0%, blood pressure <130/80 mm Hg, and total cholesterol <200 mg/dL, respectively. RESULTS: The prevalence of diagnosed diabetes was 7.8% in 2003-2004 and increased significantly in people aged 40-59 years, women, non-Hispanic whites, and obese people in the period 1999-2004. Although there was no significant change in the pattern of antidiabetic treatment, the age-adjusted percentage of people with diagnosed diabetes achieving glycemic and blood pressure target levels increased from 35.8% to 57.1% (p = 0.002) and from 35.7% to 48.3% (p = 0.04), respectively. However, there were only insignificant increases in percentages of those persons achieving total cholesterol target level (from 48.8% to 50.4%) and those achieving all 3 target levels (from 7.5% to 13.2%). CONCLUSIONS: In 1999-2004, the prevalence of diagnosed diabetes increased significantly in some subgroups of the population. However, the increases in percentages of people with diabetes achieving glycemic and blood pressure targets are encouraging, although there is room for improvement.

Components of the metabolic syndrome predictive of its development: a 6-year longitudinal study in Hong Kong Chinese.

OBJECTIVE: To investigate which of the components of the metabolic syndrome best predict its development. DESIGN: Long-term cohort of randomly selected adults. PATIENTS: One thousand five hundred and forty-eight subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study who did not have the metabolic syndrome by the US National Cholesterol Education Program (NCEP) or International Diabetes Federation (IDF) criteria at baseline. MEASUREMENTS: Waist circumference, blood pressure, glucose, triglycerides and high-density lipoprotein-cholesterol (HDL). RESULTS: After a median interval of 6.4 years, there were 219 and 143 new cases (21.9 and 14.3 per 1000 person-years) of the metabolic syndrome by the NCEP and IDF criteria, respectively. The odds ratio for the NCEP metabolic syndrome was highest for low HDL, 4.08 [95% confidence interval (CI): 2.90-5.73] and that for the IDF metabolic syndrome was highest for central obesity, 5.94 [95% CI: 3.98-8.87]. Low HDL, found in 27.8% men and 34.3% women, had the highest sensitivity for the NCEP metabolic syndrome (48% in men and 57% in women) and the IDF metabolic syndrome (41% in men and 54% in women). Central obesity had the highest positive predictive values except that triglycerides had the highest positive predictive value for the NCEP metabolic syndrome in women. The areas under the receiver operator characteristic curve for waist circumference, triglycerides and HDL were similar. A model that included waist circumference and HDL predicted the metabolic syndrome as well as a model that included all five metabolic syndrome components. CONCLUSION: Obese Chinese adults should be periodically screened for the metabolic syndrome and have waist and HDL measurement.

Relationship between the metabolic syndrome and the development of hypertension in the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2).

BACKGROUND: The metabolic syndrome is a predictor of diabetes and coronary events. We hypothesized that it also predicts hypertension. METHODS: A total of 1,944 subjects (901 men and 1,043 women; age 46 +/- 12 years) from the Hong Kong Cardiovascular Risk Factor Prevalence Survey were recruited in 1995-1996 and restudied in 2000-2004. The prevalence of hypertension and factors predicting its development were determined. RESULTS: In 2000-2004, hypertension was found in 23.2% of the men and 17.2% of the women. Of the 1,602 subjects who were normotensive at baseline, 258 subjects developed hypertension after a median interval of 6.4 years. According to the National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) criteria, the hazard ratios associated with the metabolic syndrome were 1.89 (95% confidence interval (CI): 1.41-2.54) and 1.72 (95% CI: 1.24-2.39), respectively. The positive and negative predictive values of the metabolic syndrome for identifying subjects who will develop hypertension in this population were 34.7 and 85.4% (NCEP criteria), and 33.1 and 85.5% (IDF criteria), respectively. The development of hypertension was related to the number of components of the metabolic syndrome (other than raised blood pressure), present in men (P = 0.003) and in women (P = 0.001). Using multivariate analysis, age, baseline systolic blood pressure (SBP), body mass index (BMI), and the triglycerides/high-density lipoprotein (HDL) ratio were found to be significant predictors of the development of hypertension. Compared with optimal blood pressure, the hazards of developing hypertension associated with normal or high-normal blood pressure were 2.31 (95% CI: 1.68-3.17) and 3.48 (95% CI: 2.52-4.81), respectively. CONCLUSIONS: Blood pressure, when not optimal, is the predominant predictor of hypertension. The metabolic syndrome contributes to the risk, especially when blood pressure is optimal.

Identification of factors differentially associated with isolated impaired fasting glucose and isolated post-load impaired glucose tolerance: the Hong Kong Cardiovascular Risk Factor Study.

BACKGROUND: The use of fasting and post-prandial glucose levels in the classification of hyperglycaemic states often identifies distinct subjects, but the factors determining these intermediate-isolated glucose intolerant states are yet to be clearly elucidated in Chinese subjects. METHODS: Representative subjects (n = 2769) were randomly recruited from the Hong Kong Chinese population and glycaemic status was determined using both fasting and 2h 75 g oral glucose tolerance test glucose levels. The relationship between the groups with isolated glucose intolerance and vascular risk factors was investigated using ANOVA and logistic regression analyses. RESULTS: Using either criterion, diabetes was identified in 265 (9.6%) subjects and glucose intolerance in 568 (20.5%) subjects. Of those 568, isolated impaired glucose tolerance (IGT) using the post-load criterion was identified in 49.5% and isolated impaired fasting glucose (IFG) in 30.5%. Ageing and hyperinsulinaemia were common determinants of IGT and IFG; with small hip circumference a marker of poorer early life development and being born in China rather than Hong Kong, a possible low birth weight marker was also associated with IFG. Hypertension, hypertriglyceridaemia and poor education were also associated with IGT. When we looked for factors differentially associated with these glucose intolerant states, female sex, greater hip circumference, high triglyceride levels, low fasting insulin levels, and not being born in China were independently associated with isolated IGT compared with isolated IFG. CONCLUSION: Despite common antecedents to the glucose intolerant states, isolated IFG appeared to be particularly associated with early life development, and isolated IGT was more strongly associated with obesity-related determinants such as hypertriglyceridaemia.

Endothelial nitric oxide synthase G894T (Glu298Asp) polymorphism was predictive of glycemic status in a 5-year prospective study of Chinese subjects with impaired glucose tolerance.

Subjects with impaired glucose tolerance (IGT) have a high risk of developing type 2 diabetes mellitus (DM) and its related complications. However, both environmental and genetic factors may influence the progression or regression of hyperglycemia. Polymorphisms of the endothelial nitric oxide synthase (eNOS) gene have been associated with DM in cross-sectional studies, but their predictive values in glycemic progression are not known. We examined the relationship of the eNOS promoter -T786C (-T786C), intron 4 variable tandem repeat (in4a/b), and exon 7 G894T (G894T) polymorphisms, and their haplotypes, with the long-term glycemic outcome in a Chinese cohort with IGT. Two hundred fifty-six Chinese subjects with IGT at baseline participated in a 5-year follow-up study to assess their glycemic outcome. Each individual was genotyped for the above-mentioned polymorphisms. At 5 years, 40.2% of the subjects had reverted to normal glucose tolerance; 39.9% remained in IGT/impaired fasting glucose and 19.9% had developed DM. A significant gene effect of exon 7 G894T polymorphism on glycemic status at 5 years was demonstrated, with carriers of T(894) being more likely to have persistent hyperglycemia compared with GG subjects (P = .003). On stepwise logistic regression analysis, the presence of the T allele remained a significant risk factor for persistent hyperglycemia (odds ratio, 2.72; 95% confidence interval, 1.36-5.99; T+ vs GG; P = .013), together with male sex, high body mass index, and high 2-hour glucose at baseline. No significant effect of -T786C or in4a/b polymorphism on fifth-year glycemic status was observed. The eNOS G894T polymorphism appears to be predictive of persistent hyperglycemia in Chinese subjects with IGT.

Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients.

In Caucasians, maturity-onset diabetes of the young (MODY) is mostly caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha (MODY3) and glucokinase (MODY2) genes. Most Japanese MODY patients, however, are not linked to known MODY genes. In this study, we examined the genetic and clinical characteristics of Chinese subjects with MODY. The study included 146 unrelated families fulfilling the minimum criteria for MODY: two consecutive generations of type II diabetes with at least one member diagnosed under the age of 25. We screened for mutations in the HNF-4alpha (MODY1), MODY2 and MODY3 genes by direct sequencing. Antibody to glutamic acid decarboxylase (GAD-Ab) was measured in subjects with MODY of unknown cause (MODYX). Insulin resistance index and other clinical data were compared in sex-, age- and duration-matched MODY3 and MODYX patients. In all, 13 families had MODY3 mutations and two had MODY2 mutations. No MODY1 mutation was found. Four of the 12 different MODY3 mutations were newly identified novel mutations (Q243E, A311D, P379R and P488fsdelC). In subjects with MODYX, 3% were GAD-Ab positive and 60% were overweight. Compared to MODY3 patients, MODYX patients had higher body mass index (P<0.02), higher insulin resistance index (P=0.001) and triglyceride level (P<0.02), lower HDL level (P=0.001) and more hypertension (P<0.05), but no significant difference in the prevalence of diabetic complications. In conclusion, MODY3 and MODY2 account for only 9 and 1%, respectively, of Chinese MODY. A majority of Chinese MODY patients are due to defects in unknown genes and appear to be characterized by insulin resistance.

C-reactive protein predicts the deterioration of glycemia in chinese subjects with impaired glucose tolerance.

OBJECTIVE: Recent studies have shown that C-reactive protein (CRP) predicts future risk of diabetes in healthy Caucasians. We determined whether plasma CRP level was elevated in Chinese subjects with impaired glucose tolerance (IGT) and whether CRP level could be used to predict progression to type 2 diabetes or reversion to normal glucose tolerance (NGT) in these high-risk individuals. RESEARCH DESIGN AND METHODS: A total of 228 subjects with IGT at baseline from the Hong Kong Cardiovascular Risk Factors Prevalence Study underwent repeat oral glucose tolerance testing after 2 years. Plasma high-sensitivity CRP was measured from their stored baseline samples and from 228 subjects with NGT matched for age and BMI by an immunoturbidimetric assay. RESULTS: Subjects with IGT at baseline had higher plasma CRP levels than subjects with NGT: 1.18 mg/l (0.52-2.52) vs. 0.87 mg/l (0.37-1.84), median (interquartile range), P = 0.01. At 2 years, 117 subjects with IGT reverted to NGT, 84 remained in IGT, and 21 progressed to diabetes. Individuals who progressed to diabetes had the highest plasma CRP levels at baseline (P < 0.0001). Those with baseline CRP levels in the third and top quartile had a relative risk of remaining in IGT or progressing to diabetes of 2.87 (95% CI 1.06-7.82) and 2.76 (1.06-7.31), respectively, after adjusting for anthropometric measure and lifestyle factors. CONCLUSIONS: CRP independently predicts the risk of remaining in IGT or progressing to diabetes in Chinese subjects with IGT. CRP might provide an adjunctive measure for identifying subjects with the highest risk of progression to diabetes who would derive the greatest benefits from preventive interventions.

Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes. An Asian perspective from the RENAAL Study.

OBJECTIVE: Asia is predicted to have the largest population of patients with diabetes who are at high risk for renal disease. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, approximately 17% of patients were Asians. In this subgroup analysis, we examined the characteristics, response, and adherence to treatment of the Asian population, as well as their baseline predictors of risk of renal end points. RESEARCH DESIGN AND METHODS: A total of 252 Asian patients were enrolled in the RENAAL study, which compared losartan (50 mg titrated to 100 mg) to placebo in addition to conventional antihypertensive medications in type 2 diabetic patients with nephropathy. Mean follow-up was 3.2 years. The effect of losartan therapy on renal and cardiovascular outcomes was examined, and baseline predictors of risk were determined using a Cox proportional hazards model with prespecified baseline covariates. RESULTS: Losartan reduced the risk of the primary composite end point composed of a doubling of serum creatinine, end-stage renal disease, or all-cause mortality in Asian patients by 35% (P = 0.02). No difference between losartan and placebo was observed for the cardiovascular composite outcomes. Losartan reduced the level of proteinuria by 47% (P < 0.001) and rate of decrease in renal function by 31% (0.0074). Discontinuations were lower in the losartan-treated patients. The strongest baseline predictors of risk of renal end points were proteinuria (hazard ratio 1.42, P < 0.0001) and low Hb (0.81, P < 0.0001). CONCLUSIONS: In this subgroup analysis of the RENAAL study, losartan conferred significant renal benefits and was well tolerated in Asian patients with type 2 diabetes and clinical nephropathy. Baseline proteinuria and low Hb were strong predictors of risk of renal outcomes.

Graft-vs-host-disease-associated conjunctival chemosis and central serous chorioretinopathy after bone marrow transplant.

PURPOSE: To describe bilateral conjunctival chemosis and central serous chorioretinopathy in a patient with graft-vs-host disease after bone marrow transplant. DESIGN: Interventional case report. METHODS: A 45-year-old Chinese woman developed blurring of vision 16 days after bone marrow transplant for multiple myeloma. She had graft-vs-host disease 11 days after bone marrow transplantation. On examination, vision was 0.6 in the right eye and 0.3 in the left eye. Bilateral conjunctival chemosis and multiple central serous chorioretinopathy were present. RESULTS: Treatment of graft-vs-host disease with high-dose systemic corticosteroid and cyclosporin led to the resolution of the conjunctival chemosis and central serous chorioretinopathy 3 months later. Visual acuity improved to 0.8 in both eyes. CONCLUSION: Choroidal infiltrate in graft-vs-host disease may contribute to choroidal hyperpermeability, which leads to the development of central serous chorioretinopathy in postbone marrow transplant patients.

Combined use of serum adiponectin and tumor necrosis factor-alpha receptor 2 levels was comparable to 2-hour post-load glucose in diabetes prediction.

BACKGROUND: Adipose tissue inflammation and dysregulated adipokine secretion are implicated in obesity-related insulin resistance and type 2 diabetes. We evaluated the use of serum adiponectin, an anti-inflammatory adipokine, and several proinflammatory adipokines, as biomarkers of diabetes risk and whether they add to traditional risk factors in diabetes prediction. METHODS: We studied 1300 non-diabetic subjects from the prospective Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). Serum adiponectin, tumor necrosis factor-alpha receptor 2 (TNF-α R2), interleukin-6 (IL-6), adipocyte-fatty acid binding protein (A-FABP) and high-sensitivity C-reactive protein (hsCRP) were measured in baseline samples. RESULTS: Seventy-six participants developed diabetes over 5.3 years (median). All five biomarkers significantly improved the log-likelihood of diabetes in a clinical diabetes prediction (CDP) model including age, sex, family history of diabetes, smoking, physical activity, hypertension, waist circumference, fasting glucose and dyslipidaemia. In ROC curve analysis, "adiponectin + TNF-α R2" improved the area under ROC curve (AUC) of the CDP model from 0.802 to 0.830 (P = 0.03), rendering its performance comparable to the "CDP + 2-hour post-OGTT glucose" model (AUC = 0.852, P = 0.30). A biomarker risk score, derived from the number of biomarkers predictive of diabetes (low adiponectin, high TNF-α R2), had similar performance when added to the CDP model (AUC = 0.829 [95% CI: 0.808-0.849]). CONCLUSIONS: The combined use of serum adiponectin and TNF-α R2 as biomarkers provided added value over traditional risk factors for diabetes prediction in Chinese and could be considered as an alternative to the OGTT.

Haemoglobin A1c is superior to fasting glucose in predicting the incidence of diabetes over 8 years among Chinese.

Baseline haemoglobin A1c had a higher standardized hazard ratio, and more optimal sensitivity and specificity than fasting glucose in predicting the 8-year incidence of diabetes among 530 non-diabetic Chinese from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study.

Genetic variants associated with persistent central obesity and the metabolic syndrome in a 12-year longitudinal study.

OBJECTIVE: Central obesity predisposes to various cardiometabolic diseases and is a key component of the metabolic syndrome (MetS). We have previously demonstrated that three obesity-susceptible single nucleotide polymorphisms (SNPs), rs10938397 (GNPDA2), rs8050136 (FTO) and rs17782313 (MC4R), were associated with obesity and waist circumference in cross-sectional studies in the Chinese population. In this study, we investigate whether these SNPs could also predict the persistence of central obesity and MetS in subjects from the Hong Kong Cardiovascular Risk Factors Prevalence Study (CRISPS) cohort. DESIGN AND METHODS: We genotyped these SNPs in i) 354 subjects with and 994 subjects without central obesity at both baseline and a 12-year follow-up, ii) 2214 subjects (816 cases and 1398 controls) in an MetS cross-sectional case-control study and iii) 225 subjects with and 1221 subjects without MetS at both baseline and the 12-year follow-up. RESULTS: Both FTO rs8050136 (P(age, sex-adjusted)=0.019; odds ratio (OR) (95% confidence intervals (CI)): 1.35 (1.05, 1.73)) and GNPDA2 rs10938397 (P(age, sex-adjusted)=3 × 10(-3); OR (95% CI): 1.34 (1.11, 1.63)) were significantly associated with persistent central obesity. GNPDA2 rs10938397 was also significantly associated with MetS (P(age, sex-adjusted)=0.011, OR (95% CI): 1.20 (1.04, 1.38)) in the case-control study. However, none of these SNPs showed an individual association with persistent MetS. In the combined genetic risk analyses for persistent central obesity and persistent MetS, the combined genetic risk score of the three SNPs showed an OR of 1.25 (95% CI: 1.10, 1.42; P(age, sex-adjusted)=4.92 × 10(-3)) and 1.19 (95% CI: 1.03, 1.38; P(age, sex-adjusted)=0.019) for each additional risk allele respectively. CONCLUSION: This study demonstrated that FTO and GNPDA2 variants predicted persistent central obesity in the Chinese population, further supporting their importance as obesity-susceptible genes.

High plasma level of fibroblast growth factor 21 is an Independent predictor of type 2 diabetes: a 5.4-year population-based prospective study in Chinese subjects.

OBJECTIVE: To investigate whether circulating levels of fibroblast growth factor 21 (FGF21), which previously has been shown to be elevated in obesity, could predict the development of type 2 diabetes in a 5.4-year, population-based, prospective study. RESEARCH DESIGN AND METHODS: Baseline plasma FGF21 levels were measured using an enzyme-linked immunosorbent assay in 1,900 subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). The prospective association of FGF21 with diabetes development over 5.4 years was analyzed using multiple logistic regression. RESULTS: At baseline, plasma levels of FGF21 increased progressively with worsening dysglycemia from normal glucose tolerance, through prediabetes, to diabetes (global trend, P < 0.001). Of 1,292 subjects without diabetes at baseline, a high baseline FGF21 level was a strong independent predictor for diabetes development (odds ratio 1.792; P < 0.01), together with waist circumference and fasting plasma glucose levels. CONCLUSIONS: Plasma FGF21 levels were significantly increased in subjects with prediabetes and diabetes and predicted the development of diabetes in humans.

The KCNJ11 E23K polymorphism and progression of glycaemia in Southern Chinese: a long-term prospective study.

CONTEXT: The KCNJ11 E23K variant is associated with type 2 diabetes mellitus (T2DM) in cross-sectional studies, but conflicting findings have been reported from prospective studies. OBJECTIVE: This study aimed to evaluate whether the E23K variant could predict glycaemic progression in a Southern Chinese population. METHODS/PRINCIPAL FINDINGS: We performed a long-term prospective study on 1912 subjects from the Hong Kong Cardiovascular Risk Factors Prevalence Study (CRISPS). The KCNJ11 E23K variant was associated with the progression to prediabetes after a median interval of 12 years on multinomial logistic regression analysis, even after adjustment for traditional risk factors (OR 1.29, P(age, sex, BMI and fasting plasma glucose [FPG] adjusted) = 0.02). Based on Cox proportional hazard regression analysis, the E23K variant also predicted incident prediabetes (HR 1.18, P(age, sex, BMI and FPG adjusted)= 0.021). However, E23K was not associated with the progression to T2DM in either multinomial or Cox regression analysis, and the association of E23K with glycaemic progression to either prediabetes or T2DM was significant only in unadjusted Cox regression analysis (P = 0.039). In a meta-analysis of eight prospective studies including our own, involving 15680 subjects, the E23K variant was associated with incident T2DM (fixed effect: OR 1.10, P = 4×10(-3); random effect: OR 1.11, P = 0.035). CONCLUSIONS: Our study has provided supporting evidence for the role of the E23K variant in glycaemic progression in Chinese, with its effect being more evident in the early stage of T2DM, as the subjects progressed from normal glucose tolerance to prediabetes.