Serum fibroblast growth factor 21 is a superior biomarker to other adipokines in predicting incident diabetes.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) improves glucose and lipid metabolism, but high circulating levels are found in type 2 diabetes, suggesting FGF21 resistance. Serum FGF21 predicts incident diabetes, but its performance compared to established and emerging predictors is not known. We aimed to study the performance of FGF21 in diabetes prediction, relative to other adipokines and established risk factors including 2-h plasma glucose (2hG) during the oral glucose tolerance test (OGTT). DESIGN/PARTICIPANTS/MEASUREMENTS: We studied 1380 nondiabetic subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study using the second visit (2000-2004) as baseline when serum levels of FGF21 and other adipokines were measured. Glycaemic status was assessed by OGTT. Incident diabetes was defined as fasting glucose level (FG) ≥ 7 mmol/l or 2hG ≥ 11·1 mmol/l or use of antidiabetic agents, at subsequent visits. RESULTS: A total of 123 participants developed diabetes over 9·0 years (median). On multivariable logistic regression analysis, FGF21 (P = 0·003), adipocyte fatty acid-binding protein (P = 0·003) and adiponectin (P = 0·035) were independent predictors of incident diabetes. FGF21 had the best change in log likelihood when added to a diabetes prediction model (DP) based on age, family history, smoking, hypertension, BMI, dyslipidaemia and FG. It also improved the area under ROC curve (AUROC) of diabetes prediction (DP) from 0·797 to 0·819 (P = 0·0072), rendering its performance comparable to the 'DP + 2hG' model (AUROC=0·838, P = 0·19). CONCLUSIONS: As a biomarker for diabetes prediction, serum FGF21 appeared to be superior to other adipokines and, on its own, could be considered as an alternative to the OGTT.

Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors.

OBJECTIVE: Serum levels of fibroblast growth factor-21 (FGF21), a metabolic hormone, have been shown to be elevated in subjects with adverse lipid profiles, obesity, metabolic syndrome, impaired glucose tolerance, type 2 diabetes mellitus, and hypertension. Recently, elevated serum FGF21 levels have also been reported in subjects with coronary heart disease or carotid artery plaques. However, whether serum FGF21 is independently associated with atherosclerotic diseases remains unclear. In this study, we examined the relationship between serum FGF21 levels and carotid intima-media thickness (IMT) in a large cohort of Southern Chinese subjects. APPROACH AND RESULTS: The cohort consisted of 670 subjects who underwent carotid IMT measurement. Serum FGF21 levels were measured with an ELISA kit. Serum FGF21 levels positively correlated with carotid IMT in women (r=0.32; P<0.001), but not in men (r=0.06; P=0.305). On multiple linear regression analysis, elevated serum FGF21 level in women was an independent risk factor for increased carotid IMT (P=0.039), together with age (P<0.001) and hypertension (P=0.011), in a model comprising also waist circumference, smoking history, serum creatinine, high sensitive C-reactive protein, dysglycemia, and dyslipidemia (adjusted R(2)=35.8%; P<0.001). Elevated serum FGF21 levels were also a significant independent risk factor of carotid IMT on multiple stepwise regression analysis (P=0.01). CONCLUSIONS: The present study is the first demonstration that elevated serum FGF21 levels are associated with carotid atherosclerosis in humans, independent of established risk factors including adverse lipid profiles and C-reactive protein. The role of FGF21 as a biomarker or therapeutic target of atherosclerotic diseases warrants further investigation.

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.

Association of a genetic variant in the apolipoprotein A5 gene with the metabolic syndrome in Chinese.

OBJECTIVE: Single nucleotide polymorphisms (SNPs) in the apolipoprotein A5 gene (APOA5) are associated with hypertriglyceridaemia in our population. We studied the associations of SNPs in APOA5 with the metabolic syndrome (MetS) in the Hong Kong and Guangzhou Chinese. METHODS: We genotyped five tagging SNPs in 1330 unrelated subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study cohort with follow-up after a median interval of 6·4 years; 1952 subjects from the Guangzhou Biobank Cohort Study-Cardiovascular Disease Subcohort were used to replicate the findings. The MetS was defined according to the consensus criteria proposed jointly by several organizations in 2009. RESULTS: The SNP rs662799 (-1131T>C) was associated with the MetS (odds ratio = 1·47, P = 0·00082) and the number of its components present (regression coefficient = 0·204, P = 4·6 × 10(-5) ) after adjusting for age, sex, smoking, drinking and education in Hong Kong subjects at baseline. Similar association of this SNP was found in Hong Kong subjects at follow-up (P = 0·010 and 0·00021, respectively) and in Guangzhou subjects (P = 0·0041 and 0·017, respectively). The association of rs662799 with the number of the MetS components was significant regardless of age, sex, obesity and alcohol drinking, but almost disappeared after further adjusting for plasma triglycerides. CONCLUSION: Our results showed that the -1131T>C polymorphism in APOA5 was associated with the MetS because of its strong effect on plasma triglycerides. This may partly explain the higher cardiovascular risk in people with this polymorphism.

Role of genetic variants in the gene encoding lipocalin-2 in the development of elevated blood pressure.

Lipocalin-2 is recently recognized as a biomarker of obesity and inflammation, which are both risk factors for hypertension. We therefore investigated the association of common single nucleotide polymorphisms (SNPs) in the gene encoding lipocalin-2 (LCN2) with elevated blood pressure (BP) in Hong Kong Chinese. Five tagging SNPs were genotyped in 1936 subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS-2) with a median follow-up time of 6.4 years. Elevated BP was defined as ≥130/85 mmHg or taking anti-hypertensive medication. Haplotype GGTCC was associated with elevated BP at follow-up after adjusting for age and sex (odds ratio (OR) [95% confidence interval (CI)] = 1.17 [1.01-1.36], P = 0.031). Haplotype GGTCC was also an associated plasma CRP level 11.7% (95% CI: 2.6-25.9%) higher among subjects with elevated BP after adjusting for age and sex (P = 0.036). Among 1381 subjects without elevated BP at baseline, 321 subjects developed elevated BP at follow-up. Haplotype GGTCC was associated with the development of elevated BP at follow-up after adjusting for baseline age, sex, systolic blood pressure (SBP), and follow-up duration (OR [95% CI] = 1.30 [1.06-1.58], P = 0.011). Among subjects not taking anti-hypertensive medication, carriers of the haplotype GGTCC had higher SBP than noncarriers (119.7 ± 16.4 mmHg vs. 117.9 ± 17.3 mmHg, P = 0.043). Our findings suggest, for the first time, that genetic variants in LCN2 may affect BP. Further studies on the role of lipocalin-2 in BP regulation are warranted.

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.

Adiponectin mediates the suppressive effect of rosiglitazone on plasminogen activator inhibitor-1 production.

OBJECTIVE: The purpose of this study was to examine the effects of PPAR-gamma agonist rosiglitazone, relative to sulfonylureas, on circulating levels of adiponectin and the prothrombotic factor, plasminogen activator inhibitor (PAI)-1, in type 2 diabetic patients, and to investigate, in animal models, whether the antithrombotic action of rosiglitazone was mediated through adiponectin. METHODS AND RESULTS: Our clinical study (n=64) showed that after 24-week add-on therapy, the rosiglitazone group had a greater mean reduction in plasma PAI-1 levels (25%, versus 12% in sulfonylurea group, P=0.002). Stepwise multiple linear regression analysis identified the reduction in plasma fasting glucose and the rise in adiponectin levels to be independently associated with the reduction in PAI-I concentration in the rosiglitazone-treated patients. Rosiglitazone (20 mg/kg/d) reduced adipose tissue PAI-1 mRNA expression and its plasma levels in wild-type C57 mice with diet-induced obesity (P<0.001), but this suppressive effect was attenuated in adiponectin knockout mice. Adenovirus-mediated overexpression of adiponectin led to a significant suppression of adipose tissue PAI-1 expression and its circulating concentrations in db/db diabetic mice. Our in vitro study demonstrated that recombinant adiponectin directly inhibited PAI-1 production in 3T3-L1 adipocytes. CONCLUSIONS: The antithrombotic effect of rosiglitazone is mediated, at least in part, through the suppressive effect of adiponectin on PAI-1 production.

Validation of the diabetes screening tools proposed by the American Diabetes Association in an aging Chinese population.

AIM: Diabetes is a serious global health problem. A simple and effective screening tool should have substantial public health benefit. We investigated the performance of the latest American Diabetes Association diabetes screening methods in our aging Chinese population. METHODS: Subjects without diabetes who returned for the 4th Hong Kong Cardiovascular Risk Factors Prevalence Study in 2010-2012 were evaluated for the probability of having diabetes with reference to the age- and body mass index-based screening criteria (screening criteria) and the diabetes risk test (risk test), and the conclusion drawn was compared to their measured glycaemic status. Diabetes was defined by fasting glucose ≥ 7 mmol/L or 2-hour post oral glucose tolerance test glucose ≥ 11.1 mmol/L. RESULTS: 1415 subjects, aged 58.1±10.2, were evaluated. 95 (6.7%) had diabetes. The risk test showed good accuracy (area under the receiver operating curve 0.725) in screening for diabetes with an optimal cut-off score of five. Compared to the screening criteria, the risk test had significantly better specificity (0.57 vs. 0.41, p<0.001), positive predictive value (0.12 vs. 0.09, p<0.001) and positive diagnostic likelihood ratio (1.85 vs. 1.37, p<0.001). To diagnose one case of diabetes, fewer subjects (11 vs. 18) needed to be tested for blood glucose if the risk test was adopted. CONCLUSION: The risk test appears to be a more effective screening tool in our population. It is simple to use and can be adopted as a public health strategy for identifying people with undiagnosed diabetes for early intervention.

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.

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.

Gamma-glutamyl transferase level predicts the development of hypertension in Hong Kong Chinese.

BACKGROUND: Plasma activities of alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyl transferase (GGT) are often increased in cardiometabolic diseases. We investigated if hypertension is associated with increased activities of these plasma markers. METHODS: We included 235 hypertensive and 708 normotensive subjects (mean age 47.3±9.6 and 58.0±10.2 years respectively) from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS-2) in 2000-2004 who had drank <1/week. In the follow-up study in 2005-2008 (CRISPS-3), 126 out of the 708 subjects had developed hypertension. RESULTS: Raised plasma ALT (OR=1.22 per SD of log-transformed level, P=0.045) and GGT (OR=1.38 per SD of log-transformed level, P=0.001) levels were associated with hypertension at baseline in CRISPS-2 after adjusting for covariates. Among subjects not on anti-hypertensive medications, plasma ALP, ALT and GGT were related to blood pressure (P<0.01). In subjects normotensive at CRISPS-2, plasma GGT, but not ALP, ALT and AST, was an independent predictor of new-onset hypertension at CRISPS-3 (OR=1.38 per SD of log-transformed level, P=0.020 and OR=2.68 for 3rd tertile vs. 1st tertile, P=0.004) after adjusting for covariates. CONCLUSIONS: Among the 4 plasma markers, increased GGT activity is the strongest predictor for existing and new-onset hypertension in Hong Kong Chinese.

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.

Plasma adrenomedullin level is related to a single nucleotide polymorphism in the adrenomedullin gene.

OBJECTIVE: Adrenomedullin (ADM) plays an important role in inflammation and is a marker of future cardiovascular events. We studied common single nucleotide polymorphisms (SNPs) in the gene encoding ADM and their relationship with the plasma levels of ADM and other inflammatory markers. DESIGN AND METHODS: Plasma ADM, interleukin 6 (IL6), fibrinogen, and C-reactive protein (CRP) were measured in 476 subjects from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study-2. Four tag SNPs in ADM were genotyped. RESULTS: Plasma ADM level increased with decreasing plasma IL6 level (ß=-0.116, P=0.014). Plasma ADM level was not related to plasma levels of CRP and fibrinogen, and other clinical characteristics, except age (P=0.049). The four SNPs, rs3814700, rs11042725, rs34354539, and rs4910118, had minor allele frequencies of 31.1, 28.7, 33.8, and 23.4% respectively. Carriers of the minor allele of rs4910118 had a mean plasma ADM level that was 10.5% (95% confidential interval: 2.5-17.8%) lower than the non-carriers (ß=-0.115, P=0.011). Haplotype analysis revealed a similar significant association with plasma ADM (P=0.040). In multivariate analysis, the presence of the minor allele of rs4910118, but not plasma IL6, was independently associated with plasma ADM (P=0.010). CONCLUSION: Plasma ADM correlates with plasma IL6 level, consistent with its role in inflammation. It is related to an SNP common in Chinese, independent of other covariates. ADM genotype should be included in future studies of cardiovascular risk prediction.

Relationship of plasma interleukin-6 and its genetic variants with hypertension in Hong Kong Chinese.

BACKGROUND: Interleukin-6 (IL6) plays a central role in inflammation, insulin resistance, and atherogenesis. We investigated the associations of plasma IL6 and its genetic variants with hypertension in both cross-sectional and prospective study designs. METHODS: Plasma IL6 was measured in 648 normotensive and 294 hypertensive subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS)-2 in 2000-2004 and three tagging single-nucleotide polymorphisms (SNPs) in the IL6 gene were genotyped. Among subjects normotensive in CRISPS-2 (baseline), 515 subjects were followed-up in CRISPS-3 in 2005-2008 and 100 of them had developed hypertension. RESULTS: At baseline, plasma IL6 correlated with systolic blood pressure (SBP) (r = 0.128, P < 0.001). Hypertensive subjects had significantly higher plasma IL6 after adjusting for age and sex (geometric mean (95% confidence interval (CI) = 0.60 (0.54-0.65) vs. 0.47 (0.44-0.50) ng/l, P = 0.021). In multiple logistic regression, higher plasma IL6 was associated with hypertension in women (P = 0.009), but not in men. The minor G allele of SNP rs1800796 was associated with lower plasma IL6 (geometric mean (95% CI) = 0.46 (0.41-0.51) ng/l for CG and 0.49 (0.39-0.62) ng/l for GG vs. 0.53 (0.50-0.57) ng/l for CC, P = 0.005). However, this SNP was not associated with hypertension or blood pressure at baseline. Among subjects normotensive in CRISPS-2, plasma IL6 was not associated with the development of hypertension in CRISPS-3. CONCLUSION: The SNP rs1800796 affected plasma IL6 with a small effect size. Elevated plasma IL6 is associated with prevalent hypertension in women, but not incident hypertension.

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.

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.

A genetic variant in the gene encoding adrenomedullin predicts the development of dysglycemia over 6.4 years in Chinese.

BACKGROUND: Adrenomedullin, a vasodilatory peptide, facilitates the differentiation of pre-adipocytes, and affects lipolysis and glucose uptake. We investigated the association of common single nucleotide polymorphisms (SNPs) in the gene encoding adrenomedullin (ADM) with dysglycemia in the Hong Kong Chinese population. METHODS: Four SNPs were genotyped in 1391 subjects without dysglycemia at baseline from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, which had a median follow-up time of 6.4 years. Dysglycemia included impaired fasting glucose, impaired glucose tolerance, and diabetes according to the WHO 1998 criteria. At follow-up, 382 subjects had developed dysglycemia. RESULTS: In stepwise logistic regression, the SNP rs11042725 was a significant independent predictor of the development of dysglycemia (OR=1.31, P=0.012), together with baseline age (P<0.001), plasma triglycerides (P<0.001), body mass index (P=0.004), 2-h glucose after oral glucose tolerance test (P<0.001), homeostasis model assessment of insulin resistance index (P=0.045), and follow-up duration (P=0.009). The association was more significant in women (P=0.002) and in subjects without regular exercise (P=0.001). CONCLUSIONS: Our study suggests a potential role of genetic variants in the ADM gene in the development of dysglycemia in our local Chinese population.

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.

Using glycosylated hemoglobin to define the metabolic syndrome in United States adults.

OBJECTIVE: To compare the use of GHb and fasting plasma glucose (FPG) to define the metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS: Data from the U.S. National Health and Nutrition Examination Survey 1999-2006 were used. MetS was defined using the consensus criteria in 2009. Raised blood glucose was defined as either FPG >or=100 mg/dl (5.6 mmol/l) or GHb >or=5.7%. RESULTS: In 2003-2006, there was 91.3% agreement between GHb and FPG when either was used to define MetS. The agreement was good irrespective of age, sex, race/ethnicity, BMI, and diabetes status (>or=87.4%). Similar results were found in 1999-2002. Among subjects without diabetes, only the use of GHb alone, but not FPG, resulted in significant association with cardiovascular diseases (odds ratio 1.45, P = 0.005). CONCLUSIONS: Using GHb instead of FPG to define MetS is feasible. It also identifies individuals with increased cardiovascular risk.