CPVL/CHN2 genetic variant is associated with diabetic retinopathy in Chinese type 2 diabetic patients.

OBJECTIVE: Diabetic nephropathy and retinopathy are two important microvascular diabetes complications with a high concordance rate in diabetic patients. A recent genome-wide association study in type 1 diabetic patients of European descent identified four loci to be associated with diabetic nephropathy. The aim of this study was to test the effects of single nucleotide polymorphisms (SNPs) from these four loci on diabetic nephropathy and retinopathy in Chinese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In stage 1, we recruited 1,276 type 2 diabetic patients, including 378 patients with diabetic nephropathy but no retinopathy, 374 patients with diabetic retinopathy but no nephropathy, 244 patients with both diabetic retinopathy and nephropathy, and 280 control subjects with diabetes for >10 years and no diabetic retinopathy or nephropathy. Fifty-five SNPs from four loci (CPVL/CHN2, FRMD3, CARS, and IRS2) were genotyped. The SNPs that showed associations to diabetic retinopathy or nephropathy were genotyped in stage 2 samples for replication. RESULTS: SNPs from CPVL/CHN2 and FRMD3 were associated with diabetic retinopathy with rs39059 and rs10868025 as the top SNPs (odds ratio [OR] 1.292, 95% CI 1.097-1.523, P = 0.0022, for rs39059; 1.201, 1.014-1.422, P = 0.0343, for rs10868025) in stage 1 samples. In stage 2 analysis, only rs39059 showed similar effect to diabetic retinopathy (OR 1.269, 0.989-1.628, P = 0.0689), and meta-analysis showed a significant association between rs39059 and diabetic retinopathy, with an OR of 1.285 (1.120-1.474, P = 0.0003). CPVL/CHN2 rs39059 was also associated with levels of diabetic retinopathy (P = 0.0007 for trend). However, no association was detected between these SNPs and diabetic nephropathy. CONCLUSIONS: In this study, we found CPVL/CHN2 rs39059 was associated with diabetic retinopathy in the Chinese type 2 diabetic patients.

Non-alcoholic fatty liver disease's prevalence and impact on alanine aminotransferase associated with metabolic syndrome in the Chinese.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is becoming a major public health hazard in China. The present study aimed to estimate the prevalence of NAFLD, NAFLD with abnormal serum alanine aminotransferase (ALT) levels, and determine the potential associations of ALT levels with the components of metabolic syndrome (MetS) in the absence or presence of NAFLD in Chinese adults. METHODS: A population-based cross-sectional survey was conducted with 2226 participants. Physical examinations, laboratory tests and hepatic ultrasounds were performed. Individuals were further stratified into higher or lower ALT subgroups with the upper quartiles of ALT in this population. The MetS was identified according to the criteria of the Chinese Joint Committee for Developing Chinese Guidelines (JCDCG). RESULTS: The standardized prevalence of NAFLD was 23.3% (NAFLD with abnormal ALT levels, 3.1%), 26.5% (NAFLD with abnormal ALT levels, 5.1%) in males, and 19.7% (NAFLD with abnormal ALT levels, 0.9%) in females. Multivariate logistic analysis revealed that higher ALT was significantly associated with elevated triglyceride (TG) in the non-NAFLD participants, independent of age, smoking status, drinking status, and other MetS-related measures with odds ratios (95% confidence intervals) of 3.4 (1.6-7.1) and 2.3 (1.4-3.7) in males and females, respectively. On the other hand, the higher ALT was statistically associated with elevated TG and hyperglycemia in the NAFLD cases with odds ratios of 2.2 to 2.5 (P<0.05). CONCLUSIONS: The prevalence of NAFLD has become epidemic in Shanghai adults. NAFLD combined with ALT levels may be used to identify the individuals at the different risk levels of metabolic disorders.

Variants from GIPR, TCF7L2, DGKB, MADD, CRY2, GLIS3, PROX1, SLC30A8 and IGF1 are associated with glucose metabolism in the Chinese.

BACKGROUND: Recent meta-analysis of genome-wide association studies in European descent samples identified novel loci influencing glucose and insulin related traits. In the current study, we aimed to evaluate the association between these loci and traits related to glucose metabolism in the Chinese. METHODS/PRINCIPAL FINDINGS: We genotyped seventeen single nucleotide polymorphisms (SNPs) from fifteen loci including GIPR, ADCY5, TCF7L2, VPS13C, DGKB, MADD, ADRA2A, FADS1, CRY2, SLC2A2, GLIS3, PROX1, C2CD4B, SLC30A8 and IGF1 in 6,822 Shanghai Chinese Hans comprising 3,410 type 2 diabetic patients and 3,412 normal glucose regulation subjects. MADD rs7944584 showed strong association to type 2 diabetes (p = 3.5×10(-6), empirical p = 0.0002) which was not observed in the European descent populations. SNPs from GIPR, TCF7L2, CRY2, GLIS3 and SLC30A8 were also associated with type 2 diabetes (p = 0.0487∼2.0×10(-8)). Further adjusting age, gender and BMI as confounders found PROX1 rs340874 was associated with type 2 diabetes (p = 0.0391). SNPs from DGKB, MADD and SLC30A8 were associated with fasting glucose while PROX1 rs340874 was significantly associated with OGTT 2-h glucose (p = 0.0392∼0.0014, adjusted for age, gender and BMI), the glucose-raising allele also showed association to lower insulin secretion. IGF1 rs35767 showed significant association to both fasting and 2-h insulin levels as well as insulin secretion and sensitivity indices (p = 0.0160∼0.0035, adjusted for age, gender and BMI). CONCLUSIONS/SIGNIFICANCE: Our results indicated that SNPs from GIPR, TCF7L2, DGKB, MADD, CRY2, GLIS3, PROX1, SLC30A8 and IGF1 were associated with traits related to glucose metabolism in the Chinese population.

[No association of vascular endothelial growth factor A gene rs9369425 polymorphism with glucose metabolism in Chinese Han population].

OBJECTIVE: To investigate the relationship between the vascular endothelial growth factor A gene (VEGFA) rs9369425 single nucleotide polymorphism (SNP) and type 2 diabetes in Chinese Han population. METHODS: One thousand eight hundred and ninety two type 2 diabetes patients and 1808 controls with normal glucose were recruited in this study. Phenotypes including body mass index, waist, waist hip ratio, plasma glucose and serum insulin levels of blood obtained both at 0 and 120 minute during standard 75-gram glucose oral glucose tolerance tests, were analyzed. Insulin resistance and beta cell function were assessed by homeostasis model assessment (HOMA-IR and HOMA-B). Genotyping was performed by time-of-light mass spectrum using a Sequenom platform. RESULTS: The frequencies of minor allele G in the diabetic patients and controls were 10.8% and 11.3% respectively. No significant difference of allele distribution was detected between the cases and controls (P=0.5086). No significant difference (P>0.05) was detected on the association between rs9369425 SNP and clinical phenotypes. CONCLUSION: VEGFA rs9369425 was not associated with type 2 diabetes in Chinese Han population. Whether there is association in any other loci in this gene remained to be investigated.

The metabolic syndrome increased risk of cardiovascular events in Chinese--a community based study.

BACKGROUND: Whether metabolic syndrome (MetS) could serve as a valid indicator for cardiovascular disease (CVD) is in controversy. The aim of the study was to prospectively evaluate the predictive value of the MetS for CVD events in Chinese population by different MetS definitions. METHODS: This was a community-based cohort study. MetS was defined according to the World Health Organization (WHO), the International Diabetes Federation (IDF), the National Cholesterol Education Program Adult Treatment Panel III (NCEPIII) and Joint Committee for Developing Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults (JCDCG), respectively. 2788 subjects were included. The incidence of CVD events was monitored during a 5.5-year period. RESULTS: The proportion of MetS defined by the WHO, IDF, NCEPIII and JCDCG criteria was 25.9%, 15.4%, 22.0% and 26.1%, respectively in men, and 24.5%, 28.0%, 31.1% and 23.0%, respectively in women. After adjusting for age, all four definitions were associated with increased risk of CVD events in women, but not in men. The corresponding hazard ratios (HRs) [95% confidence intervals (CIs)] in women were 2.13 (1.44-3.16), 1.49 (1.01-2.19), 1.50 (1.02-2.21) and 2.10 (1.41-3.11). The HRs remained significant with WHO and JCDCG definitions, not with the IDF and NCEPIII definitions, when factors of LDL cholesterol, and smoking were adjusted. CONCLUSION: The MetS by the WHO and JCDCG definition was associated with increased risk of CVD events in Chinese women after adjustment for age, total cholesterol, LDL cholesterol, and smoking.

PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a Chinese population.

BACKGROUND: Recent advance in genetic studies added the confirmed susceptible loci for type 2 diabetes to eighteen. In this study, we attempt to analyze the independent and joint effect of variants from these loci on type 2 diabetes and clinical phenotypes related to glucose metabolism. METHODS/PRINCIPAL FINDINGS: Twenty-one single nucleotide polymorphisms (SNPs) from fourteen loci were successfully genotyped in 1,849 subjects with type 2 diabetes and 1,785 subjects with normal glucose regulation. We analyzed the allele and genotype distribution between the cases and controls of these SNPs as well as the joint effects of the susceptible loci on type 2 diabetes risk. The associations between SNPs and type 2 diabetes were examined by logistic regression. The associations between SNPs and quantitative traits were examined by linear regression. The discriminative accuracy of the prediction models was assessed by area under the receiver operating characteristic curves. We confirmed the effects of SNPs from PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 on risk for type 2 diabetes, with odds ratios ranging from 1.114 to 1.406 (P value range from 0.0335 to 1.37E-12). But no significant association was detected between SNPs from WFS1, FTO, JAZF1, TSPAN8-LGR5, THADA, ADAMTS9, NOTCH2-ADAM30 and type 2 diabetes. Analyses on the quantitative traits in the control subjects showed that THADA SNP rs7578597 was association with 2-h insulin during oral glucose tolerance tests (P = 0.0005, empirical P = 0.0090). The joint effect analysis of SNPs from eleven loci showed the individual carrying more risk alleles had a significantly higher risk for type 2 diabetes. And the type 2 diabetes patients with more risk allele tended to have earlier diagnostic ages (P = 0.0006). CONCLUSIONS/SIGNIFICANCE: The current study confirmed the association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes. These type 2 diabetes risk loci contributed to the disease additively.

Serum C-reactive protein and risk of cardiovascular events in middle-aged and older chinese population.

The purpose of the present study was to investigate the effect of high-sensitivity C-reactive protein (hs-CRP) on the risk of cardiovascular disease (CVD) in a Chinese population. A total of 2,656 participants (aged 30 to 95 years) with baseline hs-CRP levels available were monitored for the incidence of a composite of CVD events (stroke and coronary heart disease) during a 5.5-year period. With increasing quartiles of hs-CRP (<0.47, 0.47 to 0.97, 0.97 to 2.09, and >or=2.09 mg/L), the incidence of CVD increased progressively (11.7, 16.4, 24.7, and 36.5 per 1,000 person-years, respectively). In a Cox model adjusted for other traditional risk factors (e.g., age, blood pressure, diabetes mellitus, lipids, body mass index, smoking status), elevated hs-CRP (>or=2.0 mg/L) independently predicted the risk of CVD (hazard ratio 1.39; 95% confidence interval 1.04 to 1.87). The effect was especially significant for stroke (hazard ratio 1.58; confidence interval 1.08 to 2.31). In conclusion, the results of our study suggest that elevated hs-CRP (>or=2.0 mg/L) is an effective predictor of CVD in a Chinese population.

The protective effect of the RAS inhibitor on diabetic patients with nephropathy in the context of VEGF suppression.

AIM: The aim of the present study was to explore whether renin angiotensin system (RAS) inhibitor can reduce the production of vascular endothelium growth factor (VEGF). Further, we sought to elucidate the correlation between VEGF level and certain clinical parameters, such as albumin excretion rate (AER), before and after treatment with angiotensin type 1 receptor blocker. METHODS: We recruited 166 type 2 diabetic patients at various stages of diabetic nephropathy (DN) and 46 healthy control subjects for a cross-sectional study. We recruited another 42 hypertensive type 2 diabetic patients with microalbuminuria for a longitudinal study involving a 6-month irbesartan treatment protocol. Urinary VEGF (uVEGF) levels were determined using ELISA. RESULTS: In the cross-sectional study, hypertensive type 2 diabetic patients who received RAS inhibitor presented lower uVEGF levels than those who did not receive the RAS inhibitor. Statistical analysis indicated that uVEGF level was independently correlated with the AER. In the longitudinal study involving the 6-month irbesartan treatment, we demonstrated that uVEGF levels decreased significantly in patients who achieved a 50% AER reduction (remission group, n=32). In contrast, uVEGF levels remained unchanged in patients who did not exhibit a 50% AER reduction (nonremission group, n=10). Furthermore, the change in uVEGF was significantly correlated with the change in AER (r=0.65, P<0.01) before and after 6 months of irbesartan treatment. This result held true even after we had adjusted for the decrease in average blood pressure. CONCLUSION: The protective effect of the RAS inhibitor in DN patients is associated with the suppression of VEGF. Accordingly, it may be possible to use uVEGF as a marker of DN progression. We suggest that uVEGF may be an important target for therapeutic intervention in the context of DN.

Risk factors for overweight and obesity, and changes in body mass index of Chinese adults in Shanghai.

BACKGROUND: Over the past two decades, the prevalence of overweight or obesity has increased in China. The aims of this study were to firstly assess the baseline prevelences and the risk factors for overweight and obesity, and secondly to detect the changes of body mass index (BMI) over a follow-up period in Chinese adults in Shanghai. METHODS: The data set of a population-based longitudinal study was analyzed. Anthropometric and biochemical data were collected for 5364 subjects (aged 25-95 years) during a period of 1998-2001. Among those individuals, 3032 subjects were interviewed and reexamined at the second survey from 2003 to 2004. Then the standardized prevalences for overweight and obesity were calculated using baseline data; the possible contributing factors of overweight and obesity were detected using binary logistic regression analysis; and the changes of BMI were evaluated after an average of 3.6-year follow-up period. RESULTS: (1) According to the WHO standard and the Chinese standard, the sex- and age-standardized prevalences were 27.5% and 32.4% for overweight, and 3.7% and 9.1% for obesity, respectively. (2) The risks of overweight and obesity differed among different age groups. Family history of obesity increased the risk of overweight and obesity by about 1.2-fold for both genders. Current male smokers had a lower risk of overweight and obesity (OR = 0.76, p < 0.05) than nonsmokers. In contrast, current male drinkers had a higher risk of overweight and obesity (OR = 1.42, p < 0.05) than nondrinkers. Compared with low-educated women, medium- and high- educated women were at lower risk of overweight and obesity, and the corresponding ORs (95% CIs) were 0.64 (0.52-0.79) and 0.50(0.36-0.68), respectively. (3) The annual changes of BMI means ranged from an increase of 0.1 kg/m2 to a decrease of 0.2 kg/m2 (by genders and age groups). Meanwhile, the BMI increase was statistically significant in the 35-44 years age group, and the BMI decrease was significant above 65 years for both genders. CONCLUSION: This study showed high prevalence of overweight and obesity in Shanghai metropolis populations. The risk factors of overweight and obesity were multifactorial and gender specific. After 3.6 years, BMI means changed slightly, BMI increased mainly in middle-aged individuals and decreased in old individuals.

[An analysis method to apply linkage disequilibrium maps to association study].

OBJECTIVE: To apply linkage disequilibrium (LD) maps to associations studies with high throughput single nucleotide polymorphisms (SNPs). METHODS: Seven hundred and fifty-four SNPs were genotyped in 160 Shanghai Chinese. LD maps were constructed in cases and controls separately. By comparing the decline of LD unit with distance between the two groups, disease susceptible loci were estimated. This method was compared with traditional analyses including LD analysis, single SNP and haplotype analyses. RESULTS: The analysis of LD maps could detect the chromosome regions with different LD patterns between the cases and controls. The alleles and/or haplotypes frequencies of SNPs within the regions had significantly different distributions or trends of significantly different distributions. CONCLUSION: This method may be applied to analyze the data from association studies with high throughput SNPs genotype information.

[Scanning HNF-1 alpha gene mutation in Chinese early-onset and/or multiplex diabetes pedigrees].

OBJECTIVE: To investigate the prevalence of mutations of hepatocyte nuclear factor (HNF)-1 alpha gene in Chinese families with early-onset and/or multiplex diabetes mellitus. METHODS: The studied population consisted of 247 unrelated Chinese residents in Shanghai, including 93 healthy controls and 154 probands of early-onset and/or multiplex diabetes pedigrees. The ten exons, flanking introns and minimal promoter region of HNF-1 alpha gene were screened using polymerase chain reaction-single strand conformation polymorphism and DNA sequencing. RESULTS: Fourteen substitutions were identified in 154 probands. Three variants were not observed in 93 healthy controls. Two of them (nt-128T-->G IVS2 nt+21G-->A) were not reported previously and all co-segregated with diabetes. The genotype and allele frequencies of the other eleven variants in the diabetic patients were not significantly different from those in the healthy controls. There were no significant relationships between the eleven variants of HNF-1 alpha gene and clinical variables (plasma glucose, insulin, C-peptide and fasting lipid profile). CONCLUSION: HNF-1 alpha gene is not a major cause of early-onset or multiplex diabetes pedigrees in this Chinese population in Shanghai.