Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.

AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource.

AIMS/HYPOTHESIS: Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs. METHODS: We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ± 250 kb around each EuA SNP in AfAs. RESULTS: Allele frequency differences ranged from 0.6% to 54%. F(st) exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 × 10(-8); MTNR1B, p = 8.5 × 10(-9); and FADS1, p = 2.2 × 10(-4)) or FI (GCKR, p = 5.9 × 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r(2) <0.2), suggesting allelic heterogeneity for association with FG at these loci. CONCLUSIONS/INTERPRETATION: Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.

Implication of European-derived adiposity loci in African Americans.

OBJECTIVE: Recent genome-wide association studies (GWAS) have identified multiple novel loci associated with adiposity in European-derived study populations. Limited study of these loci has been reported in African Americans. Here we examined the effects of these previously identified adiposity loci in African Americans. METHODS: A total of 46 representative single-nucleotide polymorphisms (SNPs) in 19 loci that were previously reported in GWAS in Europeans (including FTO and MC4R) were genotyped in 4992 subjects from six African-American cohorts. These SNPs were tested for association with body mass index (BMI) after adjustment for age, gender, disease status and population structure in each cohort. Meta-analysis was conducted to combine the results. RESULTS: Meta-analysis of 4992 subjects revealed seven SNPs near four loci, including NEGR1, TMEM18, SH2B1 /ATP2A1 and MC4R, showing significant association at 0.005

Independent predictive roles of eotaxin Ala23Thr, paraoxonase 2 Ser311Cys and beta-adrenergic receptor Trp64Arg polymorphisms on cardiac disease in Type 2 Diabetes--an 8-year prospective cohort analysis of 1297 patients.

AIMS: To examine the independent and joint effects of multiple genetic variants on a cardiac end-point in an 8-year prospective study of a Chinese diabetic cohort. METHODS: Seventy-seven single nucleotide polymorphisms (SNPs) of 53 candidate genes for inflammation, thrombosis, vascular tone regulation and lipid metabolism were genotyped in 1297 Chinese patients with no prior history of coronary heart disease (CHD) or heart failure at baseline. Cardiac end-point was defined by the occurrence of CHD and/or heart failure. RESULTS: In Cox regression model, after adjustment for baseline confounding variables including age, sex, smoking status, duration of diabetes, glycaemic control, lipid levels, waist circumference, blood pressure, albuminuria and estimated glomerular filtration rate, genetic variants, including Ala/Ala of SCYA11 (eotaxin) Ala23Thr, Cys/Cys or Cys/Ser of PON2 (paraoxonase 2) Ser311Cys and Arg/Arg of ADRB3 (beta3-adrenergic receptor) Trp64Arg, were independently associated with incident cardiac end-point, with respective hazard ratios (95% confidence interval) of 1.70 (1.10-2.61, P=0.037), 1.42 (1.08-1.88, P=0.013) and 3.84 (1.18-12.50, P=0.025). Analysis of the joint effect of the risk alleles showed significant increased risk of the cardiac end-point with increasing number of risk alleles (P<0.001). The adjusted risk for the cardiac end-point was 4.11 (P=0.002) for patients carrying four risk alleles compared with those carrying one or no risk allele. CONCLUSIONS: The independent risk conferred by genetic variants encoding pathways such as inflammation and lipid metabolism, not adequately reflected by conventional biomarkers, may identify high-risk individuals for intensified control of modifiable risk factors.

Association of the POU class 2 homeobox 1 gene (POU2F1) with susceptibility to Type 2 diabetes in Chinese populations.

AIMS: POU class 2 homeobox 1 (POU2F1), also known as octamer-binding transcription factor-1 (OCT-1), is a ubiquitous transcription factor that plays a key role in the regulation of genes related to inflammation and cell cycles. POU2F1 is located on chromosome 1q24, a region with linkage for Type 2 diabetes in Chinese and other populations. We examined the association of POU2F1 genetic variants with Type 2 diabetes in Hong Kong Chinese using two independent cohorts. METHODS: We genotyped five haplotype-tagging single nucleotide polymorphisms at POU2F1 in 1378 clinic-based patients with Type 2 diabetes and 601 control subjects, as well as 707 members from 179 families with diabetes. RESULTS: We found significant associations of rs4657652, rs7532692, rs10918682 and rs3767434 (OR = 1.26-1.59, 0.0003 < P(unadjusted) < 0.035) with Type 2 diabetes in the clinic-based case-control cohorts. Rs3767434 was also associated with Type 2 diabetes (OR = 1.55, P(unadjusted) = 0.013) in the family-based cohort. Meta-analysis revealed similar associations. In addition, the risk G allele of rs10918682 showed increased usage of insulin treatment during a mean follow-up period of 7 years [hazard ratio = 1.50 (1.05-2.14), P = 0.025]. CONCLUSIONS: Using separate cohorts, we observed consistent results showing the contribution of multiple variants at POU2F1 to the risk of Type 2 diabetes.

Phenotype-genotype interactions on renal function in type 2 diabetes: an analysis using structural equation modelling.

AIMS/HYPOTHESIS: Cardiovascular and renal diseases share common risk factors. We used structural equation modelling (SEM) to evaluate the independent and combined effects of phenotypes and genotypes implicated in cardiovascular diseases on renal function in type 2 diabetes. METHODS: 1,188 type 2 diabetic patients were stratified into high-risk and low-risk groups according to bimodal distributions of the logarithmically transformed (log(e)) urinary albumin:creatinine ratio and plasma creatinine levels. Models for these groups, comprising continuous and non-ranking categorical data, were developed separately to evaluate the inter-relationships among measured variables and latent factors using non-linear SEMs, Bayesian estimation and model selection as assessed by a goodness-of-fit statistic. RESULTS: Inter-correlated measured variables (obesity, glycaemia, lipid, blood pressure) and variants of the genes encoding endothelial nitric oxide synthase (NOS), beta-adrenergic receptor (ADRB), components of the renin-angiotensin system (RAS) and lipid metabolism were loaded onto their respective latent factors of phenotypes and genotypes. In addition to direct and indirect effects, latent factors of obesity, lipid and BP interacted with latent factors of ADRB and RAS genotypes to influence renal function. Together with variants of the genes encoding peroxisome proliferator-activated receptor gamma, atrial natriuretic peptide, adducin, G protein beta(3) subunit, epithelial sodium channel alpha subunit and matrix metallopeptidase 3, these parameters explained 39-80% of the variance in renal function in the high-risk and low-risk models. CONCLUSIONS/INTERPRETATION: SEM is a useful tool for confirming and quantifying multiple interactions of biological pathways with genetic determinants. The combined and interactive effects of blood pressure, lipid and obesity on renal function may have therapeutic implications, especially in type 2 diabetic individuals with genetic risk factors.

Associations of insulin-like growth factor binding protein-3 gene polymorphisms with IGF-I activity and lipid parameters in adolescents.

OBJECTIVE: Childhood obesity is a growing global epidemic. Recent studies indicate that obesity and related metabolic traits are highly heritable. Increasing evidence suggests that growth hormone (GH) and the insulin-like growth factor-I (IGF-I) axis have important functions in regulating adiposity and insulin sensitivity. Five single-nucleotide polymorphisms (SNPs) at IGF-binding protein-3 (IGFBP3) were genotyped to find their associations with IGF-1 activity level and common clinical metabolic traits. PATIENTS AND METHODS: We examined the associations of five SNPs at IGFBP3 with serum IGF-I and IGFBP-3 levels, as well as with obesity-related metabolic traits in 981 Hong Kong Chinese adolescents. Factor analysis was used to reduce the intercorrelated variables to five factor scores indicating body composition, blood pressure, IGF-I activity, triglyceride (TG)+high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC)+low-density lipoprotein cholesterol (LDL-C) factor scores. RESULTS: There was a strong association between the -202A/C polymorphism (rs2854744) and IGF-I activity (P=1.2 x 10(-6)) and TC+LDL-C factor scores (P=0.0085), corrected for age and sex. The C allele was associated with decreased IGFBP-3 levels (P=1.21 x 10(-13)), increased IGF-I/IGFBP-3 molar ratio (P=5.22 x 10(-6)) and decreased LDL-C (P=0.020). There was also a significant association between a G/A polymorphism at the 3' flanking sequence (rs13223993) of the IGFBP3 gene and the TG+HDL-C factor score (P=0.0013). The minor A allele carriers of rs13223993 had a lower HDL-C (P=0.0067) level and a tendency toward a high TG level. Haplotype analysis did not increase the significance of associations between single SNPs and phenotypes. CONCLUSION: Our results support the function of IGFBP3 gene polymorphisms in modulating IGF-I activity and lipid levels in adolescents. Given the prognostic significance of IGF-I, IGFBPs and lipids on risk of diabetes, obesity and cancer, long-term studies are required to clarify the clinical meaning of these findings.

Asthma and atopy are associated with chromosome 17q21 markers in Chinese children.

BACKGROUND: Single-nucleotide polymorphism (SNP)-based genome-wide association study revealed that markers on chromosome 17q21 were linked to childhood asthma but not atopy in Caucasians, with the strongest signal being detected for the SNP rs7216389 in the ORMDL3 gene. Such association was unknown in Chinese. This study delineated the allele and genotype frequencies of 10 SNPs at chromosome 17q21, and investigated the relationship between these SNPs and asthma and plasma IgE in southern Chinese children. METHODS: Asthmatic children and non-allergic controls were recruited from pediatric clinics. Their plasma total and aeroallergen-specific IgE concentrations were measured by immunoassay. Ten SNPs on 17q21 region were genotyped by multiplex SNaPshot, and their genotype associations with asthma traits analyzed using multivariate regression. RESULTS: 315 patients and 192 controls were enrolled. The allele frequency for C allele of rs7216389 varied significantly from 0.232 in our controls, 0.389 in Han Chinese to 0.536 in Caucasians. Asthma diagnosis was associated with rs11650680 and five other SNPs including rs7216389 (P = 0.019-0.034), whereas atopy was associated only with rs11650680 (P = 0.0004). Linear regression revealed the covariates for plasma total IgE to be significant for rs11650680 (P = 0.008-0.0002). Haplotypic associations were found with atopy and increased plasma total IgE, with the respective odds ratios and 95% confidence intervals for TTTCCGTT haplotype to be 0.21 and 0.09-0.52 (P = 0.0002) and 0.41 and 0.18-0.90 (P = 0.025). CONCLUSION: Childhood asthma and atopy are associated with chromosome 17q21 in Chinese, but such association may involve genes other than ORMDL3 in this region.

Increased leptin concentrations and lack of gender difference in Type 2 diabetic patients with nephropathy.

UNLABELLED: Leptin plays an important role in the regulation of body weight and energy balance. Women have higher circulating leptin level than men. In this study, we examined serum leptin concentrations in Type 2 diabetic men and women with or without nephropathy. Fasting plasma glucose (FPG), lipid profile, and serum leptin concentrations were measured in 34 Type 2 diabetic patients with nephropathy (DMN), 12 normoalbuminuric Type 2 diabetic subjects (DM) and 34 non-diabetic control subjects, all matched for age and body mass index (BMI). RESULT: Patients with diabetic nephropathy had lower high-density lipoprotein cholesterol and higher triglyceride, FPG, urinary albumin/creatinine ratio (ACR) and serum creatinine than the other two groups. There was a significant trend in serum leptin concentrations (P<0.001, analysis of variance ANOVA) across the three groups with the main difference being detected between DMN and control subjects (DMN: 17.5 +/- 16.8 ng/ml, DM: 14.6 +/- 10.5 ng/ml and control: 9.1 +/- 7.1 ng/ml). Women had higher serum leptin concentration than men in the control group (12.5 +/- 7.3 ng/ml versus 4.2 +/- 2.0 ng/ml, P=0.001) and in the DM group (18.9 +/- 11 ng/ml versus 8.6 +/- 5.9 ng/ml, P=0.07) whereas this gender difference was not observed in the DMN group (18.6 +/- 17.0 ng/ml versus 16.8 +/- 17.0 ng/ml, P=0.754). On multivariate analysis, ACR (=0.411, P<0.001) and BMI (=0.240, P=0.002) were independently associated with serum leptin concentrations (R2=0.194, F=22.1, P<0.001) in the whole group. In the DMN group, ACR (=0.370, P=0.016) was the only independent determinant of serum leptin concentrations (R2=0.159, F=11.4, P=0.016). Serum leptin concentrations were higher in Type 2 diabetic patients with nephropathy than normoalbuminuric diabetic patients and controls. Diabetic men with nephropathy had proportionally higher serum leptin such that the gender difference in leptin observed in non-nephropathic individuals was abolished.

Interactive effect of retinopathy and macroalbuminuria on all-cause mortality, cardiovascular and renal end points in Chinese patients with Type 2 diabetes mellitus.

AIMS: To examine the effect of albuminuria and retinopathy on the risk of cardiovascular and renal events, and all-cause mortality in patients with Type 2 diabetes. METHODS: A post-hoc analysis of 4416 Chinese patients without macrovascular complications at baseline (age 57.6 +/- 13.3 years). Glomerular filtration rate (eGFR) was estimated by the abbreviated Modification of Diet in Renal Disease Study Group Formula, further adjusted for Chinese ethnicity. Clinical end points were all-cause mortality, cardiovascular events (heart failure or angina, myocardial infarction, lower limb amputation, re-vascularization procedures and stroke) and renal end points (reduction in eGFR by more than 50% or eGFR < 15 ml/min/1.73 m2 or death as a result of renal causes or need for dialysis). RESULTS: Compared with individuals without complications, subjects with retinopathy and macroalbuminuria had higher rates of cardiovascular events (14.1 vs. 2.4%), renal events (40.0 vs. 0.8%) and death (9.3 vs. 1.7%, P < 0.001). For composite event of death, cardiovascular and renal events, the presence of retinopathy, microalbuminuria alone, macroalbuminuria alone, retinopathy with microalbuminuria or retinopathy with macroalbuminuria increased the risk [hazard ratio (95% CI)] by 1.61 (1.05 to 2.47; P = 0.04), 1.93 (1.38 to 2.69; P < 0.001), 4.34 (3.02 to 6.22; P < 0.001), 2.59 [1.76 to 3.81; P < 0.001) and 6.83 (4.89 to 9.55; P < 0.001) fold, respectively. The relative excess risk as a result of interaction between retinopathy and macroalbuminuria was 15.31, implying biological interaction in the development of renal events. CONCLUSIONS: In Chinese patients with Type 2 diabetes, retinopathy interacts with macroalbuminuria to increase the risk of composite cardio-renal events.

Phenotypic and genetic clustering of diabetes and metabolic syndrome in Chinese families with type 2 diabetes mellitus.

BACKGROUND: The aim of this study was to investigate the familiality and clustering of type 2 diabetes (T2DM) and metabolic syndrome (MES) predominantly in families with young-onset diabetes from the Hong Kong Family Diabetes Study. METHODS: One hundred and seventy-nine families (913 subjects) were ascertained through a diabetic proband. Anthropometry, glucose homeostasis, blood pressure and lipid levels were examined. Familial aggregation and inter-relationships of these traits were examined by recurrence risk ratio, heritability, genetic and environmental correlations. RESULTS: One hundred and forty families (78%) had at least one subject with early-onset T2DM (age-at-diagnosis

Association of lipoprotein lipase S447X, apolipoprotein E exon 4, and apoC3 -455T>C polymorphisms on the susceptibility to diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. In DN patients, triglyceride (TG) level is elevated and lipoprotein lipase (LPL) activity, which hydrolyzes TG, is decreased. The LPL S447X and apolipoprotein E (APOE) exon 4 polymorphisms affect TG levels, and the APOC3 -455T>C polymorphism affects LPL activity. Our aim was to examine the association of these polymorphisms with nephropathy in type 2 diabetes. We examined these polymorphisms in a case-control study of type 2 diabetic patients including 374 with DN and 392 without DN. LPL 447X-containing genotypes (447X+) were significantly decreased in DN patients [18.6 vs 25.6%, odds ratio (OR) = 0.66, p = 0.02], as were APOE epsilon3/epsilon3 genotypes (64.8 vs 73.1%, OR = 0.68, p = 0.01). In addition, combinations of genotypes [APOE epsilon3/epsilon3 and LPL 447X+ (OR = 0.56), APOC3 CC and LPL 447X+ (OR = 0.31), APOE epsilon3/epsilon3 and APOC3 CC (OR = 0.61] were protective for DN compared with the most common combination of the respective polymorphisms. Our findings suggest the importance of interactions among lipid genes in modulating the risk of DN.

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes.

AIMS/HYPOTHESIS: The mechanisms by which the calpain-10 gene (CAPN10) affects the risk of type 2 diabetes are unclear. Therefore, we investigated the effects of four polymorphisms in CAPN10 (single nucleotide polymorphism [SNP]-43, SNP-44, Insertion/Deletion [Indel]-19 and SNP-63) on insulin secretion, insulin action and abdominal fat distribution in offspring of patients with type 2 diabetes. SUBJECTS AND METHODS: Insulin secretion was determined by an IVGTT, insulin action by the hyperinsulinaemic-euglycaemic clamp and abdominal fat distribution by computed tomography in 158 non-diabetic offspring (age 34.9+/-6.3 years [mean+/-SD], BMI 26.2+/-4.9 kg/m(2)) of type 2 diabetic patients. RESULTS: SNP-43 (p=0.009 over the three genotypes, adjusted for age, sex, BMI and family relationship) and haplotypes carrying the A allele of SNP-43 were associated with intra-abdominal fat area. The A allele of SNP-43 was associated with intra-abdominal fat area in men (p=0.014) but not in women. SNP-44, InDel-19 and SNP-63 were not associated with intra-abdominal fat area or insulin action. Furthermore, we demonstrated in a separate sample of middle-aged men (n=234) who had a history of type 2 diabetes in first-degree relatives that the A allele of SNP-43 was associated with a large waist circumference, and high insulin levels in an OGTT. CONCLUSIONS/INTERPRETATION: SNP-43 of CAPN10 may contribute to the risk of diabetes by regulating abdominal obesity in subjects with high risk of type 2 diabetes.

Angiotensin-converting enzyme (ACE) inhibition in type 2, diabetic patients-- interaction with ACE insertion/deletion polymorphism.

Angiotensin-converting enzyme (ACE) insertion(I)/deletion (D) polymorphism may modify the effect of inhibition of the renin-angiotensin-aldosterone system (RAAS) on survival and cardiorenal outcomes in type 2, diabetes. A consecutive cohort of 2089 Chinese type 2 diabetic patients with mean (+/- standard deviation) age of 59.7 +/- 13.1 years were genotyped for this polymorphism by polymerase chain reaction method and were followed prospectively for a median period of 44.6 (interquartile range: 23.7, 57.5) months. Clinical outcomes, including all-cause mortality, cardiovascular and renal end points, were examined. The frequency for I allele was 67.1 and 32.9% for D allele, with observed genotype frequencies of 45.8, 42.6, and 11.6% for 3, DI and DD, respectively. ACE DD polymorphism was an independent predictor for renal end point with hazard ratio (HR) (95% confidence interval) of 1.72 (1.16, 2.56), but not for cardiovascular end point or mortality. After controlling for confounding factors, including ACE I/D genotype, the usage of RAAS inhibitors was associated with reduced risk of mortality (HR 0.34 (0.23, 0.50)) and renal end point (HR 0.55 (0.40, 0.75)). On subgroup analysis, the beneficial effects on survival (II vs DI vs DD: HR 0.29 (0.16, 0.51) vs 0.25 (0.14, 0.46) vs 1.33 (0.41, 4.31)) and renoprotection (II vs DI vs DD: 0.52 (0.30, 0.90) vs 0.43 (0.25, 0.72) vs 0.95 (0.43, 2.12)) were most evident in II and DI carriers. In conclusion, inhibition of RAAS was associated with reduced risk of mortality and occurrence of renal end point in Chinese type 2 diabetic patients. These benefits were most evident among II and DI carriers.

Triglyceride predicts cardiovascular mortality and its relationship with glycaemia and obesity in Chinese type 2 diabetic patients.

BACKGROUND: To examine the lipid profile in Chinese type 2 diabetic patients and their relationship with anthropometric parameters, glycaemic control and cardiovascular mortality. METHODS: A consecutive cohort of 562 newly referred patients with type 2 diabetes to a hospital-based diabetes centre were examined in 1996. Subjects treated with lipid lowering drugs at the time of referral were excluded. A total of 517 subjects were followed up over a mean (+/-SD) period of 4.6 +/- 0.9 years. Glycated haemoglobin (HbA1c), fasting insulin and lipid profile and anthropometric parameters were documented at the time of recruitment. Cardiovascular mortality, mainly due to coronary heart disease and stroke, was ascertained using death registry and review of hospital case notes in 2001. RESULT: Of the 517 subjects (mean age of 54.0 +/- 14.0 years), 42.6% were men. In this cohort, 63.3% of subjects were either overweight (BMI > or = 23 kg/m2) or obese (BMI > or = 25 kg/m2) using Asian criteria. The mean (+/-SD) total cholesterol (TC), LDL-Cholesterol (LDL-C), HDL-Cholesterol (HDL-C) and geometric mean (x// antilog SD) of triglycerides (TG) were 5.6 +/- 1.3 mmol/L, 3.6 +/- 1.1 mmol/L, 1.3 +/- 0.3 mmol/L and 1.46x//1.90 mmol/L respectively. TC and LDL-C correlated positively with HbA1c, HDL-C negatively with BMI and WC (waist circumference), while TG positively with HbA1c, BMI, WC and HOMA (insulin resistance estimated using the homeostasis model assessment). During the 4.6 years follow-up period, there were 61 deaths giving a total mortality rate of 11.4%, of which 15 (25%) were because of cardiovascular events. Apart from age and disease duration, logarithm of TG was significantly associated with increased risk of cardiovascular mortality (p = 0.049, relative risk = 2.97, 95% CI 1.00-8.77). CONCLUSIONS: Chinese type 2 diabetic patients had a lower prevalence of obesity, lower TG and higher HDL-C than Caucasian patients. Despite the low incidence of cardiovascular death, TG, which was closely associated with obesity indexes, was significantly associated with cardiovascular death in these patients.

The linkage and association of the gene encoding upstream stimulatory factor 1 with type 2 diabetes and metabolic syndrome in the Chinese population.

AIMS/HYPOTHESIS: The transcription factor upstream stimulatory factor 1 (USF1) regulates the expression of genes involved in glucose and lipid metabolism and has been associated with familial combined hyperlipidaemia. USF1 is located on chromosome 1q22-23, a region with evidence for linkage to type 2 diabetes and various traits of the metabolic syndrome in Chinese and other populations. The aim of this study was to investigate the linkage and association of USF1 with type 2 diabetes and the metabolic syndrome in Chinese individuals. MATERIALS AND METHODS: We genotyped three haplotype-tagging single nucleotide polymorphisms (SNPs) (rs3737787, rs2516841 and rs2516839) at USF1 in three samples of the Hong Kong Chinese population, including members of 179 families from the Hong Kong Family Diabetes Study, 1,383 hospital cases with type 2 diabetes and/or the metabolic syndrome and 454 normal control subjects. RESULTS: We found significant association of individual polymorphisms and haplotypes with type 2 diabetes and/or metabolic syndrome-related traits in the family samples using either family-based or unrelated normal control subjects. However, these variants could not explain much of the evidence for linkage in this region. Moreover, they were not associated with type 2 diabetes and/or the metabolic syndrome in the hospital cases. CONCLUSIONS/INTERPRETATION: The results are consistent with the hypothesis that variation at USF1 contributes to the risk of type 2 diabetes and the metabolic syndrome in families with strong evidence for linkage in the chromosome 1q region. However, they provide little support for USF1 as the susceptibility locus that generates the observed evidence for linkage at 1q21-25 for type 2 diabetes and/or the metabolic syndrome, and USF1 does not appear to have a major contribution to these phenotypes in the general Chinese population.

The associations of body mass index, C-peptide and metabolic status in Chinese Type 2 diabetic patients.

BACKGROUND: Chinese Type 2 diabetic subjects are generally less obese than their Caucasian counterparts. We hypothesized that lean and obese Chinese Type 2 diabetic subjects have different metabolic and insulin secretory profiles. We compared the clinical features, C peptide and metabolic status between lean/normal weight and obese diabetic subjects. STUDY DESIGN: We conducted a cross-sectional study on 521 consecutive diabetic subjects newly referred to a Diabetes Clinic in 1996. The subjects were categorized into underweight (< 18.5 kg/m(2)), normal weight (18.5-23 kg/m(2)) and overweight (>/= 23 kg/m(2)) according to the re-defined WHO criterion for obesity in Asia Pacific Region. Metabolic and anthropometric parameters were compared between groups with different levels of obesity. RESULTS: In this cohort, 5.8, 30.6 and 63.7% of subjects were underweight, normal weight and overweight, respectively, using the 'Asian' criteria. Of these 521 subjects, 20% had fasting C-peptide less than 0.2 nmol/l, suggesting insulin deficiency. Fasting C-peptide showed linear increasing trend (P < 0.001) while HbA(1c) showed decreasing trend (P = 0.001) with BMI after adjustment for duration of disease. There were more subjects in the underweight group who were treated with insulin (41.3% vs. 13.9 and 8.2%, P < 0.001). Although homeostasis model assessment was similar amongst the three groups, systolic (P = 0.006) and diastolic blood pressure (P < 0.001) and triglyceride (P < 0.001) showed increasing, while HDL-C (P < 0.001) showed decreasing, trends across different BMI groups. The underweight patients had the lowest C-peptide and highest HbA(1c) while overweight patients had the highest C-peptide, blood pressure, triglyceride but lowest HbA(1c) levels. CONCLUSION: In Chinese Type 2 diabetic patients, lean subjects had predominant insulin deficiency and obese subjects had features of metabolic syndrome. Clinicians should have low threshold to initiate insulin therapy in lean Type 2 diabetic patients with suboptimal glycaemic control. In obese diabetic patients, aggressive control of multiple cardiovascular risks is of particular importance.

Effects of gender, Helicobacter pylori and hepatitis B virus serology status on cardiovascular and renal complications in Chinese type 2 diabetic patients with overt nephropathy.

BACKGROUND: The aim of this study was to investigate whether chronic infections with Helicobacter pylori and hepatitis B virus (HBV) might affect clinical outcomes in Chinese type 2 diabetic patients with advanced nephropathy. METHODS: A prospective study of 97 type 2 diabetic patients with clinical proteinuria and renal insufficiency (median serum creatinine 200 micro mol/l). RESULTS: During a median follow-up period of 2 years, 34 developed end-stage renal disease (ESRD), 28 had cardiovascular endpoints and 11 patients had died (seven men and four women), and 52.7% developed a combined endpoint. Female patients had longer disease duration, higher blood pressure, lower body weight but higher serum creatinine and spot urine albumin : creatinine ratio as well as lower haemoglobin than male patients. On logistic regression analysis, female gender (hazard ratio: 5.91, p = 0.02), negative H. pylori serology (8.39, p = 0.004), baseline serum creatinine (1.04, p = 0.001) and haemoglobin (1.86, p = 0.01) were independent predictors for ESRD. Systolic blood pressure (1.04, p = 0.003), prior treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists (3.41, p = 0.04) and positive hepatitis B surface antigen (4.88, p = 0.025) were independent predictors for cardiovascular endpoints. Female gender (7.89, p = 0.002) and baseline serum creatinine (1.05, p < 0.001) were independent predictors for combined death and cardio-renal endpoints. CONCLUSIONS: In Chinese type 2 diabetic patients with clinical proteinuria renal insufficiency, there were high rates of death and cardio-renal outcomes. Female gender, low haemoglobin and negative H. pylori serology were important predictors for ESRD, whereas chronic HBV infection was associated with increased cardiovascular risks.