Weihui Yu

Genome-wide association study identifies three novel loci for type 2 diabetes

Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.

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

Aims/hypothesisMost 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.MethodsWe 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.ResultsWe 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 (pmeta = 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 (pmeta = 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/interpretationOur 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.

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.

Effects of GCK, GCKR, G6PC2 and MTNR1B Variants on Glucose Metabolism and Insulin Secretion

Background Single nucleotide polymorphisms (SNPs) from GCK, GCKR, G6PC2 and MTNR1B were found to modulate the fasting glucose levels. The current study aimed to replicate this association in the Chinese population and further analyze their effects on biphasic insulin secretion. Methods/Principal Findings SNPs from GCK, GCKR, G6PC2 and MTNR1B were genotyped in the Shanghai Chinese, including 3,410 type 2 diabetes patients and 3,412 controls. The controls were extensively phenotyped for the traits related to glucose metabolism and insulin secretion. We replicated the association between GCK rs1799884, G6PC2 rs16856187 and MTNR1B rs10830963 and fasting glucose in our samples (p = 0.0003∼2.0×10−8). GCK rs1799884 and G6PC2 rs16856187 showed association to HOMA-β, insulinogenic index and both first- and second-phases insulin secretion (p = 0.0030∼0.0396). MTNR1B rs10830963 was associated to HOMA-β, insulinogenic index and first-phase insulin secretion (p = 0.0102∼0.0426), but not second-phase insulin secretion (p = 0.9933). Combined effect analyses showed individuals carrying more risk allele for high fasting glucose tended to have a higher glucose levels at both fasting and 2 h during OGTTs (p = 1.7×10−13 and 0.0009, respectively), as well as lower HOMA-β, insulinogenic index and both first- and second-phases insulin secretion (p = 0.0321∼1.1×10−7). Conclusions/Significance We showed that SNPs from GCK, G6PC2 and MTNR1B modulated the fasting glucose levels in the normoglycaemic population while SNPs from G6PC2 and GCKR was associated with type 2 diabetes. Moreover, we found GCK and G6PC2 genetic variants were associated to both first- and second-phases insulin secretion while MTNR1B genetic variant was associated with first-phase insulin secretion, but not second-phase insulin secretion.

Effects of KCNQ1 Polymorphisms on the Therapeutic Efficacy of Oral Antidiabetic Drugs in Chinese Patients With Type 2 Diabetes

The aim of this study was to explore the impact of KCNQ1 variants on the responses to oral antidiabetic drugs in a Chinese study population. A 48‐week randomized pharmacogenetics study compared the effects of repaglinide and rosiglitazone in 209 newly diagnosed patients with type 2 diabetes. In the repaglinide cohort, individuals who were rs2237892 TT homozygotes exhibited lower 2‐h glucose levels and significantly higher cumulative attainment rates of target 2‐h glucose levels (Plog‐rank = 0.0383) than the C allele carriers; patients with a greater number of rs2237892 C alleles showed larger augmentations in both fasting insulin and homeostasis model assessment of insulin resistance (HOMA‐IR) (P = 0.0166 and 0.0026, respectively); moreover, the rs2237895 C allele was also associated with greater increments in both fasting insulin and HOMA‐IR (P = 0.0274 and 0.0259, respectively). In contrast, only an association between rs2237897 and decrease in 2‐h glucose levels was detected in the rosiglitazone cohort (P = 0.0321). Our results indicated that KCNQ1 polymorphisms are associated with repaglinide efficacy, and might also be associated with rosiglitazone response, in Chinese patients with type 2 diabetes.

Cancer Incidence and Mortality in Patients with Type 2 Diabetes Treated with Human Insulin: A Cohort Study in Shanghai

Aim The aim was to investigate the association between human insulin and cancer incidence and mortality in Chinese patients with type 2 diabetes. Methods We recruited 8,774 insulin-naïve diabetes patients from the Shanghai Diabetes Registry (SDR). The follow-up rate was 85.4%. All subjects were divided into the insulin use cohort (n = 3,639) and the non-insulin use cohort (n = 5,135). The primary outcome was the first diagnosis of any cancer. The secondary outcome was all-cause mortality. Cox proportional hazards model was used to estimate the relative risk (RR) of cancer and mortality. Results We observed 98 cancer events in the insulin use cohort and 170 in the non-insulin use cohort. Cancer incidence rates were 78.6 and 74.3 per 10,000 patients per year in the insulin users and the non-insulin users, respectively. No significant difference in cancer risk was observed between the two cohorts (adjusted RR = 1.20, 95% CI 0.89–1.62, P = 0.228). Regarding site-specific cancers, only the risk of liver cancer was significantly higher in the insulin users compared to that in the non-insulin users (adjusted RR = 2.84, 95% CI 1.12–7.17, P = 0.028). The risks of overall mortality (adjusted RR = 1.89, 95% CI 1.47–2.43, P<0.0001) and death from cancer (adjusted RR = 2.16, 95% CI 1.39–3.35, P = 0.001) were all significantly higher in the insulin users than in the non-insulin users. Conclusion There was no excess risk of overall cancer in patients with type 2 diabetes who were treated with human insulin. However, a significantly higher risk of liver cancer was found in these patients. Moreover, insulin users showed higher risks of overall and cancer mortality. Considering that individuals treated with insulin were more likely to be advanced diabetic patients, caution should be used in interpreting these results.

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.

A variation in NOS1AP gene is associated with repaglinide efficacy on insulin resistance in type 2 diabetes of Chinese

AbstractAim:To investigate a potential association between SNP rs10494366 in the neural nitric oxide synthase adaptor protein (NOS1AP) and efficacy of repaglinide (an insulin secretagogue) in newly diagnosed Shanghai Chinese type 2 diabetes patients.Methods:A total of 104 newly diagnosed type 2 diabetes patients (69 men, 35 women) were recruited and treated with repaglinide for 24 weeks. Anthropometric measurements, clinical laboratory tests were obtained at baseline and after 24-week treatment. Genotyping was performed by sequencing.Results:The baseline value of BMI, HOMA-IR, HOMA-B, and fasting insulin level were significantly different between GG, GT, and TT genotypes (P=0.024, 0.030, 0.005, and 0.007, respectively). Carriers of TT genotype were in significant insulin resistance at baseline. After 24-week repaglinide monotherapy, the Δ value of fasting insulin (P=0.019) and HOMA-IR (P=0.011) were significantly different. TT carriers had the least insulin resistance after treatment. The mixed model analysis showed that the variation had an interaction effect with repaglinide treatment only on HOMA-IR (P=0.013).Conclusion:A common variant in rs10494366 is associated with repaglinide monotherapy efficacy on insulin resistance in newly diagnosed Shanghai Chinese type 2 diabetes patients.

Association between KCNQ1 genetic variants and obesity in Chinese patients with type 2 diabetes

Aims/hypothesisThere is evidence of overlap between susceptibility loci for type 2 diabetes and obesity. The aim of this study is to explore the association between the established type 2 diabetes locus KCNQ1 and obesity in Han Chinese.MethodsWe recruited 6,667 and 6,606 diabetic case–control samples from Shanghai and Hong Kong, respectively. Of the samples, 7.5% and 6.3% were excluded because of genotyping failure or data missing in the association analyses of rs2237892 and rs2237895 with obesity/BMI, respectively.ResultsWe found that rs2237892 was associated with lower BMI and lower incidence of overweight/obesity in diabetic patients from Hong Kong (BMI, β = −0.0060 per diabetes risk C allele for log10BMI [95% CI −0.0088, −0.0032; p = 2.83 × 10−5]; overweight/obesity, OR 0.880 for C allele [95% CI 0.807, 0.960; p = 0.004]) and in the meta-analysis of cases from the two regions (BMI, combined β = −0.0048 per C allele for log10BMI [95% CI −0.0070, −0.0026; p = 2.20 × 10−5]; overweight/obesity, combined OR 0.890 for C allele [95% CI 0.830, 0.955; p = 0.001]). rs2237895 was also related to decreased BMI (combined β = −0.0042 per diabetes risk C allele for log10BMI [95% CI −0.0062, −0.0022; p = 4.30 × 10−5]). A significant association with waist circumference was detected for rs2237892 in the pooled analyses (β = −0.0026 per C allele for log10[waist circumference] [95% CI −0.0045, −0.0007; p = 0.007]). However, neither an association with the risk of being overweight or obese nor associations with quantitive traits were detected for rs2237892 or rs2237895 in controls.ConclusionOur findings indicate that KCNQ1 is associated with obesity in Chinese patients with type 2 diabetes.

Beneficial Effects of an 8-Week, Very Low Carbohydrate Diet Intervention on Obese Subjects

Aim. To investigate the effects of weight loss during an 8-week very low carbohydrate diet (VLCD) on improvement of metabolic parameters, adipose distribution and body composition, and insulin resistance and sensitivity in Chinese obese subjects. Methods. Fifty-three healthy obese volunteers were given an 8-week VLCD. The outcomes were changes in anthropometry, body composition, metabolic profile, abdominal fat distribution, liver fat percent (LFP), and insulin resistance and sensitivity. Results. A total of 46 (86.8%) obese subjects completed the study. The VLCD caused a weight loss of -8.7 ± 0.6 kg (mean ± standard error (SE), P < 0.0001) combined with a significant improvement of metabolic profile. In both male and female, nonesterified fatty acid (NEFA) significantly decreased (-166.2 ± 47.6  μ mol/L, P = 0.001) and β -hydroxybutyric acid (BHA) increased (0.15 ± 0.06 mmol/L, P = 0.004) after eight weeks of VLCD intervention. The significant reductions in subcutaneous fat area (SFA), visceral fat area (VFA), and LFP were -66.5 ± 7.9 cm(2), -35.3 ± 3.9 cm(2), and -16.4 ± 2.4%, respectively (all P values P < 0.0001). HOMA IR and HOMA β significantly decreased while whole body insulin sensitivity index (WBISI) increased (all P values P < 0.001). Conclusion. Eight weeks of VLCD was an effective intervention in obese subjects. These beneficial effects may be associated with enhanced hepatic and whole-body lipolysis and oxidation.