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The trans-ancestral genomic architecture of glycemic traits.
Chen, J, Spracklen, CN, Marenne, G, Varshney, A, Corbin, LJ, Luan, J, Willems, SM, Wu, Y, Zhang, X, Horikoshi, M, et al
Nature genetics. 2021;(6):840-860
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Abstract
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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Rationale, Design, and Baseline Characteristics of Beijing Prediabetes Reversion Program: A Randomized Controlled Clinical Trial to Evaluate the Efficacy of Lifestyle Intervention and/or Pioglitazone in Reversion to Normal Glucose Tolerance in Prediabetes.
Luo, Y, Paul, SK, Zhou, X, Chang, C, Chen, W, Guo, X, Yang, J, Ji, L, Wang, H
Journal of diabetes research. 2017;:7602408
Abstract
Background. Patients with prediabetes are at high risk for diabetes and cardiovascular disease (CVD). No study has explored whether intervention could revert prediabetes to normal glycemic status as the primary outcome. Beijing Prediabetes Reversion Program (BPRP) would evaluate whether intensive lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia and improve the risk factors of CVD as well. Methods. BPRP is a randomized, multicenter, 2 × 2 factorial design study. Participants diagnosed as prediabetes were randomized into four groups (conventional/intensive lifestyle intervention and 30 mg pioglitazone/placebo) with a three-year follow-up. The primary endpoint was conversion into normal glucose tolerance. The trial would recruit 2000 participants (500 in each arm). Results. Between March 2007 and March 2011, 1945 participants were randomized. At baseline, the individuals were 53 ± 10 years old, with median BMI 26.0 (23.9, 28.2) kg/m2 and HbA1c 5.8 (5.6, 6.1)%. 85% of the participants had IGT and 15% had IFG. Parameters relevant to glucose, lipids, blood pressure, lifestyle, and other metabolic markers were similar between conventional and intensive lifestyle intervention group at baseline. Conclusion. BPRP was the first study to determine if lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia in Chinese population. Major baseline parameters were balanced between two lifestyle intervention groups. This trial is registered with www.chictr.org.cn: ChiCTR-PRC-06000005.
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The characteristics of newly diagnosed adult early-onset diabetes: a population-based cross-sectional study.
Zou, X, Zhou, X, Ji, L, Yang, W, Lu, J, Weng, J, Jia, W, Shan, Z, Liu, J, Tian, H, et al
Scientific reports. 2017;:46534
Abstract
To investigate the characteristics of newly diagnosed early-onset diabetes in the Chinese population, 2801 newly diagnosed diabetes participants without known diabetes or pre-diabetes in a national cross-sectional survey were analysed. Participants were divided into quartiles (22-43, 44-52, 53-61 and >61 years) according to age of diabetes onset and the first group were defined as early-onset diabetes group. Early-onset diabetes group had lower systolic blood pressure (SBP), total cholesterol, low density lipoprotein cholesterol, 2-hour post prandial blood glucose and urine albumin creatinine ratio. There was no difference in body mass index, Homeostasis model assessment (HOMA) of beta cell function and diabetes family history between early-onset diabetes participants and any other age groups. HOMA of insulin resistance (IR) scores and disposition index 30 minutes after glucose load (DI30) were increased in early-onset diabetes participants. The beta cell function declination was more deteriorated in early-onset diabetes participants. Male gender, triglycerides, HOMA-IR and DI30 were positively associated with an earlier age at diagnosis. In conclusion, patients diagnosed with diabetes at a younger age are characterized by a similar cardiovascular risk profile with increased insulin resistance and more severe beta cell failure than patients diagnosed at a later age.
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Prediction of the 20-year incidence of diabetes in older Chinese: Application of the competing risk method in a longitudinal study.
Liu, X, Fine, JP, Chen, Z, Liu, L, Li, X, Wang, A, Guo, J, Tao, L, Mahara, G, Tang, Z, et al
Medicine. 2016;(40):e5057
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Abstract
The competing risk method has become more acceptable for time-to-event data analysis because of its advantage over the standard Cox model in accounting for competing events in the risk set. This study aimed to construct a prediction model for diabetes using a subdistribution hazards model.We prospectively followed 1857 community residents who were aged ≥ 55 years, free of diabetes at baseline examination from August 1992 to December 2012. Diabetes was defined as a self-reported history of diabetes diagnosis, taking antidiabetic medicine, or having fasting plasma glucose (FPG) ≥ 7.0 mmol/L. A questionnaire was used to measure diabetes risk factors, including dietary habits, lifestyle, psychological factors, cognitive function, and physical condition. Gray test and a subdistribution hazards model were used to construct a prediction algorithm for 20-year risk of diabetes. Receiver operating characteristic (ROC) curves, bootstrap cross-validated Wolber concordance index (C-index) statistics, and calibration plots were used to assess model performance.During the 20-year follow-up period, 144 cases were documented for diabetes incidence with a median follow-up of 10.9 years (interquartile range: 8.0-15.3 years). The cumulative incidence function of 20-year diabetes incidence was 11.60% after adjusting for the competing risk of nondiabetes death. Gray test showed that body mass index, FPG, self-rated heath status, and physical activity were associated with the cumulative incidence function of diabetes after adjusting for age. Finally, 5 standard risk factors (poor self-rated health status [subdistribution hazard ratio (SHR) = 1.73, P = 0.005], less physical activity [SHR = 1.39, P = 0.047], 55-65 years old [SHR = 4.37, P < 0.001], overweight [SHR = 2.15, P < 0.001] or obesity [SHR = 1.96, P = 0.003], and impaired fasting glucose [IFG] [SHR = 1.99, P < 0.001]) were significantly associated with incident diabetes. Model performance was moderate to excellent, as indicated by its bootstrap cross-validated discrimination C-index (0.74, 95% CI: 0.70-0.79) and calibration plot.Poor self-rated health, physical inactivity, being 55 to 65 years of age, overweight/obesity, and IFG were significant predictors of incident diabetes. Early prevention with a goal of achieving optimal levels of all risk factors should become a key element of diabetes prevention.
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The changing relationship between HbA1c and FPG according to different FPG ranges.
Guan, X, Zheng, L, Sun, G, Guo, X, Li, Y, Song, H, Tian, F, Sun, Y
Journal of endocrinological investigation. 2016;(5):523-8
Abstract
PURPOSE Since the American Diabetes Association included hemoglobin A1c (HbA1c) in the diagnostic criteria for diabetes in 2010, the clinical use of HbA1c has remained controversial. We explored the use of HbA1c for diagnosing diabetes and intermediate hyperglycemia in comparison with fasting plasma glucose (FPG). METHODS We screened 3710 adult subjects (mean age = 55.24 years) comprising 1704 males and 2006 females. We drew an receiver operating characteristic (ROC) curve to evaluate the ability of HbA1c to diagnose diabetes and intermediate hyperglycemia according to FPG. We used Kappa coefficient and Pearson's correlation coefficient to evaluate the relationship between HbA1c and FPG in different FPG ranges. RESULTS The areas under ROC curve to diagnose diabetes and intermediate hyperglycemia were 0.859 (95 % CI 0.827-0.892) and 0.633 (95 % CI 0.615-0.651). The kappa coefficients between FPG and HbA1c for diagnosis of diabetes and intermediate hyperglycemia were 0.601 (P < 0.001) and 0.104 (P < 0.001). The Pearson's correlation coefficient of FPG and HbA1c was 0.640 (P < 0.001), but when we classified FPG as normal, intermediate hyperglycemia and diabetes, the coefficients became 0.07 (P = 0.002), 0.185 (P < 0.001) and 0.760 (P < 0.001), respectively. CONCLUSIONS The relationship between HbA1c and FPG changed according to the different FPG ranges. When FPG was higher, the relationship was stronger. HbA1c and FPG were highly consistent in diagnosing diabetes, but they were not in predicting intermediate hyperglycemia.
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Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.
Liu, CT, Raghavan, S, Maruthur, N, Kabagambe, EK, Hong, J, Ng, MC, Hivert, MF, Lu, Y, An, P, Bentley, AR, et al
American journal of human genetics. 2016;(1):56-75
Abstract
Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.
Wessel, J, Chu, AY, Willems, SM, Wang, S, Yaghootkar, H, Brody, JA, Dauriz, M, Hivert, MF, Raghavan, S, Lipovich, L, et al
Nature communications. 2015;:5897
Abstract
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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Prevalence of cardiovascular disease and risk factors in the Chinese population with impaired glucose regulation: the 2007-2008 China national diabetes and metabolic disorders study.
Yang, Z, Xing, X, Xiao, J, Lu, J, Weng, J, Jia, W, Ji, L, Shan, Z, Liu, J, Tian, H, et al
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2013;(6):372-4
Abstract
Cardiovascular disease (CVD) is one of the most common chronic diseases in China. This aim of this study is to determine the prevalence of CVDs and risk factors in Chinese impaired glucose regulation subjects.We used a multistage, stratified sampling method to select subjects from the general Chinese population aged 20 years and older. Subjects underwent an oral glucose tolerance test to identify normal glucose tolerance (NGT) and impaired glucose regulation including isolated impaired fasting glucose (i-IFG), impaired glucose tolerance (i-IGT), and combined IFG/IGT and diabetic mellitus (DM). A logistic regression analysis was performed to examine the association between glucose abnormalities and CVD events.We identified that 34 293 subjects had NGT, 1 469 i-IFG, 4 571 i-IGT, 957 IFG/IGT and 4 949 DM. The age-sex standardized prevalence rate of cardiovascular disease was 1.06% (95% CI 0.87-1.28), 1.79% (95% CI 1.37-2.33) and 3.83% (95% CI 2.79-5.24) in NGT, impaired glucose regulation and DM, respectively. Among impaired glucose subjects, prevalence of defined CVD risk factors (smoking, overweight, obesity, hypertension and dyslipidemia) was 29.52% (95% CI: 27.8-31.21), 36.25% (95% CI: 34.29-38.26), 10.05% (95% CI: 8.86-11.37), 36.43% (95% CI: 34.53-38.36) and 69.96% (95% CI: 67.87-71.98), respectively. Compared to 1 risk factor, the odds ratios (ORs) of CVDs with 2, 3 or 4 risk factors were 1.94 (95% CI: 0.74-5.09), 2.76 (95% CI: 1.06-7.21) and 5.84 (95% CI: 1.68-20.26), respectively. Additionally, compared to i-IFGs, ORs of CVDs with i-IGT and IFG/IGT were 2.88 (95%CI 1.36-6.01) and 2.12 (95% CI 0.83-5.44), respectively.The prevalence of cardiovascular risk factors was high in the Chinese impaired glucose regulation population. The postprandial hyperglycemia is more associated with CVD than isolated fasting hyperglycemia.
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Impact of baseline BMI on glycemic control and weight change with metformin monotherapy in Chinese type 2 diabetes patients: phase IV open-label trial.
Ji, L, Li, H, Guo, X, Li, Y, Hu, R, Zhu, Z
PloS one. 2013;(2):e57222
Abstract
BACKGROUND Differences exist between treatment recommendations regarding the choice of metformin as first-line therapy for type 2 diabetes patients according to body mass index (BMI). This study compared the efficacy of metformin monotherapy among normal-weight, overweight, and obese patients with newly diagnosed type 2 diabetes. METHODS In this prospective, multicenter, open-label study in China, patients aged 23-77 years were enrolled 1∶1:1 according to baseline BMI: normal-weight (BMI 18.5-23.9 kg/m(2); n = 125); overweight (BMI 24.0-27.9 kg/m(2); n = 122) or obese (BMI ≥28 kg/m(2); n = 124). Extended-release metformin was administered for 16 weeks (500 mg/day, up-titrated weekly to a maximum 2,000 mg/day). The primary efficacy endpoint was the effect of baseline BMI on glycemic control with metformin monotherapy, measured as the change from baseline in glycosylated hemoglobin (HbA1c) at week 16 compared among BMI groups using ANCOVA. Other endpoints included comparisons of metformin's effects on fasting plasma glucose (FPG), lipid levels and body weight. RESULTS Mean HbA1c decreases at week 16, adjusted for baseline values, were -1.84%, -1.78% and -1.78% in normal-weight, overweight and obese patients, (P = 0.664); body weight decreased by 2.4%, 3.9% and 3.5%, respectively. FPG levels decreased similarly over time in all BMI groups (P = 0.461) and changes from baseline in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) did not differ significantly among BMI groups at week 16 (P = 0.143 and 0.451, respectively). CONCLUSIONS Baseline BMI had no impact on glycemic control, weight change or other efficacy measures with metformin monotherapy. These data suggest that normal-weight type 2 diabetes patients would derive the same benefits from first-line treatment with metformin as overweight and obese patients, and are not at increased risk of excess weight loss. TRIAL REGISTRATION ClinicalTrials.gov NCT00778622.