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  • American Diabetes Association  (5)
  • Lee, Heung Man  (5)
  • 1
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    Online Resource
    Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes
    American Diabetes Association ; 2023
    In:  Diabetes Care Vol. 46, No. 6 ( 2023-06-01), p. 1271-1281
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 46, No. 6 ( 2023-06-01), p. 1271-1281
    Abstract: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications. RESEARCH DESIGN AND METHODS We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442–547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases. RESULTS We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13–1.30]; P = 2.4 × 10−8) and BP (β ± SE 0.130 ± 0.017; P = 4.1 × 10−14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10−4). Patients with CC genotype of rs10171703 had & gt;40% reduction in either cardiovascular events in response to BP control (2.9 × 10−8 & lt; P & lt; 3.6 × 10−5), those with CT genotype had no difference (0.0726 & lt; P & lt; 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10−3). CONCLUSIONS We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc22-2331
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 2
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    A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. 7 ( 2018-07-01), p. 1414-1427
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. 7 ( 2018-07-01), p. 1414-1427
    Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db17-0914
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 80085-5
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  • 3
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    Shortened Leukocyte Telomere Length Is Associated With Glycemic Progression in Type 2 Diabetes: A Prospective and Mendelian Randomization Analysis
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 3 ( 2022-03-01), p. 701-709
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 3 ( 2022-03-01), p. 701-709
    Abstract: Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and the risk of glycemic progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin. RESULTS The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 ± 1.16 vs. 4.69 ± 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio [95% CI] for each unit decrease [to ∼0.2 kilobases] : 1.10 [1.06–1.14]), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (β = −0.05 [−0.06 to −0.04] ). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35–2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12–1.70). CONCLUSIONS Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 0149-5992
    URL: Article
    DOI: 10.2337/dc21-1609
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
    detail.hit.zdb_id: 441231-X
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  • 4
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    Shortened Relative Leukocyte Telomere Length Is Associated With Prevalent and Incident Cardiovascular Complications in Type 2 Diabetes: Analysis From the Hong Kong Diabetes Register
    American Diabetes Association ; 2020
    In:  Diabetes Care Vol. 43, No. 9 ( 2020-09-01), p. 2257-2265
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 43, No. 9 ( 2020-09-01), p. 2257-2265
    Abstract: Several studies support potential links between relative leukocyte telomere length (rLTL), a biomarker of biological aging, and type 2 diabetes. This study investigates relationships between rLTL and incident cardiovascular disease (CVD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Consecutive Chinese patients with type 2 diabetes (N = 5,349) from the Hong Kong Diabetes Register for whom DNA obtained at baseline was stored and follow-up data were available were studied. rLTL was measured by using quantitative PCR. CVD was diagnosed on the basis of ICD-9 code. RESULTS Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all P & lt; 0.001). Subjects with CVD at baseline had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than did subjects without CVD (4.6 ± 1.2 ΔΔCt) (P & lt; 0.001). Of the 4,541 CVD-free subjects at baseline, the 1,140 who developed CVD during follow-up had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than those who remained CVD-free after adjusting for age, sex, smoking, and albuminuria status (4.7 ± 1.2 ΔΔCt) (P & lt; 0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (for each unit decrease, hazard ratio 1.252 [95% CI 1.195–1.311], P & lt; 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA1c, eGFR, and ACR (hazard ratio 1.141 [95% CI 1.084–1.200], P & lt; 0.001). CONCLUSIONS rLTL is significantly shorter in patients with type 2 diabetes and CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in patients with type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc20-0028
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
    detail.hit.zdb_id: 1490520-6
    detail.hit.zdb_id: 441231-X
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  • 5
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    Low HDL Cholesterol, Metformin Use, and Cancer Risk in Type 2 Diabetes
    American Diabetes Association ; 2011
    In:  Diabetes Care Vol. 34, No. 2 ( 2011-02-01), p. 375-380
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 34, No. 2 ( 2011-02-01), p. 375-380
    Abstract: The AMP-activated protein kinase (AMPK) pathway is a master regulator in energy metabolism and may be related to cancer. In type 2 diabetes, low HDL cholesterol predicts cancer, whereas metformin usage is associated with reduced cancer risk. Both metformin and apolipoprotein A1 activate the AMPK signaling pathway. We hypothesize that the anticancer effects of metformin may be particularly evident in type 2 diabetic patients with low HDL cholesterol. RESEARCH DESIGN AND METHODS In a consecutive cohort of 2,658 Chinese type 2 diabetic patients enrolled in the study between 1996 and 2005, who were free of cancer and not using metformin at enrollment or during 2.5 years before enrollment and who were followed until 2005, we measured biological interactions for cancer risk using relative excess risk as a result of interaction (RERI) and attributable proportion (AP) as a result of interaction. A statistically significant RERI & gt;0 or AP & gt;0 indicates biological interaction. RESULTS During 13,808 person-years of follow-up (median 5.51 years), 129 patients developed cancer. HDL cholesterol & lt;1.0 mmol/L was associated with increased cancer risk among those who did not use metformin, but the association was not significant among those who did. Use of metformin was associated with reduced cancer risk in patients with HDL cholesterol & lt;1.0 mmol/L and, to a lesser extent, in patients with HDL cholesterol ≥1.0 mmol/L. HDL cholesterol & lt;1.0 mmol/L plus nonuse of metformin was associated with an adjusted hazard ratio of 5.75 (95% CI 3.03–10.90) compared with HDL cholesterol ≥1.0 mmol/L plus use of metformin, with a significant interaction (AP 0.44 [95% CI 0.11–0.78]). CONCLUSIONS The anticancer effect of metformin was most evident in type 2 diabetic patients with low HDL cholesterol.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc10-1509
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2011
    detail.hit.zdb_id: 1490520-6
    detail.hit.zdb_id: 441231-X
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