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  • 1
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    Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies
    American Diabetes Association ; 2013
    In:  Diabetes Vol. 62, No. 9 ( 2013-09-01), p. 3282-3291
    Details
    In: Diabetes, American Diabetes Association, Vol. 62, No. 9 ( 2013-09-01), p. 3282-3291
    Abstract: Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks’ gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db12-1692
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2013
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  • 2
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    279-OR: Placental IGFBP1 Is Associated with Insulin Sensitivity during Pregnancy and Is an Early Biomarker for Gestational Diabetes
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: Pregnancy is associated with a profound reduction in insulin sensitivity (IS) that contributes to gestational diabetes (GDM), but the placental factors that lower IS in pregnancy are not fully known. We conducted genome-wide RNA sequencing in 450 placenta samples from a prospective pregnancy cohort (Gen3G). Participants provided plasma samples in the 1st trimester and completed 75g oral glucose tolerance tests in the late 2nd trimester, from which IS was estimated via the Matsuda index. We used regression analyses to test differential expression of 15,232 placental genes related to maternal IS, adjusting for gestational age at delivery, fetal sex, maternal age, gravidity, BMI, and 37 surrogate variables (to account for technical variability). Among the top differentially expressed genes, lower placental expression of IGFBP1 was significantly associated with lower maternal IS (P=1.7×10-4). In 837 Gen3G women, lower IGFPB1 circulating protein was strongly associated with lower IS (r=0.50, P & lt;0.001) and predicted GDM risk (1st trimester median levels: 23,884 pg/mL in no GDM vs 14,363 pg/mL in GDM, adjusted OR=0.55 [0.39-0.75] per quartile increase; P=1.5×10-4). The association between plasma IGFBP1 and IS was replicated in two pregnancy cohorts: SPRING (n=165 with GDM risk factors, r=0.54, P & lt;0.001) and MOMS (n=97 matched GDM cases and controls, r=0.55, P & lt;0.001). The association of lower plasma IGFBP1 with greater risk of GDM was replicated in SPRING (adjusted OR=0.66 per quartile increase, P=0.07) and MOMS (adjusted OR=0.45 per quartile increase, P & lt;0.001). In SPRING, plasma IGFBP1 protein were markedly elevated in the 1st and 2nd trimesters compared to postpartum (P & lt;0.001), consistent with placental origin. Our results suggest that the placenta expresses high levels of IGFBP1, which influences IGF-1 bioavailability and is released in maternal circulation to regulate IS in pregnancy, highlighting it as a promising early plasma biomarker of GDM risk. Disclosure M.Hivert: None. S.Karumanchi: None. C.E.Powe: Consultant; Mediflix, Inc., Other Relationship; Wolters Kluwer Health. F.White: None. C.Allard: None. K.James: None. S.Majid: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. A.Edlow: Consultant; Mirvie, Inc, Research Support; Merck & Co., Inc. L.Bouchard: None. P.Jacques: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD094150)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-279-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 3
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    Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. 3 ( 2020-03-01), p. 484-492
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. 3 ( 2020-03-01), p. 484-492
    Abstract: The placenta participates in maternal insulin sensitivity changes during pregnancy; however, mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75-g oral glucose tolerance tests at ∼26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using Illumina EPIC arrays. Using linear regression models to quantify associations at 720,077 cytosine-guanine dinucleotides (CpGs), with adjustment for maternal age, gravidity, smoking, BMI, child sex, and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index (P & lt; 6.94 × 10−8). Among genes annotated to these 188 CpGs, we found enrichment in targets for miRNAs, in histone modifications, and in parent-of-origin DNA methylation including the H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1. Mendelian randomization analyses revealed five loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-0798
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 4
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    193-OR: Physiology-Informed Type 2 Diabetes Genetic Clusters and Gestational Diabetes
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Background: We previously described physiology-informed genetically-anchored type 2 diabetes (T2D) clusters based on associations between glycemic traits and T2D-associated variants discovered in prior GWAS. Cluster polygenic scores (PSs) delineate T2D subtypes with distinct features (e.g., reduced beta-cell function, obesity, lipodystrophy-like). These PSs have not been tested for association with gestational diabetes (GDM). Methods: We tested for associations between PSs (beta-cell, proinsulin, lipodystrophy, obesity, liver/lipid) and traits at 24-30 weeks gestation in the Gen3G cohort (N=582, 97% white non-Hispanic) with linear regression (β=change per 1 SD increase in PS). In 3 cohorts [Gen3G, HAPO (N=1369, 100% white non-Hispanic) MGH2(N=621, 62% white non-Hispanic)], we tested for associations between PSs and GDM using logistic regression and conducted fixed effects meta-analyses. Results: The beta-cell PS was associated with higher 1-hr OGTT glucose (β=4.5 mg/dl, P & lt;0.001) and lower insulin secretory response (β=-45.7 Stumvoll 1st phase index, P=0.02). The obesity PS was associated with higher BMI (β=0.5 kg/m2, P=0.03) and HbA1c (β=0.03%, P=0.02). The lipodystrophy PS was associated with higher 1-hr OGTT glucose (β=2.6 mg/dl, P=0.03), higher fasting triglycerides (TGs) (β=6 mg/dl, P=0.01), and lower insulin sensitivity (β=-0.6 Matsuda index, P=0.005). The liver/lipid PS was associated with lower fasting TGs (β=-11 mg/dl, P & lt;0.001). In 3-cohort meta-analyses (297 cases), only the beta-cell PS was associated with GDM (OR 1.19, P=0.009). There was heterogeneity across cohorts for the liver/lipid PS-GDM association. No PS was associated with birth weight. Adjustment for maternal age and genetic principal components did not alter results. Conclusion: Clusters of T2D-associated genetic variants derived based on physiology outside of pregnancy are associated with expected traits in pregnancy. A cluster representing reduced beta-cell function is associated with GDM. Disclosure C.E. Powe: None. M. Udler: None. S. Hsu: None. A. Kuang: None. C. Allard: None. A. Manning: None. L. Bouchard: None. P. Perron: None. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. W. Lowe: None. D. Scholtens: None. M. Hivert: None. Funding American Diabetes Association (1-15-ACE-26 to M-F.H.); National Institutes of Health (K23DK113218); Robert Wood Johnson Foundation; Harold Amos Medical Faculty Development Award (72456)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-193-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 5
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    Plasma Proteomic Risk Markers of Incident Type 2 Diabetes Reflect Physiologically Distinct Components of Glucose-Insulin Homeostasis
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. 5 ( 2023-05-01), p. 666-673
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. 5 ( 2023-05-01), p. 666-673
    Abstract: High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including β-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. Article Highlights Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-0628
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 6
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    Genetic Determinants of Glycemic Traits and the Risk of Gestational Diabetes Mellitus
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. 12 ( 2018-12-01), p. 2703-2709
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. 12 ( 2018-12-01), p. 2703-2709
    Abstract: Many common genetic polymorphisms are associated with glycemic traits and type 2 diabetes (T2D), but knowledge about genetic determinants of glycemic traits in pregnancy is limited. We tested genetic variants known to be associated with glycemic traits and T2D in the general population for associations with glycemic traits in pregnancy and gestational diabetes mellitus (GDM). Participants in two cohorts (Genetics of Glucose regulation in Gestation and Growth [Gen3G] and Hyperglycemia and Adverse Pregnancy Outcome [HAPO]) underwent oral glucose tolerance testing at 24–32 weeks’ gestation. We built genetic risk scores (GRSs) for elevated fasting glucose and insulin, reduced insulin secretion and sensitivity, and T2D, using variants discovered in studies of nonpregnant individuals. We tested for associations between these GRSs, glycemic traits in pregnancy, and GDM. In both cohorts, the fasting glucose GRS was strongly associated with fasting glucose. The insulin secretion and sensitivity GRSs were also significantly associated with these traits in Gen3G, where insulin measurements were available. The fasting insulin GRS was weakly associated with fasting insulin (Gen3G) or C-peptide (HAPO). In HAPO (207 GDM case subjects), all five GRSs (T2D, fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity) were significantly associated with GDM. In Gen3G (43 GDM case subjects), both the T2D and insulin secretion GRSs were associated with GDM; effect sizes for the other GRSs were similar to those in HAPO. Thus, despite the profound changes in glycemic physiology during pregnancy, genetic determinants of fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity discovered outside of pregnancy influence GDM risk.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-0203
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 7
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    Genetic Loci and Physiologic Pathways Involved in Gestational Diabetes Mellitus Implicated Through Clustering
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. 1 ( 2021-01-01), p. 268-281
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. 1 ( 2021-01-01), p. 268-281
    Abstract: Hundreds of common genetic variants acting through distinguishable physiologic pathways influence the risk of type 2 diabetes (T2D). It is unknown to what extent the physiology underlying gestational diabetes mellitus (GDM) is distinct from that underlying T2D. In this study of & gt;5,000 pregnant women from three cohorts, we aimed to identify physiologically related groups of maternal variants associated with GDM using two complementary approaches that were based on Bayesian nonnegative matrix factorization (bNMF) clustering. First, we tested five bNMF clusters of maternal T2D-associated variants grouped on the basis of physiology outside of pregnancy for association with GDM. We found that cluster polygenic scores representing genetic determinants of reduced β-cell function and abnormal hepatic lipid metabolism were associated with GDM; these clusters were not associated with infant birth weight. Second, we derived bNMF clusters of maternal variants on the basis of pregnancy physiology and tested these clusters for association with GDM. We identified a cluster that was strongly associated with GDM as well as associated with higher infant birth weight. The effect size for this cluster’s association with GDM appeared greater than that for T2D. Our findings imply that the genetic and physiologic pathways that lead to GDM differ, at least in part, from those that lead to T2D.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-0772
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 8
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    Heterogeneous Contribution of Insulin Sensitivity and Secretion Defects to Gestational Diabetes Mellitus
    American Diabetes Association ; 2016
    In:  Diabetes Care Vol. 39, No. 6 ( 2016-06-01), p. 1052-1055
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 39, No. 6 ( 2016-06-01), p. 1052-1055
    Abstract: To characterize physiologic subtypes of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS Insulin sensitivity and secretion were estimated in 809 women at 24–30 weeks' gestation, using oral glucose tolerance test–based indices. In women with GDM (8.3%), defects in insulin sensitivity or secretion were defined below the 25th percentile in women with normal glucose tolerance (NGT). GDM subtypes were defined based on the defect(s) present. RESULTS Relative to women with NGT, women with predominant insulin sensitivity defects (51% of GDM) had higher BMI and fasting glucose, larger infants (birth weight z score 0.57 [−0.01 to 1.37] vs. 0.03 [−0.53 to 0.52] , P = 0.001), and greater risk of GDM-associated adverse outcomes (57.6 vs. 28.2%, P = 0.003); differences were independent of BMI. Women with predominant insulin secretion defects (30% of GDM) had BMI, fasting glucose, infant birth weights, and risk of adverse outcomes similar to those in women with NGT. CONCLUSIONS Heterogeneity of physiologic processes underlying hyperglycemia exists among women with GDM. GDM with impaired insulin sensitivity confers a greater risk of adverse outcomes.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc15-2672
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2016
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  • 9
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    354-OR: Physiologic Pathways in Pregnancy Glycemic Regulation Implicated through Genetic Clustering Analysis
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Background: Genetic determinants of glycemic regulation in pregnancy are poorly understood. Methods: We studied 35 glycemia-related traits measured during pregnancy and 191 genetic variants identified in prior genome-wide association studies of type 2 diabetes (T2D) or gestational glycemia. Using linear regression, we quantified associations between glucose-raising alleles and traits measured in 582 women at 24-28 weeks gestation. We clustered traits and variants using Bayesian nonnegative matrix factorization (bNMF) to identify physiologic pathways involved in pregnancy glucose metabolism. Results: In a plurality of bNMF iterations (22/50), 5 clusters emerged, with highly weighted traits and loci suggesting distinct physiologic pathways. Cluster 1: reduced insulin secretory response (lower insulin/c-peptide, greater insulin sensitivity); loci included several known or suspected to affect beta-cell function (ABO, CDKN2B, SLC30A8, CDKN1B). Cluster 2: obesity-related hyperglycemia (higher percent body fat, BMI, fasting/post-load glucose); loci included known obesity/T2D loci (MCR4, FTO) and loci previously tied to beta-cell function that associated with higher glucose and greater adiposity pregnant women (MTNR1B, GLP2R). Cluster 3: insulin resistance (reduced insulin sensitivity, higher fasting insulin/c-peptide, greater insulin secretory response); loci included LYPLAL1 and ANKRD55 (known to harbor insulin resistance variants). Cluster 4 traits suggested reduced adiposity with post-load glucose intolerance. Cluster 5 traits suggested a favorable metabolic profile (lower cholesterol and glucose, higher disposition index and insulin sensitivity). Conclusion: Genetic variants can be grouped to identify physiologic mechanisms at play in gestational glycemic regulation. Associations between physiologically-informed variant clusters, gestational diabetes, and related perinatal outcomes await testing in well-powered cohorts. Disclosure C.E. Powe: None. M. Udler: None. C. Allard: None. J. Kim: None. P. Perron: None. L. Bouchard: None. J.C. Florez: None. M. Hivert: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-15-ACE-26 to M-F.H.); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK113218, K24DK110550); Robert Wood Johnson Foundation; Fonds de la recherche du Québec en santé
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-354-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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