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  • 1
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    CRISPR Mediated Deletion of a Proxy 19.2kb Distal to the T2D GWAS-Implicated SLC30A8 R325W Variant Impacts RAD21 and UTP23 Gene Expression in HepG2 Cells
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Genome wide association studies (GWAS) have revealed multiple loci for type 2 diabetes (T2D). However, given that GWAS generally only reports genomic signals associated with a given trait, there is need for follow-up characterization. Despite key reports of missense variants within SLC30A8 conferring protection of T2D risk, there is still need to better understand the relationship between the GWAS signal and mechanism at this locus. The application of ’Assay for Transposase Accessible Chromatin combined with sequencing’ (ATAC-seq) to Endo-BH1, SGBS and HepG2 cell lines, representing models for pancreatic beta-cells, adipose and liver respectively, allowed us to filter for putatively informative proxy SNPs (r2 & gt;0.8) coinciding with open chromatin at this locus. Following sequencing on the Illumina Hi-Seq platform, the sentinel SNP itself coincided with open chromatin, namely rs13266634 (a missense R325W variant), in both Endo-BH1 and SGBS; however, in HepG2 this region was closed while proxy rs9650069 was open, situated 3’ to SLC30A8 and 19.2kb from rs13266634. We elected to generate CRISPR/Cas9 mediated deletions immediately around rs9650069 in a mixed cell setting. Following confirmation of deletion by sequencing, we assessed changes in expression for all genes in the corresponding topological associating domain (TAD), namely SLC30A8, AARD, EIF3H, RAD21, TRPS1 and UTP23. Two genes revealed a significant change in expression when normalized to beta-actin, namely RAD21 and UTP23, yielding 5.58 fold and 4.57 fold decreases, respectively. Given that according to GTEx the expression of SLC30A8 is largely contained to the pancreas, this gene was not expressed in this cell setting and thus the impact of this deletion on this gene could not be assessed. This effort implicates an enhancer element for these genes in a liver cell model as being a part of the machinery genetically controlling this locus. Disclosure K.M. Hodge: None. S. Lu: None. M. Leonard: None. J.A. Pippin: None. A. Chesi: None. A.D. Wells: None. M. Johnson: None. S.F. Grant: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1714-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 2
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    247-OR: Variant-to-Gene-Mapping Analyses Reveal a Role for Pancreatic Islet Cells in Conferring Genetic Susceptibility to Sleep-Related Traits
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Altered glucose metabolism observed in sleep dysregulation has been reported to contribute to obesity and type 2 diabetes (T2D) risk. We elected to investigate if known sleep loci exert any of their effect in the pancreatic alpha and beta-cell setting. To establish genetic commonalities between sleep and metabolic disorders, we conducted linkage disequilibrium (LD) genetic correlation analyses with publicly available GWAS summary statistics for 4 sleep-associated traits (insomnia, chronotype, short and long sleep), T2D and obesity. Insomnia was significantly correlated with both T2D (genetic correlation (rg)=0.2; P=2.4x10-11) and obesity (rg=0.13; P=0.0021), as was short sleep (T2D, rg=0.2; P=1.8x10-10; obesity, rg=0.22; and P=5.1x10-7) and long sleep (T2D, rg=0.23; P=3.1x10-10; obesity rg=0.09; P=0.019). Chronotype was significantly correlated with T2D only (rg=0.05; P=0.038). Using partitioned LD score regression we then intersected summary statistics with our ATAC-seq and high-resolution promoter-focused Capture C data to assess enrichment of sleep trait SNPs within promoter-interacting open chromatin regions in both the human beta-cell line, EndoC-BH1, and sorted human alpha-cells. EndoC-BH1 was highly significantly enriched for chronotype loci (P=2.2x10-7). Furthermore there was significant enrichment for insomnia (P=0.01) and short sleep (P=0.017). The alpha-cells were also significantly enriched for chronotype (P=0.0016), insomnia (P=0.0076), short sleep (P=0.022), along with long sleep (P=0.034). Motivated by these observations, subsequent variant-to-gene mapping implicated 32, 37 and 6 putative effector genes for insomnia, chronotype and short sleep, respectively, in EndoC-BH1. For alpha-cells, 55, 54, 10 and 5 genes were implicated for insomnia, chronotype, short and long sleep, respectively. Our data suggest that a subset of sleep-related loci confer their effects via cells in pancreatic islets. Disclosure C. Lasconi: None. M. C. Pahl: None. J. A. Pippin: None. C. Su: None. M. Johnson: None. A. Chesi: None. A. D. Wells: None. K. H. Kaestner: None. S. F. A. Grant: None. Funding National Institutes of Health (UM1DK126194)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-247-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 3
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    A High Resolution Capture-C Promoter "Interactome" Implicates Causal Genes at Type 2 Diabetes GWAS Loci
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: GWAS has revealed many loci for type 2 diabetes (T2D). However, GWAS just reports genomic signals and not necessarily the precise localization of effector genes, with eQTLs making inferences to only a subset of such loci. Chromatin conformation capture-based techniques that detect contacts between distant regions of the genome offer an opportunity to understand GWAS signals that principally reside in non-coding regions, thus likely influencing regulatory elements. To move beyond analyzing one locus at a time and to improve on the low resolution of available Hi-C data, we developed a high resolution Capture-C based method to simultaneously characterize the genome-wide interactions of all human promoters in any cell type. We applied this to the immortalized human β-cell line, EndoC-βH1, a model relevant to T2D. We designed a custom Agilent SureSelect library targeting both ends of DpnII restriction fragments that overlap promoters of protein-coding, plus noncoding, transcripts, totaling 36,691 RNA baited fragments. Following sequencing, we investigated significant interactions at varying resolutions depending on how the fragments were leveraged and/or collapsed. In parallel, we generated ATAC-seq open chromatin maps to filter for informative proxy SNPs (r2 & gt;0.8) to each of the 104 T2D independent sentinels reported to date, yielding overall 150 (harbored in 94 DpnII fragments) for 50 of these loci. By filtering our promoter ’interactome’ results at 4 DpnII fragment resolution (median distance between interacting regions ∼115kb, median region size =1,440bp) based on these proxies and openness of the regions they interact with, we observed contacts relevant to 17 of the original loci. Some ’nearest’ genes were supported e.g., GIPR and ZFAND3, while at other loci more distant genes were implicated e.g., OGFOD2 at ’MPHOSPH9’ and MESP2 at ’AP3S2’. In conclusion, we observed informative contacts at putative effector genes for 16% of T2D GWAS loci in this particular cellular context. Disclosure E. Manduchi: None. M. Johnson: None. M. Leonard: None. S. Lu: None. K.M. Hodge: None. A. Chesi: None. A.D. Wells: None. S.F.A. Grant: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1705-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 4
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    305-OR: Genomic Basis to Shared Influences on Pubertal Timing and Type 2 Diabetes
    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: Earlier pubertal onset in girls is associated with later-life type 2 diabetes (T2D) risk. Studies have shown that age at menarche (AAM), a marker of girls’ pubertal timing, and T2D are genetically correlated genome-wide. Since both AAM and T2D also correlate with BMI, the biological link between the two traits could be mediated via BMI. As the most recent genome-wide association study (GWAS) for T2D also adjusted for BMI, we queried if AAM and T2D remain correlated after removing the effect of BMI on T2D. Leveraging such large-scale GWAS data, LD Score Regression revealed that the genetic correlation between AAM and T2D (rg (SE)=-0.24 (0.02) P=2.2x10-22) was only partly attenuated after BMI adjustment (rg (SE)=-0.1 (0.03) P=0.0002), suggesting that BMI does not entirely explain the puberty-T2D link. Five of the 13 significant GWAS-implicated loci associated with both AAM and T2D do not associate with BMI, further supporting that BMI is not the only mediator between the two traits. Given that causal effector genes are unknown at most GWAS loci, identification of target genes at these shared loci should provide key biological insights. To implicate effector genes, we first identified all SNPs in LD with the sentinel SNPs. We then extracted the subsets of proxy SNPs in open chromatin, determined by ATAC-seq, in primary cells or cell lines relevant to this trait area [beta cells (EndoC-βH1), adipose (SGBS and MSC-derived adipocytes), and—given recent findings in both AAM and BMI studies—brain (neural precursors, microglia, astrocytes and hypothalamic neurons)]. Using high resolution Capture-C, we detected consistent physical contacts between open-proxy SNPs and candidate effector genes. Our results support direct SNP-to-gene promoter contacts for at least four of these shared loci (one not associated with BMI) including TSPAN3 at ‘AC046168.1’ and TFAP2D at ‘TFAP2B’, along with leads at the ‘MTCH2/CELF1’ and ‘MAP2K5’ loci. Follow-up experiments are needed to determine the physiological roles of implicated target genes. Disclosure D.L. Cousminer: None. R. Mishra: None. M.A. Argenziano: None. E. Manduchi: None. K.M. Hodge: None. C. Su: None. M. Leonard: None. S. Lu: None. J.A. Pippin: None. M. Johnson: None. A.D. Wells: Research Support; Self; GlaxoSmithKline plc. A. Chesi: None. B.F. Voight: None. S.F. Grant: None. Funding American Diabetes Association (1-17-PDF-077 to D.L.C.); National Institutes of Health
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-305-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 5
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    245-OR: CIS-Regulatory Architecture of Human ESC-Derived Hypothalamic Neuron Differentiation Aids in Variant-to-Gene Mapping of Type 2 Diabetes Related Traits
    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: Dysregulation of hypothalamus-mediated metabolic homeostasis influences risk factors for T2D, such as BMI, pubertal timing and sleep. However, the gene regulatory landscape of the hypothalamus remains unclear. We characterized the physical relationships among gene promoters and their corresponding cis-regulatory elements in human embryonic stem cell (ESC)-derived hypothalamic cells by integrating RNA-seq, ATAC-seq and promoter-focused Capture C profiles. We conducted this effort in an in vitro model of hypothalamic neurons using human ESCs at 3 stages of differentiation: ESCs, hypothalamic progenitors (HPs) and hypothalamic-like neurons (HNs). We identified 87,170 open chromatin regions (OCRs) contacting promoters in at least 1 stage of HN differentiation. Interestingly, we observed that regardless of gene expression pattern during differentiation, overall accessibility of interacting OCRs first increased during the transition to HP, then decreased following differentiation to HN. In order to relate these findings to GWAS data, we tested for enrichment of SNPs within promoter-interacting OCRs. We found significant associations with BMI, sleep traits, age at menarche (AAM) and major depressive disorder (MDD). We mapped these trait-associated variants to their physically interacting genes. We identified 2 putative effector genes for AAM (RPS26 and SUOX at chr12q13.2) and 1 for BMI (DHRS11), which were also supported by colocalized hypothalamus eQTLs in GTEx. Additionally, HyPrColoc analyses revealed several putative effector genes associated with & gt;1 trait, including ZRANB2 for AAM, BMI and MDD, and FEZF1 for AAM and BMI, the latter being known to harbor Mendelian mutations that impair puberty. Taken together, our analyses provide insight into cis-regulatory architecture during hypothalamic development and how it may contribute to phenotypes associated with T2D risk. Disclosure M.C. Pahl: None. S.H. Littleton: None. C. Doege: None. K.M. Hodge: None. M. Leonard: None. S. Lu: None. R. Hammond: None. K. Boehm: None. C. Lasconi: None. C. Su: None. A. Chesi: None. J.A. Pippin: None. M. Johnson: None. A.D. Wells: None. B.F. Voight: None. R. Leibel: None. S.F. Grant: None. D.L. Cousminer: None. Funding American Diabetes Association (1-17-PDF-077 to D.L.C.); National Institutes of Health (K99HD099330-01); National Center for Research Resources (UL1RR024134); National Center for Advancing Translational Sciences (UL1TR000003); Institute for Translational Medicine and Therapeutics; Children’s Hospital of Philadelphia
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-245-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 6
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    298-OR: Variant-to-Gene Mapping at the Childhood Obesity Locus on chr12q13 and Subsequent Luciferase Assay Analyses Implicate rs71329as a Causal Variant within the 3’ UTR of FAIM2
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. Supplement_1 ( 2022-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. Supplement_1 ( 2022-06-01)
    Abstract: A key limitation of genome-wide association studies (GWAS) is that they do not specify either the underlying causal variant (s) or the effector gene (s) at a given locus. The widely reproduced obesity FAIM2 locus, named arbitrarily after the nearest gene, is relatively understudied given it is more strongly associated in children than in adults. Our previously reported trans-ancestral GWAS meta-analysis of childhood obesity enabled fine-mapping of the FAIM2 locus; in the ‘credible set’ of 6 SNPs, rs71329 had the highest probability of being causal. This non-coding variant resides in the 3’ untranslated region (UTR) of FAIM2. Given that obesity-related GWAS signals have been reported to be enriched in genes relevant to neuronal function, we generated ATAC-seq and high-resolution promoter-focused Capture C data in both primary astrocytes and ESC-derived hypothalamic neurons to carry out variant-to-gene mapping at this locus. We observed that rs71329 occupied a region of open chromatin, therefore a putatively functional element, and made physical contact with the FAIM2 promoter. These findings were also supported by both GTEx testes eQTL data and a transcriptome-wide association study in brain tissue. We sought to determine in vitro if the rs71329alleles influence enhancer activity in primary astrocytes. Using technical replicates repeated 8 times, the non-risk allele region increased luciferase reporter expression relative to the FAIM2 promoter alone by a fold change of 1.87, while the risk allele decreased expression by a fold change of 0.68 (non-risk allele+FAIM2 promoter vs. risk allele+FAIM2 promoter P & lt;0.0001) . Our results show that rs71329resides in an enhancer element and suggest that the risk allele within the 3’ UTR of FAIM2 decreases the expression of this putative effector gene, which then confers risk of childhood obesity and in turn type 2 diabetes later in life. Disclosure S.H.Littleton: None. J.Bradfield: None. J.A.Pippin: None. C.Su: None. A.Chesi: None. A.D.Wells: Stock/Shareholder; Johnson & Johnson. R.I.Berkowitz: Research Support; Eisai Inc., Novo Nordisk. M.C.Pahl: None. S.F.Grant: None. Funding National Institutes of Health (HD056465)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-298-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 7
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    Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 5 ( 2021-05-01), p. 1219-1227
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 5 ( 2021-05-01), p. 1219-1227
    Abstract: In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor. RESEARCH DESIGN AND METHODS In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data. RESULTS Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02−1.06, P & lt; 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85–1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment–baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03−1.12; P = 0.0002) for incident type 2 diabetes. CONCLUSIONS In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc20-2842
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 8
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    Risk Factors for the Development of Retinopathy in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Experience
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 11 ( 2022-11-01), p. 2653-2661
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 11 ( 2022-11-01), p. 2653-2661
    Abstract: To determine glycemic and nonglycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time in adults at high risk for developing T2D, including after they developed diabetes. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, with DR defined as typical lesions of DR (microaneurysms, exudates, hemorrhage, or worse) in either eye. RESULTS By DPPOS year 16 (∼20 years after random assignment into DPP), 24% of 1,614 participants who had developed T2D and 14% of 885 who remained without diabetes had DR. In univariate analyses, using results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared with non-Hispanic White (NHW) race, and higher HbA1c, fasting and 2-h plasma glucose levels during an oral glucose tolerance test, weight, and history of hypertension, dyslipidemia, and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared with NHW (odds ratio [OR] 0.36, 95% CI 0.20–0.66), and average HbA1c was associated with more DR (OR 1.92, 95% CI 1.46–1.74 per SD [0.7%] increase in HbA1c). CONCLUSIONS DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc22-0860
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 9
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    Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 12 ( 2021-12-01), p. 2775-2782
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 12 ( 2021-12-01), p. 2775-2782
    Abstract: To determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. RESEARCH DESIGN AND METHODS From 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively. RESULTS Over a median of 21 years (interquartile range 20–21), 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 [95% CI 0.79, 1.25]), cancer (HR 1.04 [95% CI 0.72, 1.52] ), or cardiovascular disease (HR 1.08 [95% CI 0.70, 1.66]). Similarly, lifestyle modification did not impact all-cause (HR 1.02 [95% CI 0.81, 1.28] ), cancer (HR 1.07 [95% CI 0.74, 1.55]), or cardiovascular disease (HR 1.18 [95% CI 0.77, 1.81] ) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality. CONCLUSIONS Cancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc21-1046
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 10
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    Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. 8 ( 2023-08-01), p. 1161-1172
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. 8 ( 2023-08-01), p. 1161-1172
    Abstract: Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (P & lt; 9 × 10−9). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, β = 0.39 [95% CI 0.28, 0.50] ; P = 2.8 × 10−12). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, β = −7.55 [95% CI −9.88, −5.22]; P = 3.2 × 10−10) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) & lt; 1.0 × 10−4]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-0702
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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