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  • 1
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    Birthweight and early-onset type 2 diabetes in American Indians: differential effects in adolescents and young adults and additive effects of genotype, BMI and maternal diabetes
    Springer Science and Business Media LLC ; 2019
    In:  Diabetologia Vol. 62, No. 9 ( 2019-9), p. 1628-1637
    Details
    In: Diabetologia, Springer Science and Business Media LLC, Vol. 62, No. 9 ( 2019-9), p. 1628-1637
    Type of Medium: Online Resource
    ISSN: 0012-186X , 1432-0428
    URL: Article
    DOI: 10.1007/s00125-019-4899-9
    RVK:
    XA 40615
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 1458993-X
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  • 2
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    Birth Weight and Early Onset Type 2 Diabetes Mellitus: A Prospective Observational Study of American Indians Reveals Differential Effects in Adolescents and Young Adults
    Elsevier BV ; 2018
    In:  SSRN Electronic Journal
    Details
    In: SSRN Electronic Journal, Elsevier BV
    Type of Medium: Online Resource
    ISSN: 1556-5068
    URL: Article
    DOI: 10.2139/ssrn.3228239
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
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  • 3
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    1460-P: Type 2 Diabetes Polygenic Score in Addition to Clinical Factors for Prediction of Diabetes Incidence in an Indigenous American Population
    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: Type 2 diabetes (T2D)-associated variants, derived from genome-wide association studies (GWAS), have largely been reproducible across populations, but there is limited information on how polygenic scores (PS) based on these variants add to clinical factors for predicting diabetes incidence, particularly in non-European populations. Methods: A longitudinal study of diabetes was conducted in an Indigenous study population native to the Southwestern U.S. At each exam, a 75-g oral glucose tolerance test was administered with measurement of fasting and 2-hour plasma glucose (FPG, 2hPG). Genotypes were available from a GWAS for 2783 participants aged ≥ 20 years without diabetes at baseline, with imputed genotypes based on whole genome sequence data from 296 individuals from the population. PSs for participants were constructed and weighted using genome-wide significant variants in a T2D GWAS meta-analysis in European-descent populations (n=245; Mahajan 2018). Survival analyses were conducted to predict diabetes incidence in 2 models: (1) age, sex, BMI, FPG; (2) age, sex, BMI, FPG, T2D PS. Area under the receiver-operating characteristic curve (AUC) was calculated using a nonparametric method for survival analysis. Results: 903 cases (32.5%) of diabetes occurred during 25,110 person-years of follow-up. The hazard ratio for T2D PS, controlled for age, sex, BMI and FPG, was 1.27 per SD (P=1.5×10-12). Cumulative incidence at 10 years was 0.076 in the lowest quartile for the prediction score based on clinical factors alone and 0.509 in the highest quartile. For the model including PS, corresponding values were 0.075 and 0.524. AUC was 0.710 for the model with clinical factors alone and 0.721 for the model including T2D PS. Conclusion: Weighted T2D PSs based on 245 variants were informative in predicting T2D incidence in Indigenous Americans; however, the improvement in prediction beyond clinical factors alone was modest. Disclosure L.E. Wedekind: None. S. Kobes: None. W. Hsueh: None. L. Baier: None. W.C. Knowler: None. A. Mahajan: None. M.I. McCarthy: Advisory Panel; Self; Illumina. Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Zoe Global Ltd. Employee; Self; Genentech, Inc. Research Support; Self; AbbVie Inc., Merck & Co., Inc., Sanofi-Aventis, Servier, Takeda UK. R.L. Hanson: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1460-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
    detail.hit.zdb_id: 1501252-9
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  • 4
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    1709-P: Assessing the Role of 211 “Established” Type 2 Diabetes Variants in American Indians
    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: Genome-wide association studies (GWAS) have identified many variants associated with type 2 diabetes (T2D), but there is little information on their effects in high risk populations such as American Indians. We analyzed 211 primary variants, associated with T2D (P & lt;5.0×10-8) in published GWAS, in 7659 American Indian participants in a population study (33.5% with T2D)- updating our previous study of 63 variants. Genotypes came from a custom Axiom array that captures common variation in American Indians; imputation was performed using whole genome sequence data from 266 Pima Indians. Variants were tested for association with T2D in a mixed model accounting for relatedness with adjustment for age, sex and the 1st 5 genetic principal components to account for population stratification. Heterogeneity was tested by comparing odds ratios (ORs) in American Indians with published ORs. A weighted polygenic risk score across all 211 variants was analyzed. Nominally significant (P & lt;0.05) and directionally consistent replication was observed for 21 of the 211 variants. Notable associations were with rs2237895 in KCNQ1 (OR=1.29, P=2.5×10-8) and rs4929965 in INS/IGF2 (OR=1.28, P=9.8×10-8). Significant heterogeneity was seen for 23 variants- 21 had weaker effects in American Indians than in published values. A summary test over all variants showed effects were generally weaker in American Indians (P=4.0×10-11). The polygenic risk score was strongly associated with T2D (OR=1.38 per SD, P=2.8×10-22). The risk score was also associated with reduced insulin secretion measured by a 25 g intravenous glucose tolerance test (by 10% per SD, P=0.005, n=300 all with normal glucose tolerance), but not insulin sensitivity measured by a hyperinsulinemic-euglycemic “clamp” (P=0.78, n=557 all nondiabetic). These findings suggest that established T2D risk variants generally also affect T2D risk in American Indians (although effects tend to be weaker) and that they act predominantly through diminished insulin secretion. Disclosure R.L. Hanson: None. L.E. Wedekind: None. W. Hsueh: None. S. Kobes: None. L.J. Baier: None. C. Bogardus: None. W.C. Knowler: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-1709-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 5
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    1701-P: Genome-Wide Association Study Identifies Novel Potential Associations with Birth Weight in a Southwestern American Indian Population
    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: Epidemiologic studies in many populations have shown that birth weight is associated with risk of type 2 diabetes (T2D) in adulthood. In a Southwestern American Indian population, lower and higher birth weight groups are at higher risk for T2D than those with normal birth weight. We performed a genome-wide association study (GWAS) of birth weight in 3700 Southwestern American Indians (2037 female; 1663 male). 496,190 SNPs (allele frequency & gt;1%) were directly genotyped using an Axiom array designed to capture common variation in this community (Affymetrix; Santa Clara, CA). Birth weight was ascertained from Arizona state and medical records. T2D was determined according to American Diabetes Association criteria at a research exam or during clinical care. Birth weight data were normalized separately by sex and analyzed for genetic associations using a mixed model (SOLAR-Eclipse; Catonsville, MD) accounting for genetic relationships (based on genetic markers among all pairs of individuals) and adjusted for birth year and the 1st 5 genetic principal components. We identified 41 variants suggestively associated (p & lt;0.0001) with birth weight. The strongest associations are with rs4799141 in PARD6G (β=-0.14 SD per T allele; p=7.5E-6), rs17333221 in MEOX2 (β=-0.15 SD per C allele; p=1.0E-5), rs11704996 in TRIOBP (β=0.15 SD per A allele; p=1.0E-5) and a missense variant in ABCC8, R1420H (β=0.41 SD per H allele; p=1.5E-5). 5 of the 41 variants are also nominally associated with T2D (p & lt;0.05) in 7659 individuals from this population; the most notable was the R1420H variant in ABCC8, which we previously reported as associated with T2D (OR=2.2, p=3.0E-5) and for which activating mutations cause hyperinsulinemic hypoglycemia of infancy. In sum, we identified novel suggestive genetic associations with birth weight, which require confirmation in additional studies, and show that R1420H in ABCC8 is a strong genetic determinant of birth weight in this population. Disclosure L.E. Wedekind: None. W. Hsueh: None. S. Kobes: None. M.T. Olaiya: None. W.C. Knowler: None. L.J. Baier: None. R.L. Hanson: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-1701-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 6
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    Epidemiology of Type 2 Diabetes in Indigenous Communities in the United States
    Springer Science and Business Media LLC ; 2021
    In:  Current Diabetes Reports Vol. 21, No. 11 ( 2021-11)
    Details
    In: Current Diabetes Reports, Springer Science and Business Media LLC, Vol. 21, No. 11 ( 2021-11)
    Type of Medium: Online Resource
    ISSN: 1534-4827 , 1539-0829
    URL: Article
    DOI: 10.1007/s11892-021-01406-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2094158-4
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  • 7
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    1132-P: Genetic Relationships between Birth Weight and Type 2 Diabetes
    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: There is considerable evidence that birth weight is associated with increased risk of type 2 diabetes (T2D) in adulthood. However, evidence from populations with high prevalence of T2D on the genetic relationships between birth weight and T2D is limited. Data were obtained from a genome-wide association study (GWAS) in an Indigenous population from the Southwest US with high prevalence of T2D in which the relationship of T2D with birth weight is “U-shaped." Weighted polygenic scores (PSs) were constructed using imputed genotypes for genome-wide significant single-nucleotide polymorphisms (SNPs) from GWAS meta-analyses for birth weight (EGG Consortium, 126 SNPs) and T2D (DIAGRAM Consortium, 293 SNPs). Associations of birth weight PS and T2D PS with T2D and birth weight were calculated, accounting for participants’ pairwise relationships, using linear mixed models. Birth weight data (n=3700) were normalized separately by sex and analyzed for associations, adjusted for birth year, gestational age and the first 5 genetic principal components (PCs). T2D (n=7659) data were analyzed for associations, adjusted for age, sex, birth year and the first 5 genetic PCs. Birth weight PS had a significant, positive association with birth weight (β=0.134 SD birth weight per SD PS (95% CI 0.101, 0.168); p=4.1×10-15). The T2D PS was likewise significantly, positively associated with T2D (OR=1.48 per SD (1.38, 1.58); p=8.1×10-31). The birth weight PS was significantly, inversely associated with T2D (OR=0.91 (0.85, 0.97); p=0.0043); we found no evidence for a non-linear relationship between birth weight PS and T2D (p=0.80). The T2D PS was not significantly associated with birth weight (β=-0.005 (-0.040, 0.030); p=0.80). Results indicate that genetic variants that associate with birth weight and T2D from larger European GWAS largely also influence these traits in this Indigenous population. Current findings also support the notion that many variants conferring susceptibility to low birth weight also confer susceptibility to T2D. Disclosure L. E. Wedekind: None. W. Hsueh: None. M. Olaiya: None. S. Kobes: None. L. Baier: None. W. C. Knowler: None. A. Mahajan: Employee; Self; Genentech, Inc. M. Mccarthy: Employee; Self; Genentech, Inc. R. L. Hanson: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-1132-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 8
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    141-OR: Associations between Type 2 Diabetes Partitioned/Process-Specific Polygenic Scores and Metabolic Traits
    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: Polygenic scores (PS) for type 2 diabetes (T2D) associate strongly with disease status. Since T2D is heterogenous, using “partitioned” PS (pPS) that capture distinct etiological processes may improve clinical utility. A previous study in Europeans identified 6 pPS from genetic clusters (GCs) based on association patterns across traits, among 3T2D-associated variants: adiposity (GC1) , lipids (GC2) , insulin action (GC3) , beta cell function (GC4, GC5) , and mixed features (GC6) . Few data exist on how pPS associate with T2D and subphenotypes in non-European populations. The current analysis reconstructed these pPS using genotypes for 245 of the 3variants captured in a genome-wide association study in an Indigenous study population from the Southwest US. pPS associations were analyzed with T2D (N=7659) , % body fat (PFAT, non-diabetic only, n=557) , insulin action from hyperinsulinemic-euglycemic “clamp” (logM, non-diabetic only, n=557) , and acute insulin response from an IVGTT (lgAIR, normal glucose tolerance only, n=404) . Results (table) show that T2D pPS strongly associate with the subphenotype corresponding to the putative etiologic mechanism. These results demonstrate transferability of the phenotypic classifications of the T2D pPS and suggest that genetic influences on adiposity, insulin action, and insulin secretion contribute to development of T2D in this population. Disclosure L.E.Wedekind: None. W.Hsueh: None. S.Kobes: None. L.Baier: None. C.Bogardus: None. W.C.Knowler: None. A.Mahajan: Employee; Genentech, Inc. M.Mccarthy: Employee; Genentech, Inc. R.L.Hanson: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-141-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 9
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    1476-P: Genetic Relationships between Puberty Onset and Type 2 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: Early puberty onset is a risk factor for type 2 diabetes (T2D). In this study we aimed to determine whether these phenotypes are associated via genetic variation that contributes to both T2D and puberty onset. We, thus, investigated the associations of a polygenic score (PS) for T2D and a PS for age of menarche (AAM) with parameters of adolescent growth and T2D status in an Indigenous population from the Southwestern US with a high T2D prevalence. Genotypic and clinical data were obtained from a longitudinal study. Two key parameters of the adolescent growth spurt, including age at take-off (ATO) and age at peak velocity (APV), were derived from the Preece-Baines growth model, a parametric growth curve for longitudinal height data. PSs were constructed using imputed genotypes, where variants for the T2D-PS (n=289) and the AAM-PS (n= 275) were selected from genome-wide significant variants in European meta-analyses (DIAGRAM Consortium and Reprogen Consortium, respectively). Associations between PS and T2D status (N=7659) were adjusted for age, sex, birth year and the first 5 genetic PCs. Associations with ATO and APV (N=787) were adjusted for birth year, sex, maternal diabetes and the first 5 genetic principal components (PCs). Associations were calculated using linear mixed models, accounting for genetic relationships. The T2D-PS had a significant, positive association with T2D (OR=1.47 per SD [95% CI 1.38, 1.57]; p=4.05×10−30). We found no association of the T2D-PS with ATO (p=0.11) nor APV (p=0.20). Conversely, genetically-predicted later puberty onset (AAM-PS) had a significant, inverse association with T2D (OR=0.92 per SD [95% CI 0.86, 0.98] ; p=0.0194). The AAM-PS also associated with ATO (r=0.11, p=0.0013) and APV (r=0.13, p=1.8×10−04). Our results suggest that many variants that associate with AAM and T2D in large European cohorts also affect these traits in this Indigenous population. They also support the notion that variants that associate with early puberty onset also confer susceptibility to T2D. Disclosure M.J.Ramirez-luzuriaga: None. S.Kobes: None. L.E.Wedekind: None. W.Hsueh: None. L.Baier: None. R.L.Hanson: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-1476-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 10
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    Genome-Wide Association Study of Inflammatory Cytokines in Southwestern Native Americans Identifies Novel Association between WWOX and Serum TNF-? Levels
    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: Inflammatory processes may contribute to type 2 diabetes (T2D), but there is limited information about genetic associations with circulating levels of inflammatory cytokines. We performed a genome-wide association study (GWAS) of cytokines in 1061 nondiabetic Southwestern Native Americans (500 women; 561 men). Fasting serum concentrations of interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor-α (TNF-α) were measured using EMD Millipore assays. Genotypic data on 496,190 single-nucleotide polymorphisms (SNPs) with minor allele frequency & gt;1% were derived from an Affymetrix Axiom array designed to capture common variation in Pima Indians. Data were normalized and analyzed for associations using a mixed model accounting for familial relationships, adjusted for age, sex and genetic principal components 1-5. The strongest associations were on chromosome 3 near A4GNT with IL-6 levels (rs2724711 p=4.2×10-6), and on chromosome 7 with PAI-1 levels (rs1608488 (p=8.3×10-7). An association of genome-wide statistical significance (rs1862840; p=1.2×10-8) was observed on chromosome 16 near WWOX with TNF-α levels. Each copy of the G allele (frequency=0.12) confers a 0.41-SD increase in TNF-α levels. In a larger cohort of Southwestern Native Americans, rs1862840 was not associated with T2D (N=7,659; p=0.17). Among 3,983 nondiabetic subjects it did associate with 2 hour corrected insulin response (β=0.06-SD decrease per G allele copy, p=0.011). Among 300 normal glucose tolerant subjects it associated with the acute insulin response to intravenous glucose (β=20% decrease per G allele copy, p=0.045). This study identified a novel association for TNF-α levels at WWOX (a gene previously implicated in T2D and insulin secretion in Han Chinese study populations) and suggests potential genetic links between inflammation and insulin secretion. Disclosure L.E. Wedekind: None. M. Walter: None. S. Kobes: None. P. Chen: None. W. Hsueh: None. R. Nelson: None. L. Baier: None. W.C. Knowler: None. R.L. Hanson: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1713-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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