Publication Type: Original Research

August, 2017

Genetically driven hyperglycemia increases risk of coronary artery disease separately from type 2 diabetes

Diabetes Care 2017;40:687-693

Merino J, Leong A, Posner DC, Porneala B, Masana L, Dupuis J, Florez JC

OBJECTIVE: This study tested the hypothesis that genetically raised hyperglycemia increases coronary artery disease (CAD) risk separately from the risk conferred by type 2 diabetes as a whole. RESEARCH DESIGN AND METHODS: We conducted a Mendelian randomization (MR) analysis using summary-level statistics from the largest published meta-analyses of genome-wide association studies (GWAS) for fasting glucose …

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August, 2017

Type 2 diabetes variants disrupt function of SLC16A11 through two distinct mechanisms

Cell 2017:170-199-212

Rusu V*, Hoch E*, Mercader JM, Tenen DE, Gymrek M, Hartigan CR, DeRan M, von Grotthuss M, Fontanillas P, Spooner A, Guzman G, Deik AA, Pierce KA, Dennis C, Clish CB, Carr SA, Wagner BK, Schenone M, Ng MCY, Chen BH; MEDIA Consortium; SIGMA T2D Consortium, Centeno-Cruz F, Zerrweck C, Orozco L, Altshuler DM, Schreiber SL, Florez JC†, Jacobs SBR, Lander ES†

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ?20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that …

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August, 2017

Variation in Maturity-Onset Diabetes of the Young genes influence response to interventions for diabetes prevention

J Clin Endocrinol Metab. 2017 Aug 1;102(8):2678-2689

Billings LK, Jablonski KA, Warner AS, Cheng YC, McAteer JB, Tipton L, Shuldiner AR, Ehrmann DA, Manning AK, Dabelea D, Franks PW, Kahn SE, Pollin TI, Knowler WC, Altshuler D, Florez JC

CONTEXT: Variation in genes that cause Maturity-Onset Diabetes of the Young (MODY) has been associated with diabetes incidence and glycemic traits. OBJECTIVES: This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. DESIGN AND SETTING: This was a secondary analysis of a multicenter randomized clinical trial, the …

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August, 2016

Genome-wide association study of the modified Stumvoll Insulin Sensitivity Index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci

Diabetes 2016;65:3200-3211

Walford GA*, Gustafsson S*, Rybin D*, (…), Meigs JB, Dupuis J, Ingelsson E, Florez JC.

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose …

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August, 2016

The genetic architecture of type 2 diabetes

Nature 2016;536:41-47

Fuchsberger C*, Flannick J*, Teslovich TM*, Mahajan A*, Agarwala V*, Gaulton KJ*, (…), Florez JC, Scott LJ, Morris AP, Kang HM, Boehnke M, Altshuler D, McCarthy MI.

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to …

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August, 2015

Genetic evidence for a causal role of obesity in diabetic kidney disease

Diabetes 2015;64:4238-4246

Todd JN, Dahlström EH, Salem RM, Sandholm N, Forsblom C; FinnDiane Study Group, McKnight AJ, Maxwell AP, Brennan E, Sadlier D, Godson C, Groop PH, Hirschhorn JN, Florez JC

Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but establishing causality from observational data is problematic. We aimed to test whether obesity is causally related to DKD using Mendelian randomization, which exploits the random assortment of genes during meiosis. In 6,049 subjects with type 1 diabetes, we used a …

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August, 2015

The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH): Design of a pharmacogenetic resource for type 2 diabetes

PLoS ONE 2015;10:e0121553

Walford GA, Colomo N, Todd JN, Billings LK, Fernandez M, Chamarthi B, Warner AS, Davis J, Littleton KR, Hernandez AM, Fanelli RR, Lanier A, Barbato C, Ackerman RJ, Khan SQ, Bui R, Garber L, Stolerman ES, Moore AF, Huang C, Kaur V, Harden M, Taylor A, Chen L, Manning AK, Huang P, Wexler D, McCarthy RM, Lo J, Thomas MK, Grant RW, Goldfine A, Hudson MS, Florez JC

OBJECTIVE: Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and …

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August, 2015

Pathways targeted by anti-diabetes drugs are enriched for multiple genes associated with type 2 diabetes risk

Diabetes 2015;64:1470-1483

Segrè AV, Wei N, DIAGRAM Consortium, MAGIC investigators, Altshuler D, Florez JC

Genome-wide association studies (GWAS) have uncovered >65 common variants associated with type 2 diabetes (T2D); however, their relevance for drug development is not yet clear. Of note, the first two T2D-associated loci (PPARG and KCNJ11/ABCC8) encode known targets of antidiabetes medications. We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D. …

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August, 2014

Metabolite Traits and Genetic Risk Provide Complementary Information for the Prediction of Future Type 2 Diabetes

Diabetes Care 2014;37:2508-2514

Walford GA, Porneala BC, Dauriz M, Vassy JL, Cheng S, Rhee EP, Wang TJ, Meigs JB, Gerszten RE, Florez JC

OBJECTIVE A genetic risk score (GRS) comprised of single nucleotide polymorphisms (SNPs) andmetabolite biomarkers have each been shown, separately, to predict incident type 2 diabetes. We tested whether genetic and metabolite markers provide complementary information for type 2 diabetes prediction and, together, improve the accuracy of prediction models containing clinical traits. RESEARCH DESIGN AND METHODS …

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August, 2014

The influence of rare genetic variation in SLC30A8 on diabetes incidence and beta-cell function

J Clin Endocrinol Metab 2014;99:E926-E930

Billings LK, Jablonski KA, Ackerman RJ, Taylor A, Fanelli RR, McAteer JB, Guiducci C, Delahanty LM, Dabelea D, Kahn SE, Franks PW, Hanson RL, Maruthur NM, Shuldiner A, Mayer-Davis EJ, Knowler WC, Florez JC for the Diabetes Prevention Program Research Group

CONTEXT/OBJECTIVE: The variant rs13266634 in SLC30A8, encoding a ?-cell-specific zinc transporter, is associated with type 2 diabetes. We aimed to identify other variants in SLC30A8 that increase diabetes risk and impair ?-cell function, and test whether zinc intake modifies this risk. DESIGN/OUTCOME: We sequenced exons in SLC30A8 in 380 Diabetes Prevention Program (DPP) participants and …

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