The goal of this R01DK78616 renewal is to identify new type 2 diabetes (T2D) quantitative trait (QT) loci in a large trans-four-ethnic sample (N~103,000: ~26K African American, ~46K European, ~14K Hispanic and ~17K Asian) using staged genome-wide association studies with meta-analysis (GWAS-MA). In the trans- ethnic sample we will further test gene-environment and gene-gene interactions and gene pathways, and in longitudinal data, test candidate loci for physiological effects and for T2D prediction. Our links with other NIDDK studies offer immediate follow-up for next-generation sequencing (U01 DK085526) and trials of clinical application of genetics for T2D prevention (R21 DK084527). The significant recent, dramatic increase in T2D in the U.S., especially in minority groups, is an escalating clinical and public health challenge. Variation in genetic background coupled with increasing obesity accounts for rising T2D in the U.S.. In people of European ancestry, large-scale GWAS-MA have successfully outlined T2D common genetic architecture, with consortia studies led by our group and our collaborators recently contributing >50 new T2D risk or T2D QT loci. Large trans-ethnic GWAS-MA is a key next step in T2D gene discovery.
Specific Aims are to: 1) Identify novel T2D QT-associated variants using GWAS-MA in large, non-diabetic, trans-ethnic samples. We hypothesize that: a) staged GWAS-MA of T2D QTs in a large non-diabetic African American sample will identify novel loci associated with T2D physiology and T2D risk and b) joining the African American T2D QT GWAS-MA with three other groups for a large trans-four-ethnic T2D QT GWAS-MA will identify additional loci;2) Use the large trans-ethnic sample to find more loci, fine map, and suggest mechanism by tests of gene-environment, gene-gene and gene pathway analyses, specifically, accounting for SNP x BMI, weight change, ethnicity and other interactors;and 3) Use longitudinal population-based data to iluminate the evolution of T2D physiology over time, define the allelic spectrum of risk in U.S. ethnic groups, and test if novel T2D-related variants aid T2D risk prediction. The trans-four-ethnic GWAS-MA will provide an unparalleled resource for genetic discovery, studies of interactions and pathways hypothesized to underlie T2D and its related QTs, and help better define the value of T2D genetics for physiological targeting, population prediction and personalized prevention to improve health in minority and non-minority groups the U.S..

Public Health Relevance

We aim to identify novel type 2 diabetes (T2D) quantitative trait (QT) loci in ~103,000 individuals of African American, European, Hispanic and East Asian ancestry using staged genome-wide association study with meta-analysis. QTs include fasting glucose, insulin and hemoglobin A1c. T2D is increasing dramatically in the U.S., especially in minority groups. Current approaches to control of T2D seem insufficient, and new approaches are needed. Large-scale genetic studies have successfully outlined the common genetic architecture of T2D and T2D QTs in people of European ancestry. We aim to provide the same knowledge for minority groups in the U.S. especially affected by T2D to improve diagnosis, prevention and care.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078616-07
Application #
8663239
Study Section
Special Emphasis Panel (ZDK1-GRB-J (M2))
Program Officer
Akolkar, Beena
Project Start
2007-07-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
$656,882
Indirect Cost
$102,272
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Heianza, Yoriko; Sun, Dianjianyi; Ma, Wenjie et al. (2018) Gut-microbiome-related LCT genotype and 2-year changes in body composition and fat distribution: the POUNDS Lost Trial. Int J Obes (Lond) 42:1565-1573
Sun, Dianjianyi; Heianza, Yoriko; Li, Xiang et al. (2018) Genetic, epigenetic and transcriptional variations at NFATC2IP locus with weight loss in response to diet interventions: The POUNDS Lost Trial. Diabetes Obes Metab 20:2298-2303
Merino, Jordi; Leong, Aaron; Liu, Ching-Ti et al. (2018) Metabolomics insights into early type 2 diabetes pathogenesis and detection in individuals with normal fasting glucose. Diabetologia 61:1315-1324
Goni, Leticia; Sun, Dianjianyi; Heianza, Yoriko et al. (2018) A circadian rhythm-related MTNR1B genetic variant modulates the effect of weight-loss diets on changes in adiposity and body composition: the POUNDS Lost trial. Eur J Nutr :
Jun, Goo; Manning, Alisa; Almeida, Marcio et al. (2018) Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees. Proc Natl Acad Sci U S A 115:379-384
Heianza, Yoriko; Sun, Dianjianyi; Li, Xiang et al. (2018) Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial. Gut :
McKeown, Nicola M; Dashti, Hassan S; Ma, Jiantao et al. (2018) Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis. Diabetologia 61:317-330
Sun, D; Wang, T; Heianza, Y et al. (2018) Birthweight and cardiometabolic risk patterns in multiracial children. Int J Obes (Lond) 42:20-27
Han, Liyuan; Duan, Donghui; Zhang, Shuang et al. (2018) Effects of the interaction between glycated haemoglobin genetic risk score and postpartum weight reduction on glycaemic changes: A gene-weight interaction analysis. Diabetes Obes Metab 20:2733-2739
Goni, Leticia; Sun, Dianjianyi; Heianza, Yoriko et al. (2018) Macronutrient-specific effect of the MTNR1B genotype on lipid levels in response to 2 year weight-loss diets. J Lipid Res 59:155-161

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