We propose to examine, in a large prospective nested case-control study of 4,300 ethnically diverse postmenopausal women, the roles of two inflammatory cytokines (i.e., TNF-a and IL-6), an acute-phase reactant (i.e., C-reactive protein), three markers of endothelial activation (i.e., ICAM-l, VCAM-l, and E-selectin), and genetic variants in six related candidate genes in the development of type 2 diabetes mellitus (DM). Although accumulating data linking inflammation and endothelial dysfunction to obesity and insulin resistance suggest central roles of these biochemical markers in the etiology of type 2 DM, little prospective data are available examining their roles as predictors for future risk of type 2 DM, especially among women and minority groups. In a focused series of studies employing blood samples obtained at baseline from approximately 83,000 postmenopausal women free of cardiovascular disease or type 2 DM participating in the Women's Health Initiative Observational Study Cohort, we will determine prospectively the independent and joint contributions of the above biochemical markers in predicting future risk of type 2 DM. In parallel, we will examine genetic variants, particularly those within the coding and promoter regions, of the six specific candidate genes that directly affect inflammation/endothelial activation (including TNF, NOS3, and PPARgamma) and obesity and insulin resistance (TNF-alpha, PPARgamma, UCP2, CAPN10, and aP2). In addition, we will conduct a comprehensive evaluation of polymorphisms within several promising candidate genes of type 2 DM susceptibility using analysis of haplotype frequency with state-of-the art genotyping technology and statistical methods. Furthermore, most genetic studies of type 2 DM have come from Caucasian or American-Indian populations and limited data are available from other ethnic populations. Because previous studies have demonstrated that the susceptibility genes may vary significantly across different populations, comparison of data from different ethnic groups will improve our understanding of genetic predictors for future risk of type 2 DM. Findings from this series of comprehensive yet focused analyses could shed new light on the etiology of type 2 DM, especially among minority Americans such as Hispanic/Latinos, Blacks/Africans, and Asians/Pacific Islanders who bear a disproportionately high burden of this disease yet have been poorly studied. Knowledge gained from this proposed study may suggest new intervention strategies to lower the incidence of type 2 DM in the general population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062290-03
Application #
6780966
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Mckeon, Catherine T
Project Start
2002-08-01
Project End
2005-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$500,898
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Lin, Xiaochen; Chan, Katie Kei-Hang; Huang, Yen-Tsung et al. (2018) Genetic Determinants for Leisure-Time Physical Activity. Med Sci Sports Exerc 50:1620-1628
Kabat, Geoffrey C; Kim, Mimi Y; Lane, Dorothy S et al. (2018) Serum glucose and insulin and risk of cancers of the breast, endometrium, and ovary in postmenopausal women. Eur J Cancer Prev 27:261-268
Bao, Wei; Baecker, Aileen; Song, Yiqing et al. (2015) Adipokine levels during the first or early second trimester of pregnancy and subsequent risk of gestational diabetes mellitus: A systematic review. Metabolism 64:756-64
Chan, Kei Hang K; Chacko, Sara A; Song, Yiqing et al. (2015) Genetic variations in magnesium-related ion channels may affect diabetes risk among African American and Hispanic American women. J Nutr 145:418-24
Song, Yan; Huang, Yen-Tsung; Song, Yiqing et al. (2015) Birthweight, mediating biomarkers and the development of type 2 diabetes later in life: a prospective study of multi-ethnic women. Diabetologia 58:1220-30
Ma, Yunsheng; Balasubramanian, Raji; Pagoto, Sherry L et al. (2013) Relations of depressive symptoms and antidepressant use to body mass index and selected biomarkers for diabetes and cardiovascular disease. Am J Public Health 103:e34-43
Chan, Kei Hang K; Niu, Tianhua; Ma, Yunsheng et al. (2013) Common genetic variants in peroxisome proliferator-activated receptor-? (PPARG) and type 2 diabetes risk among Women's Health Initiative postmenopausal women. J Clin Endocrinol Metab 98:E600-4
Song, Yiqing; Liu, Simin (2012) Magnesium for cardiovascular health: time for intervention. Am J Clin Nutr 95:269-70
Ye, Eva Qing; Chacko, Sara A; Chou, Elizabeth L et al. (2012) Greater whole-grain intake is associated with lower risk of type 2 diabetes, cardiovascular disease, and weight gain. J Nutr 142:1304-13
Culver, Annie L; Ockene, Ira S; Balasubramanian, Raji et al. (2012) Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med 172:144-52

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