AS132 - A Prospective Study of Genetic and Biochemical Predictors of Type 2 Diabetes Mellitus

This page provides study documentation for AS132. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Simin Liu, MD, ScD, Epidemiology, School of Public Health, UCLA


The major aim of the current proposal is to investigate genetic and biochemical markers of inflammation and endothelial dysfunction as determinants of type 2 diabetes mellitus (DM) among a large and ethnically diverse cohort of postmenopausal women with archived blood specimens.  This proposal focuses on women in the observational study (OS) component of the Women’s Health Initiative (WHI) in which a total of 93,726 women will be followed for an average of 9 years. WHI is a National Institutes of Health (NIH)-sponsored study that focuses on the causes and treatments of health problems in postmenopausal women. WHI includes both a clinical trial (CT) and an observational study (OS) and will follow almost 162,000 women ages 50 to 79 for 15 years, making it the largest study in women ever undertaken in the United States. The large prospective database of diverse ethnic populations provides a unique opportunity to evaluate these novel and promising biomarkers and variations in related candidate genes as predictors of Type 2 DM, especially among minority groups. This proposal seeks funds only for the costs of managing and assaying these novel markers of endothelial dysfunction and inflammation in blood samples already collected at baseline and for the data analyses outlined below. Because the large costs associated with cohort assembly, follow-up, blood collection, storage, and endpoint validation are already funded as part of the WHI (N01-WH-2-2110), the current proposal also represents an exceptionally cost-effective means to study the etiology of type 2 DM.  The specific aims of the present proposal are the followings:


1. To examine inflammatory and endothelial biomarkers as risk factors of type 2 DM, we hypothesize that:

2. To evaluate promising candidate genes that are related to insulin resistance, particularly, endothelial dysfunction and inflammation as predictors of type 2 DM; specifically, we propose to:

Each of the proposed biomarkers can be readily measured in the WHI-OS archived specimens. We will first assess the independent and joint contributions of these novel inflammatory cytokines, acute-phase reactant, and activated endothelial markers in the development of Type 2 DM in a large and ethnically diverse cohort of postmenopausal women.   Second, we will focus on specific candidate genes that are both physiological relevant and that some contributions of these genes to predicting type 2 DM risk have been suspected but not yet confirmed. These will include genes that directly affect endothelial dysfunction (including TNF-a, NOS3, PPARg ), obesity and insulin resistance (TNF-a, PPARg, UCP2, CAPN10, and aP2). We also propose to conduct a comprehensive and yet focused evaluation of polymorphisms within several promising candidate genes of type 2 DM susceptibility. Furthermore, most genetic studies of type 2 DM have come from Caucasian or American-Indian populations and little 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 certainly improve our understanding of the genetic contributions in the etiology of type 2 DM.  Findings from this series of comprehensive and focused analyses among ethnically diverse groups of women could shed new light on the etiology of Type 2 DM and may suggest new intervention strategies to reduce the incidence of type 2 DM, especially in minority populations.


Some of the publications related to this ancillary study are:

Ms369 - Liu S, Tinker L, Song Y, Rifai N, Bonds DE, Cook NR, Heiss G, Howard BV, Hotamisligil GS, Hu FB, Kuller LH, Manson JE. A prospective study of inflammatory cytokines and diabetes mellitus in a multiethnic cohort of postmenopausal women. Arch Intern Med. 2007 Aug 13-27;167(15):1676-85.

Ms376 - Song Y, Manson JE, Tinker L, Rifai N, Cook NR, Hu FB, Hotamisligil GS, Ridker PM, Rodriguez BL, Margolis KL, Oberman A, Liu S. Circulating levels of endothelial adhesion molecules and risk of diabetes in an ethnically diverse cohort of women. Diabetes. 2007 Jul;56(7):1898-904. Epub 2007 Mar 27.

Ms486 - Song Y, Manson JE, Tinker L, Howard BV, Kuller LH, Nathan L, Rifai N, Liu S. Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: The Women's Health Initiative Observational Study. Diabetes Care. 2007 Jul;30(7):1747-52. Epub 2007 Apr 27.

Ms550 - Song Y, You NC, Hsu YH, Sul J, Wang L, Tinker L, Eaton CB, Liu S. Common genetic variation in calpain-10 gene (CAPN10) and diabetes risk in a multi-ethnic cohort of American postmenopausal women. Hum Mol Genet. 2007 Dec 1;16(23):2960-71. Epub 2007 Sep 12.

Ms554 - Hsu Y, Niu T, Song Y, Tinker L, Kuller LH, Liu S. Genetic variants in the UCP2-UCP3 gene cluster and risk of diabetes in the Women's Health Initiative Observational Study. Diabetes. 2008 Apr;57(4):1101-7. Epub 2008 Jan 25.

Ms555 - Chan KH, Niu T, Ma Y, You NC, Song Y, Sobel EM, Hsu YH, Balasubramanian R, Qiao Y, Tinker L, Liu S. Common genetic variants in Peroxisome Proliferator-Activated Receptor-γ (PPARG) and Type 2 Diabetes risk among Women's Health Initiative postmenopausal women. J Clin Endocrinol Metab. 2013 Mar;98(3):E600-4. doi: 10.1210/jc.2012-3644. Epub 2013 Feb 5

Ms572 - Chan KH, Song Y, Hsu YH, You NC, F Tinker L, Liu S. Common genetic variants in Fatty Acid-Binding Protein-4 (FABP4) and clinical diabetes risk in the Women's Health Initiative Observational Study. Obesity (Silver Spring). 2010 Jan 28. [Epub ahead of print]

Ms582 - Chao C, Song Y, Cook N, Tseng CH, Manson JE, Eaton C, Margolis KL, Rodriguez B, Phillips LS, Tinker LF, Liu S. The lack of utility of circulating biomarkers of inflammation and endothelial dysfunction for Type 2 diabetes risk prediction among postmenopausal women: The Women's Health Initiative Observational Study. Arch Intern Med. 2010 Sep 27;170(17):1557-65

Ms594 - Ma Y, Hébert JR, Li W, Bertone-Johnson ER, Olendzki B, Pagoto SL, Tinker L, Rosal MC, Ockene IS, Ockene JK, Griffith JA, Liu S. Association between dietary fiber and markers of systemic inflammation in the Women's Health Initiative Observational Study. Nutrition. 2008 Oct;24(10):941-9. Epub 2008 Jun 18.

Ms660 - Lee CC, You NC, Song Y, Hsu YH, Manson J, Nathan L, Tinker L, Liu S. Relation of genetic variation in the gene coding for c-reactive protein with its plasma protein concentrations: Findings from the Women's Health Initiative Observational Cohort. Clin Chem. 2009 Feb;55(2):351-60. Epub 2008 Dec 18

Ms664 - Song Y, You NC, Hsu YH, Howard BV, Langer RD, Manson JE, Nathan L, Niu T, F Tinker L, Liu S. FTO polymorphisms are associated with obesity but not diabetes risk in postmenopausal women. Obesity (Silver Spring). 2008 Nov;16(11):2472-80. Epub 2008 Sep 11.

Ms688 - Chacko SA, Song Y, Nathan L, Tinker L, de Boer IH, Tylavsky F, Wallace R, Liu S. Relations of dietary magnesium intake to biomarkers of inflammation and endothelial dysfunction in an ethnically diverse cohort of postmenopausal women. Diabetes Care. 2010 Feb;33(2):304-10. Epub 2009 Nov 10

Ms719 - Ma Y, Balasubramanian R, Pagoto SL, Schneider KL, Culver AL, Olendzki B, Tinker L, Liu S, Safford M, Sepavich DM, Rosal MC, Ockene JK, Carnethon M, Zorn M, Hébert JR. Elevated depressive symptoms, antidepressant use, and diabetes in a large multiethnic national sample of postmenopausal women. Diabetes Care. 2011 Sep 12. [Epub ahead of print]

Ms1148 - Chan KH, Brennan K, You NC, Lu X, Song Y, Hsu YH, Chaudhuri G, Nathan L, Tinker L, Liu S. Common variations in the genes encoding c-reactive protein, tumor necrosis factor, and interleukin-6, and the risk of clinical diabetes in the Women’s Health Initiative Observational Study. Clin Chem. 2010 Dec 13. [Epub ahead of print]

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.