AS254 - Telomere and its biochemical and genetic regulators as predictors for clinical diabetes in women diabetes in women

Investigator Names and Contact Information

Simin Liu, MD, ScD

Introduction/Intent

Age-dependent telomere shortening, observed in most somatic cells, impairs cellular function and viability of the aged organism and has been associated with a variety of age-related complex diseases such as diabetes, vascular dementia and atherosclerosis. Cross-sectional studies show that diabetic cases have average shorter telomere length in leukocytes compared with non-diabetic controls. Moreover, individual differences in telomere length in rodents and humans suggest that this parameter is genetically determined. Telomere length is regulated by telomerase and telomere-associated proteins, including TRF1, TRF2, POT1, TIN2, RAP1, and TPP1, which are the components of telomere structure. Furthermore, obesity has long been recognized as an important cause of type 2 diabetes and insulin resistance. Adiposity is associated with systemic inflammation and oxidative stress, two fundamental pathophysiological processes that accelerate chromosomal telomere erosion in humans. The relationship between telomere length, inflammation, and type 2 diabetes in humans remains largely unexplored, however. Therefore, we proposed to investigate, in a large prospective cohort of multiethnic postmenopausal women, the roles of inflammation and oxidative stress in affecting telomere regulation and risk of type 2 diabetes.

Aims

Our main goal is to understand the roles of telomere length and its regulators (both genetic and biochemical) in the development of type 2 diabetes among multiethnic postmenopausal women participated in the Women’s Health Initiative Observational Study (WHIOS). The specific aims are:

1: To prospectively examine the relation between leukocyte telomere length and risk of type 2 diabetes in postmenopausal women. Telomere length as measured in peripheral blood leukocytes has emerged as an important biomarker of aging and age-related diseases. Previous cross-sectional studies have found that telomere length in peripheral white blood cells is shorter among patients with type 2 diabetes than the length among non-diabetic controls. However, there are as yet no prospective data examining the role of telomere length in subsequent diabetes occurrence. We hypothesize that subjects with a shorter telomere length at baseline would have an elevated risk of type 2 diabetes later in life. With the advantage of using the data from a large prospective cohort study – WHI-OS, we will be the first to test our hypothesis regarding the role of telomeres in the development of type 2 diabetes.

2. To define specific functional single nucleotide polymorphisms (SNPs) of genes that regulate telomere length in a multiethnic cohort of postmenopausal women, and to evaluate their roles in affecting telomere length as well as in the risk of developing type 2 diabetes in these women. Telomere length is determined in part by inherited genetic factors. Variation in genes that regulate telomere stability and maintenance may influence telomere length and risk of type 2 diabetes. We plan to examine genes coding for telomere-regulation proteins, including telomeric repeat binding factor 1 and 2 (TRF1 and TRF2), protection of telomeres 1 (POT1), human TRF2-interacting telomeric protein (hRAP1), TRF1-interacting nuclear factor 2 (TIN2), and TIN2- and POT1-organizing protein (TPP1). We propose to examine genetic variants in telomere-related genes in relation to the risk of type 2 diabetes, and assess the interactions between telomere length and these genetic variants on diabetes risk. We will conduct comprehensive evaluation of important and common SNP in those genes and their association with telomere length, as well as their influence on the risk of type 2 diabetes. We hypothesize that SNPs in those genes may affect their protein structures and functions and thereby accelerate telomere shortening. Thus, common genetic variations in these genes may be associated with risk of type 2 diabetes through their effects on telomere length.

3. To examine the associations between plasma concentrations of inflammatory cytokines and markers of endothelial dysfunction and telomere length in postmenopausal women. We have previously observed in these women that: inflammatory cytokines including C-reactive protein(CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-a), and endothelial dysfunction markers including intercellular adhesion molecule-1 (ICAM1), vascular celladhesion molecule-1(VCAM), and E-selectin were elevated among type 2 diabetes cases in comparison to that in controls.

Results/Findings

Some of the publications related to this ancillary study are:

Ms1224 - You NC, Chen BH, Song Y, Lu X, Chen Y, Manson JE, Kang M, Howard BV, Margolis KL, Curb JD, Phillips LS, Stefanick ML, Tinker LF, Liu S. A prospective study of leukocyte telomere length and risk of type 2 diabetes in postmenopausal women. Diabetes. 2012 Jul 24. [Epub ahead of print]

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Papers section of this website.