PHARMACOGENETICS OF INSULIN RESISTANCE IN PCOS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polycystic Ovary Syndrome (PCOS) is a endocrine disorder affecting 6-7% of reproductive-aged women. Women with PCOS have dysfunction of the ovaries that leads to elevated levels of male hormones (androgens). As long-term consequences they may develop infertility, type 2 diabetes mellitus (DM), uterine endometrial cancer, and cardiovascular disease (CVD). Diagnostic criteria for PCOS was defined in 1990 by the National Institutes of Health (NIH) to consist of: 1) clinical and/or biochemical evidence of elevated androgens, 2) chronic lack of ovulation, and 3) exclusion of similar related disorders. PCOS is inherited as a complex genetic disorder meaning that more than one gene may be involved, that the genes may interact with each other and/or with environmental elements. 30%-40% of sisters and 20%-30% of mothers of affected women also have PCOS. However, the identification of the responsible gene or genes has been difficult. The molecular genetic studies of PCOS have thus far been limited to investigations of candidate genes. These studies have focused on genes that may account for particular features of PCOS such as insulin secretion and action or obesity. Pharmacogenetics involves the study of genetic variants that alter response to drug therapy. There has been little work in the pharmacogenetics of insulin action and insulin resistance. Insulin resistance is an associated factor in PCOS indicating a need for some insulin resistance pharmacogenetic studies. Metformin is the drug currently in widespread clinical use and the most throughly investigated for treatment of PCOS. There is increasing evidence that genetic variation is best described by groups of associated polymorphisms or common variations in DNA sequence, referred to as haplotypes. Haplotypes reflect global gene structure, encompassing chromosomal blocks that have remained unbroken by recombination during the population history of the gene. Because of this we plan to use haplotypes as a means to uncover the relation between specific variants in candidate genes and the response to metformin therapy. Existing DNA samples and cell lines from IRB approved #3786, Dairy Research Institute for Genetics amp; Nutrition Epidemiology, Caucasian population will be used to identify the key single nucleotide polymorphism (SNP) sites for the haplotypes to be genotyped in this study. At this time, this study is being conducted in a small number of subjects to demonstrate our ability to carry out the protocol. Success in this pilot study will increase our ability to achieve funding from the NIH which will allow us to begin the full scale study.