THE GENETIC INHERITANCE OF POLYCYSTIC OVARY SYNDROME

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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. OBJECTIVE: Quantify the prevalence of specific DNA polymorphisms associated with polycystic ovary syndrome (PCOS), diabetes, and obesity in women with PCOS, family members of women with PCOS, and controls (women without PCOS). DESIGN: Prospective case-control RESEARCH PLAN: Participants include women aged 18-39 with a diagnosis of PCOS based upon amenorrhea/oligomenorrhea (10/year) and no hirsutism. Participants will complete a brief assessment of hair patterns using the modified Ferriman-Gallwey survey. They will have blood pressure, pulse, height, and weight measured. After fasting for 10 hours, subjects will have approximately 30 cc of blood drawn for hormonal levels and polymorphism studies. Serum samples will be analyzed for the following: glucose, HbA1C, CBC, liver function tests, lipids, and TSH. Serum samples will be frozen and stored for the following (when funding becomes available): total and free testosterone, progesterone, prolactin, dihydoepiandrostendione sulfate (DHEAS), 17-hydroxyprogesterone, LH, FSH, insulin, tissue plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1). Hormones will be run on reproductive-aged females only. Questionnaire, lab results, and hair survey will be used to determine if a person has PCOS. Whole blood for PCR will be collected in EDTA and frozen and stored at -20 degrees C. Candidate genes will be chosen from those which have been associated (or are identified in the future) with PCOS, obesity, or diabetes (such as the Beta 3 adrenergic receptor, TNF-Alpha, and insulin receptor gene VNTR). DNA will be isolated using a commercially available kit. Specific genes of interest will be isolated and amplified with polymerase chain reaction (PCR). PCR products will be incubated with specific restriction enzymes for sites of interest. Resulting digested DNA fragments will be run on a 2.5% agarose gel, stained with ethidium bromide, and analyzed under ultraviolet light. Occurrence rates of specific polymorphisms will be reported in the PCOS groups, family member group, and control group. CLINICAL RELEVANCE: PCOS, like diabetes, displays an inheritance suggestive of a genetic linkage. Genes place individuals at varying degrees of risk for insulin resistance, PCOS, type 2 diabetes, and even specific end organ damage. Determining distinct polymorphisms associated with PCOS and insulin resistance in valuable because it may predict a patient's disease progression or response to treatment. Specific polymorphisms will be correlated with ethnicity, BMI, and laboratory profiles to characterized and further define specific subsets within PCOS. Future treatments will be targeted to these subsets to improve efficacy.