THE GENETICS OF INSULIN RESISTANCE IN FAMILIES WITH POLYCYSTIC OVARY SYNDROME
Polycystic ovary syndrome (PCOS) is a familial disorder characterized by major metabolic consequences related to insulin resistance (IR), including T2DM and metabolic syndrome (MS). There is mounting evidence, which supports association of each of G-174C variant in IL-6 and Pro12Ala variant in PPAR? genes with PCOS-associated biochemical or metabolic features in hyperandrogenic and PCOS adults/adolescents. The major aim of this study was to demonstrate the ability to enroll PCOS probands, who have one or more clinically PCOS-diagnosed woman, and their multigenerational family members for a total sample size of 100-125 to study IR and inflammation markers in such families. Additional important aims were to test for linkage between the IL6 and PPAR? genes loci and for associations between the IL6G-174C SNP and the Pro12Ala PPAR? SNP with IR, MS and its components, serum inflammation levels (IL-6 and CRP) and testosterone in this special population of PCOS families. IR was defined by a HOMA-IR value > 3.9 in adults and HOMA-IR values which are age-gender specific in adolescents. MS was defined according to the ATP III diagnostic criteria in adults and the same criteria, modified for age in adolescents. In total, 101 individuals were recruited from 9 multigenerational extended families; eight of the families were Caucasian and the remaining was African American. No evidence for linkage of each of the IL6 and the PPAR? markers to any of the examined phenotypes was found. However, interesting significant SNP-phenotype associations were found in this population of PCOS families. The Ala12 allele was found to be negatively associated with diastolic blood pressure (DBP) and with fasting glucose. Moreover, the G allele of the IL6 SNP was found to be positively associated with DBP, serum IL6 and testosterone levels. These associations are particularly important because they were adjusted for covariates which are known or were found to be significantly associated with the outcome in our population and were the results of the variance components association test, a test which accounts for family relationships. The findings are of major public health significance, mainly because they are the first to be reported in PCOS extended families.
Advisor:Joseph M. Zmuda, Ph.D.; Selma F. Witchel, M.D.; Candace M. Kammerer, Ph.D.; Evelyn O. Talbott, Dr.P.H.
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:08/07/2006