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Genetic factors in premature ovarian failure Bretherick, Karla Lucia

Abstract

Approximately 1% of women will experience menopause before the age of 40, a condition known as premature ovarian failure (POF). The goal of this thesis was to identify genetic causes of POF by examining a number of candidate factors in POF patients and control women. Carriers of FMR1 premutations (55-200 CGG repeats) are known to be at increased risk of POF. A higher prevalence of alleles between 35-54 repeats was found among POF patients (p=0.01), suggesting that risk for POF may extend outside the classic premutation range. There was no evidence for any difference in FMRI promoter methylation or gene expression between cases and controls. Allele distributions of gene polymorphisms in the androgen receptor (AR), estrogen receptor (ß, sex hormone binding globulin, and FSH receptor genes did not differ between POF patients and controls. However, haplotype at the estrogen receptor a gene, ESRI, was found to be associated with POF in a simple dominant manner (RR=9.7; 95% CI=2.6-35.6). Although the functional effect of this haplotype could not be confirmed, it may confer a more active promoter that influences risk by increasing the rate of follicular atresia. X-chromosome inactivation (XCI) skewing can indicate an abnormal X chromosome and may therefore be increased in POF patients. There was no increase in skewed XCI >90% in patients with secondary amenorrhea, however, there was a significant increase in 4 POF patients with primary amenorrhea (p=0.001). No X-chromosome abnormalities were detectable by high resolution DNA microarray, and skewed XCI may be explained by a trisomic rescue event causing reduced follicular pool. Age-related chromosome factors were assessed to determine if POF patients demonstrate an increased rate of cellular aging. With age, XCI skewing and AR methylation increase and telomere length decreases. There was no difference in skewing or methylation between patients and controls. Surprisingly telomere length was increased in POF patients (p=0.04), a finding that may be explained by abnormal estrogen exposure. Genotype at the longevity-associated APOE gene was not associated with POF. In conclusion, these findings have illuminated several new areas of research in this field and provide background for future research into POF pathogenesis.

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