Article

Examination of reproductive aging milestones among women who carry the FMRI premutation

Department of Gynecology and Obstetrics, Emory University, Atlanta, Georgia, United States
Human Reproduction (Impact Factor: 4.59). 09/2007; 22(8):2142-52. DOI: 10.1093/humrep/dem148
Source: PubMed

ABSTRACT The fragile X premutation is characterized by a large CGG repeat track (55-199 repeats) in the 5' UTR of the FMR1 gene. This X-linked mutation leads to an increased risk for premature ovarian failure; interestingly, the association of repeat size with risk is non-linear. We hypothesize that the premutation-associated ovarian insufficiency is due to a diminished oocyte pool and examined reproductive aging milestones by repeat size group to determine if the same non-linear association is observed.
We analyzed cross-sectional reproductive history questionnaire data from 948 women with a wide range of repeat sizes.
We have confirmed the non-linear relationship among premutation carriers for ovarian insufficiency. The mid-range repeat size group (80-100 repeats), not the highest group, had an increased risk for: altered cycle traits (shortened cycle length, irregular cycles and skipped cycles), subfertility and dizygotic twinning. Smoking, a modifiable risk, decreased the reproductive lifespan of women with the premutation by about 1 year, similar to its effect on non-carriers. As expected, premutation carriers were found to be at an increased risk for osteoporosis.
Possible molecular mechanisms to explain the non-linear repeat size risk for ovarian insufficiency are discussed.

Download full-text

Full-text

Available from: Kira C Taylor, Jan 07, 2014
0 Followers
 · 
104 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Are fragile X mental retardation gene 1 (FMR1) CGG repeats in the normal and intermediate range (up to 55 repeats) associated with primary ovarian insufficiency (POI) in a large case-control study? No association was found between CGG repeats of intermediate size and POI compared with controls. CGG repeats in the FMR1 gene in the premutation range (55-200 repeats) have consistenly associated with POI. Intermediate range CGG repeats have been considered for a potential association with POI. A case-control study in 375 well-phenotyped Dutch women diagnosed with POI and 3368 controls with natural menopause ≥40 years of age. The FMR1 CGG repeat number was determined by PCR amplification in women diagnosed with POI and women with a known age at natural menopause ≥40 years. The prevalence of intermediate sized CGG repeats (45-54 repeats) was compared between POI cases and controls using Fisher's exact test. Differences in mean CGG repeat lengths on allele 1 and allele 2 between POI cases and controls were tested using analysis of variance. The frequency of intermediate sized CGG repeats on the allele with the longest triple repeat number was not statistically significantly different between POI cases and controls (2.7 and 3.8%, respectively, odds ratio 0.72, 95% confidence interval: 0.38-1.39, P = 0.38). In women with POI, linear regression analysis for age at POI diagnosis and CGG repeat size also failed to show any association (β = -0.018, P = 0.74). FMR1 CGG repeat lengths in POI cases and controls were genotyped in two different laboratories. The distributions of CGG repeats may vary among the different ethnic populations in our study. Also, in our study women with primary amenorrhea (N = 17) were included in the POI group. We found no association between intermediate sized CGG repeats and POI compared with controls. Therefore, a role for FMR1 CGG repeat sizes up to 55 repeats in the ovarian ageing process may be questioned. Moreover, there seems limited value in the evaluation of normal- and intermediate FMR1 repeat size in the diagnostic work-up of women affected by POI, or for prognostic purposes in women at risk of developing POI. The Prospect-EPIC study was funded by 'Europe Against Cancer' Program of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organization for Health Research and Development; World Cancer Research Fund (WCRF) and the Dutch Heart Association.
    Human Reproduction 05/2014; 29(7). DOI:10.1093/humrep/deu095 · 4.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: STUDY QUESTION: Is there an association between the number of CGG repeats in the FMR1 gene in the normal and intermediate range and age at natural menopause? SUMMARY ANSWER: The number of CGG repeats in the normal and intermediate range in the FMR1 gene was not associated with age at natural menopause. WHAT IS KNOWN ALREADY: Excessive triple CGG repeats in the FMR1 gene have been widely associated with primary ovarian insufficiency. Recently, the number of CGG repeats in the normal and intermediate range (up to 55 repeats) was found to be associated with serum levels of anti-Müllerian hormone and follicle-stimulating hormone, as markers for ovarian ageing. This suggests that repeats in the normal and intermediate range could be involved in the rate of exhaustion of the ovarian primordial follicle pool and ultimately the timing of menopause. STUDY DESIGN, SIZE: Cross-sectional study in a population-based sample of 3611 Caucasian women with natural menopause. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FMR1 CGG repeat number was determined by PCR amplification in 3611 women with a known age at natural menopause. A possible relation between CGG repeats in the normal and intermediate range (up to 55 repeats) and menopausal age were analysed in various ways, including linear regression analysis and analysis of variance. MAIN RESULTS AND THE ROLE OF CHANCE: The number of CGG repeats in the normal and intermediate range in the FMR1 gene was not associated with age at natural menopause. The mean age at menopause was 50.30 (±4.2) years for women with <45 repeats and 50.64 (±3.4) years for women with intermediate-sized repeats (P = 0.37). Linear regression analysis of the number of CGG repeats showed no association with menopausal age (β = 0.019, P = 0.16). LIMITATIONS, REASONS FOR CAUTION: In our cohort, age at menopause was self-reported and determined retrospectively. WIDER IMPLICATIONS OF THE FINDINGS: Earlier observations suggesting that the number of CGG repeats in the normal and intermediate range is associated with the individual variation of the ovarian ageing process could not be confirmed in the current, large sample size study. A relation between the number of CGG repeats in the normal and intermediate range and age at natural menopause appeared to be absent. This finding questions the role of CGG repeat sizes in the ovarian ageing process. STUDY FUNDING/COMPETING INTEREST(S): N.C.O.-M., Y.T.S. and H.K.P.A. have nothing to declare. M.V. is financially supported by a grant from the Dutch Organisation for Scientific Research (NWO). F.J.B. is a member of the external advisory board for Merck Serono, The Netherlands, and does consultancy work for MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. TRIAL REGISTRATION NUMBER: Not applicable.
    Human Reproduction 11/2012; 28(2). DOI:10.1093/humrep/des392 · 4.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The premutation of the FMR1 gene (defined as between 55 and 200 CGG repeats) is estimated to affect 1 in 149 females and 1 in 643 males, and some people who carry the FMR1 premutation display signs of impairment. Method: This study focuses on 82 premutation carrier mothers (M age = 51.4 years; SD = 7.7) of adolescent and adult children with fragile X syndrome (FXS). A Gene × Environment interaction approach examined the ways in which the experience of negative life events interacts with genetic vulnerability to predict depressive symptoms, anxiety, and daily cortisol levels. Results: The associations of life events with all 3 dependent measures were associated with CGG repeat length but in a curvilinear manner. Mothers with midsize CGG repeats who experienced above-average numbers of negative life events in the previous year had more depressive symptoms and anxiety and had a blunted cortisol awakening response, as compared with those with higher or lower repeat lengths. However, mothers with midsize CGG repeats who experienced below-average numbers of negative life events in the previous year had the lowest levels of depressive symptoms and anxiety, and they exhibited the typical cortisol response to awakening, meeting the criteria for differential susceptibility. Conclusions: This research extends our understanding of the phenotypic effects of the expansion of the FMR1 gene, and it adds to the growing literature on the curvilinear relationship between CGG repeat length and mental and physical health. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
    Health Psychology 12/2011; 31(5):612-22. DOI:10.1037/a0026528 · 3.95 Impact Factor