FMRI CGG Repeats:Reference Levels and Race-Ethnic Variation in Women With Normal Fertility (Study of Women’s Health Across the Nation)

Abstract

, and potentially women with high normal (35)(36)(37)(38)(39)(40)(41)(42)(43)(44) or low normal (<28) CGG repeats, are at risk of premature ovarian aging. The scarcity of population data on CGG repeats <45 CGG, and variation in raceethnicity, makes it difficult to determine true associations. DNA was analyzed for FMR1 CGG repeat lengths from 803 women (386 caucasians, 219 African Americans, 102 Japanese, and 96 Chinese) from the US-based Study of Women's Health Across the Nation (SWAN). Participants had 1 menses in the 3 months before enrollment, 1 pregnancy, no history of infertility or hormonal therapy, and menopause 46 years. Statistical analyses used Fisher exact tests. Among these women with normal reproductive histories, significant FMR1 repeat length differences were found across race-ethnicity for both the longer (P ¼ .0002) and the shorter (P < .0001) alleles. The trinucleotide length variance was greater for non-Asian than Asian women (P < .0001), despite identical median values. Our data indicate that short allele lengths <25 CGG on one or both alleles are more common in non-Asian than Asian women. We confirm the minor allele in the 35 to 39 CGG range among Asians as reported previously. Only 2 (0.3%) premutation carriers were identified. These data demonstrate that FMR1 distributions do vary by race-ethnicity, even within the ''normal'' range. This study indicates the need to control for race-ethnicity in FMR1 ovarian aging research and provides race-ethnic population data for females separated by allele.

Distribution of the FMR1 gene in females by race/ethnicity: women with diminished ovarian reserve versus women with normal fertility (SWAN study)

“…No race-ethnic differences were observed among the DOR cases on allele 2 (p=0.441). Race-ethnic differences in the CGG repeat length on allele 2 were observed among the controls and have been reported previously (20). …”

“…Thus, the modal CGG repeat lengths for cases are within 1 repeat of the modal lengths for controls even after stratification by the two race-ethnic groups. Comparing Caucasian vs Asian DOR cases for allele 1, Figure 1a indicates that alleles shorter than 26 CGG were more common in Caucasian than Asian women, which is also observed for the SWAN controls, as previously reported (20). …”

“…Race-ethnic comparisons were restricted to Caucasian vs. Asian women, because (a) the sample size of African-Americans in the case group was limited, and (b) data to separate Chinese and Japanese ethnicities were unavailable in the case group. In a previous analysis (20) the SWAN Chinese and Japanese groups had similar FMR1 CGG repeat lengths. Quantitative comparisons of CGG repeat length, separate for alleles 1 and 2, were completed by one-way ANOVA, with the allele 2 counts analyzed after log-transformation.…”

“…Cases with single PCR peaks enrolled prior to April 2012 were confirmed as homozygous with Southern Blot testing (62% of cases); cases with single PCR peaks enrolled after that date were presumed to be homozygous. See Pastore et al (20) for further details on the FMR1 lab testing.…”

Study of the Genetic Etiology of Primary Ovarian Insufficiency: FMR1 Gene

“…There is no consensus about the estimated prevalence of FMR1 alleles and this prevalence varies between geographical areas and the population assessed [41,44,45]. …”