The FMR1 gene partially appears to control ovarian reserve, with a specific ovarian sub-genotype statistically associated with a polycystic ovary (PCO)- like phenotype. Some forms of PCO have been associated with autoimmunity. We, therefore, investigated in multiple regression analyses associations of ovary-specific FMR1 genotypes with autoimmunity and pregnancy chances (with in vitro fertilization, IVF) in 339 consecutive infertile women (455 IVF cycles), 75 with PCO-like phenotype, adjusted for age, race/ethnicity, medication dosage and number of oocytes retrieved. Patients included 183 (54.0%) with normal (norm) and 156 (46%) with heterozygous (het) FMR1 genotypes; 133 (39.2%) demonstrated laboratory evidence of autoimmunity: 51.1% of het-norm/low, 38.3% of norm and 24.2% het-norm/high genotype and sub-genotypes demonstrated autoimmunity (p=0.003). Prevalence of autoimmunity increased further in PCO-like phenotype patients with het-norm/low genotype (83.3%), remained unchanged with norm (34.0%) and decreased in het-norm/high women (10.0%; P<0.0001). Pregnancy rates were significantly higher with norm (38.6%) than het-norm/low (22.2%, p=0.001). FMR1 sub-genotype het-norm/low is strongly associated with autoimmunity and decreased pregnancy chances in IVF, reaffirming the importance of the distal long arm of the X chromosome (FMR1 maps at Xq27.3) for autoimmunity, ovarian function and, likely, pregnancy chance with IVF.

Competing Interests:The authors have read the journal's policy and have the following conflicts: NG and DHB are listed as co-inventors on a number of pending United States patents and one already granted patent, which, peripherally, relate to this manuscript. Those patents claim: (1) Therapeutic benefits from supplementation of women with DOR with dehydroepiandrosterone (DHEA). Since some patients in this study were DHEA supplemented, this may have relevance. (2) Diagnostic benefits from determining triple CGG nucleotide repeats on the FMR1 gene in attempts to assess and predict ovarian reserve. NG is owner of the Center for Human Reproduction (CHR), where this study was conducted. The authors confirm that these conflicts do not alter our adherence to all the PLoS ONE policies on sharing data and materials.