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BACKGROUND: Folate metabolism is critical to embryonic development, influencing neural tube defects (NTD) and recurrent early pregnancy loss. Polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) have been associated with dizygotic (DZ) twinning through pregnancy loss. METHODS: The C677T and A1298C polymorphisms in MTHFR were genotyped in 258 Australasian families (1016 individuals) and 118 Dutch families (462 individuals) of mothers of DZ twins and a population sample of 462 adolescent twin families (1861 individuals). Haplotypes were constructed from the alleles, and transmission of the MTHFR haplotypes to mothers of DZ twins and from parents to twins in the adolescent twin families analysed. RESULTS: The C677T and A1298C were common in all three populations (frequencies > 0.29). There was strong linkage disequilibrium (D′ = 1) between the variants, showing that specific combinations of alleles (haplotypes) were transmitted together. Three haplotypes accounted for nearly all the variation. There was no evidence of any association between MTHFR genotype and twinning in mothers of twins, or of the loss of specific MTHFR genotypes during twin pregnancies. CONCLUSIONS: It is concluded that variation in twinning frequency is not associated with MTHFR genotype. [ABSTRACT FROM AUTHOR]

BACKGROUND Spontaneous dizygotic (DZ) twinning in humans is under genetic control. In sheep, heterozygous loss of function mutations in bone morphogenetic protein 15 (BMP15) increase ovulation and hence twinning rates. METHODS To investigate the role of BMP15 in human twinning, we typed 14 common variants, 4 rare novel variants initially detected by sequencing 279 mothers of DZ twins (MODZT) and 17 variants previously associated with premature ovarian failure (POF) in 933 DZ twinning families. We also typed five additional POF associated GDF9 variants. RESULTS There was some evidence for association between DZ twinning and a common intronic BMP15 variant (rs3897937), but this was not significant after correction for multiple testing. Three of the four novel variants (p.Pro174Ser, p.Ala311Thr and p.Arg392Thr) occurred in 1–5 MODZT but were not detected in 1512 controls. We also detected three POF associated mutations in both BMP15 and GDF9 at low frequencies in MODZT and controls. CONCLUSIONS We conclude that neither rare nor common BMP15 variants play a significant role in the variation in human DZ twinning. [ABSTRACT FROM AUTHOR]

BACKGROUND Endometriosis is a polygenic disease with a complex and multifactorial aetiology that affects 8–10% of women of reproductive age. Epidemiological data support a link between endometriosis and cancers of the reproductive tract. Fibroblast growth factor receptor 2 (FGFR2) has recently been implicated in both endometrial and breast cancer. Our previous studies on endometriosis identified significant linkage to a novel susceptibility locus on chromosome 10q26 and the FGFR2 gene maps within this linkage region. We therefore hypothesized that variation in FGFR2 may contribute to the risk of endometriosis. METHODS We genotyped 13 single nucleotide polymorphisms (SNPs) densely covering a 27 kb region within intron 2 of FGFR2 including two SNPs (rs2981582 and rs1219648) significantly associated with breast cancer and a total 40 tagSNPs across 150 kb of the FGFR2 gene. SNPs were genotyped in 958 endometriosis cases and 959 unrelated controls. RESULTS We found no evidence for association between endometriosis and FGFR2 intron 2 SNPs or SNP haplotypes and no evidence for association between endometriosis and variation across the FGFR2 gene. CONCLUSIONS Common variation in the breast-cancer implicated intron 2 and other highly plausible causative candidate regions of FGFR2 do not appear to be a major contributor to endometriosis susceptibility in our large Australian sample. [ABSTRACT FROM AUTHOR]

BACKGROUND Endometriosis is a polygenic disease with a complex and multifactorial aetiology that affects 8–10% of women of reproductive age. Epidemiological data support a link between endometriosis and cancers of the reproductive tract. Fibroblast growth factor receptor 2 (FGFR2) has recently been implicated in both endometrial and breast cancer. Our previous studies on endometriosis identified significant linkage to a novel susceptibility locus on chromosome 10q26 and the FGFR2 gene maps within this linkage region. We therefore hypothesized that variation in FGFR2 may contribute to the risk of endometriosis. METHODS We genotyped 13 single nucleotide polymorphisms (SNPs) densely covering a 27 kb region within intron 2 of FGFR2 including two SNPs (rs2981582 and rs1219648) significantly associated with breast cancer and a total 40 tagSNPs across 150 kb of the FGFR2 gene. SNPs were genotyped in 958 endometriosis cases and 959 unrelated controls. RESULTS We found no evidence for association between endometriosis and FGFR2 intron 2 SNPs or SNP haplotypes and no evidence for association between endometriosis and variation across the FGFR2 gene. CONCLUSIONS Common variation in the breast-cancer implicated intron 2 and other highly plausible causative candidate regions of FGFR2 do not appear to be a major contributor to endometriosis susceptibility in our large Australian sample. [ABSTRACT FROM AUTHOR]

STUDY QUESTIONS: DO DNA variants in the growth regulation by estrogen in breast cancer 1 (GREB1) region regulate endometrial GREB1 expression and increase the risk of developing endometriosis in women? SUMMARY ANSWER: We identified new single nucleotide polymorphisms (SNPs) with strong association with endometriosis at the GREB 1 locus although we did not detect altered GREB 1 expression in endometriosis patients with defined genotypes. WHAT IS ALREADY KNOWN: Genome-wide association studies have identified the GREB 1 region on chromosome 2p25.1 for increasing endometriosis risk. The differential expression of GREB 1 has also been reported by others in association with endometriosis disease phenotype. STUDY DESIGN, SIZE, DURATION: Fine mapping studies comprehensively evaluated SNPs within the GREB 1 region in a large-scale data set (.2500 cases and .4000 controls). Publicly available bioinformatics tools were employed to functionally annotate SNPs showing the strongest association signal with endometriosis risk. Endometrial GREB1 mRNA and protein expression was studied with respect to phases of the menstrual cycle (n = 2-45 per cycle stage) and expression quantitative trait loci (eQTL) analysis for significant SNPs were undertaken for GREB1 [mRNA (n = 94) and protein (n = 44) in endometrium]. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants in this study are females who provided blood and/or endometrial tissue samples in a hospital setting. The key SNPs were genotyped using Sequenom MASS ARRAY. The functional roles and regulatory annotations for identified SNPs are predicted by various publicly available bioinformatics tools. Endometrial GREB1 expression work employed qRT-PCR, western blotting and immunohistochemistry studies. MAIN RESULTS AND THE ROLE OF CHANCE: Fine mapping results identified a number of SNPs showing stronger association (0.004, P, 0.032) with endometriosis risk than the original GWASSNP (rs 13394619) (P = 0.034). Some of these SNPs were predicted to have functional roles, for example, interaction with transcription factor motifs. The haplotype (a combination of alleles) formed by the risk alleles from two common SNPs showed significant association (P = 0.026) with endometriosis and epistasis analysis showed no evidence for interaction between the two SNPs, suggesting an additive effect of SNPs on endometriosis risk. In normal human endometrium, GREB1 protein expression was altered depending on the cycle stage (significantly different in late proliferative versus late secretory, P, 0.05) and cell type (glandular epithelium, not stromal cells). However, GREB 1 expression in endometriosis cases versus controls and eQTL analyses did not reveal any significant changes. LIMITATIONS, REASONS FOR CAUTION: In silico prediction tools are generally based on cell lines different to our tissue and disease of interest. Functional annotations drawn from these analyses should be considered with this limitation in mind. We identified cell-specific and hormone-specific changes in GREB 1 protein expression. The lack of a significant difference observed following our GREB 1 expression studies may be the result of moderate power on mixed cell populations in the endometrial tissue samples. WIDER IMPLICATIONS OF THE FINDINGS: This study further implicates the GREB1 region on chromosome 2p25.1 and the GREB1 gene with involvement in endometriosis risk. More detailed functional studies are required to determine the role of the novel GREB 1 transcripts in endometriosis pathophysiology. [ABSTRACT FROM AUTHOR]