title: Genetic polymorphisms of DNMT3L involved in hypermethylation of chromosomal ends are associated with greater risk of developing ovarian endometriosis.
abstract: Endometrioma is a common ovarian cyst associated with pain and infertility, but its pathogenesis remains enigmatic. Demonstration of the subtelomeric location of hypermethylation in endometrioma has been reported by genome-wide profiling of methylated promoters. Recently, rs113593938, a polymorphism in the DNA methyltransferase 3-like (DNMT3L) gene has been associated with subtelomeric hypomethylation. We investigated the association between endometrioma and rs113593938, rs8129776, rs7354779, and rs2276248, which were chosen for thoroughly covering the locus of interest. We enrolled 127 patients with histologically proved endometrioma and no associated deep endometriotic lesions and 317 healthy subjects for a case-control genetic association study. Genotyping was performed after PCR amplification of the region encompassing the polymorphisms, restriction enzyme digestion, and detection of fragments on an agarose gel. Differences in genotype and allele distributions between cases and controls were tested for each polymorphism separately using the χ(2) test. The rs8129776 was significantly associated with endometrioma (P = 0.003). Haplotype analysis showed a higher risk for the patients carrying the ACCC+T haplotypes for rs8129776, rs7354779, rs113593938, and rs2276248 (odds ratio, 7.15; 95% CI, 2.63 to 19.44). We report, for the first time to our knowledge, the association of DNMT3L genetic variants and endometrioma; DNMT3L expression itself was not modified. Our study constitutes a first milestone toward a plausible role of DNMT3L in the establishment of specific DNA methylation patterns in endometrioma.
authors.affiliation: Department of Gynecology and Obstetrics 2, Cochin University Hospital, Paris Descartes University, Public Hospitals of Paris (AP-HP), Paris, France. bruno.borghese@inserm.fr
authors.forename: Bruno
authors.initials: B
authors.lastname: Borghese
authors.forename: Pietro
authors.initials: P
authors.lastname: Santulli
authors.forename: Delphine
authors.initials: D
authors.lastname: Héquet
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pierre
authors.forename: Dominique
authors.initials: D
authors.lastname: de Ziegler
authors.forename: Daniel
authors.initials: D
authors.lastname: Vaiman
authors.forename: Charles
authors.initials: C
authors.lastname: Chapron
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D004715:Endometriosis / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D010049:Ovarian Diseases / Q000235:genetics*; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: C412484:DNMT3L protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases