title: Aberrant sperm DNA methylation predicts male fertility status and embryo quality.
abstract: OBJECTIVE
  To evaluate whether male fertility status and/or embryo quality during in vitro fertilization (IVF) therapy can be predicted based on genomewide sperm deoxyribonucleic acid (DNA) methylation patterns.
  
  
  METHODS
  Retrospective cohort study.
  
  
  METHODS
  University-based fertility center.
  
  
  METHODS
  Participants were 127 men undergoing IVF treatment (where any major female factor cause of infertility had been ruled out), and 54 normozoospermic, fertile men. The IVF patients were stratified into 2 groups: patients who had generally good embryogenesis and a positive pregnancy (n = 55), and patients with generally poor embryogenesis (n = 72; 42 positive and 30 negative pregnancies) after IVF.
  
  
  METHODS
  Genomewide sperm DNA methylation analysis was performed to measure methylation at >485,000 sites across the genome.
  
  
  METHODS
  A comparison was made of DNA methylation patterns of IVF patients vs. normozoospermic, fertile men.
  
  
  RESULTS
  Predictive models proved to be highly accurate in classifying male fertility status (fertile or infertile), with 82% sensitivity, and 99% positive predictive value. Hierarchic clustering identified clusters enriched for IVF patient samples and for poor-quality-embryo samples. Models built to identify samples within these groups, from neat samples, achieved positive predictive value ≥ 94% while identifying >one fifth of all IVF patient and poor-quality-embryo samples in each case. Using density gradient prepared samples, the same approach recovered 46% of poor-quality-embryo samples with no false positives.
  
  
  CONCLUSIONS
  Sperm DNA methylation patterns differ significantly and consistently for infertile vs. fertile, normozoospermic men. In addition, DNA methylation patterns may be predictive of embryo quality during IVF.
authors.affiliation: Department of Surgery, University of Utah Andrology and IVF Laboratories, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Aston
authors.affiliation: Molecular and Computational Biology, University of Southern California, Los Angeles, California.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Uren
authors.affiliation: Department of Surgery, University of Utah Andrology and IVF Laboratories, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Jenkins
authors.affiliation: Episona, Inc, Glendale, California.
authors.forename: Alan
authors.initials: A
authors.lastname: Horsager
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah; Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Cairns
authors.affiliation: Molecular and Computational Biology, University of Southern California, Los Angeles, California.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Smith
authors.affiliation: Department of Surgery, University of Utah Andrology and IVF Laboratories, University of Utah School of Medicine, Salt Lake City, Utah; Department of Obstetrics and Gynecology and Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah. Electronic address: douglas.carrell@hsc.utah.edu.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Carrell
mesh_terms: D001755:Blastocyst / Q000473:pathology*; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005298:Fertility / Q000235:genetics; D005307:Fertilization in Vitro; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007248:Infertility, Male / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011247:Pregnancy; D018873:Pregnancy Rate; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D012307:Risk Factors; D013094:Spermatozoa / Q000473:pathology*; D016896:Treatment Outcome
keywords: DNA methylation; IVF outcome; Sperm DNA; embryo; genomewide; male infertility; microarray