title: Circadian clock-related genetic risk scores and risk of placental abruption.
abstract: BACKGROUND
  The circadian clock plays an important role in several aspects of female reproductive biology. Evidence linking circadian clock-related genes to pregnancy outcomes has been inconsistent. We sought to examine whether variations in single nucleotide polymorphisms (SNPs) of circadian clock genes are associated with PA risk.
  
  
  METHODS
  Maternal blood samples were collected from 470 PA case and 473 controls. Genotyping was performed using the Illumina Cardio-MetaboChip platform. We examined 119 SNPs in 13 candidate genes known to control circadian rhythms (e.g., CRY2, ARNTL, and RORA). Univariate and penalized logistic regression models were fit to estimate odds ratios (ORs); and the combined effect of multiple SNPs on PA risk was estimated using a weighted genetic risk score (wGRS).
  
  
  RESULTS
  A common SNP in the RORA gene (rs2899663) was associated with a 21% reduced odds of PA (P < 0.05). The odds of PA increased with increasing wGRS (Ptrend < 0.001). The corresponding ORs were 1.00, 1.83, 2.81 and 5.13 across wGRS quartiles. Participants in the highest wGRS quartile had a 5.13-fold (95% confidence interval: 3.21-8.21) higher odds of PA compared to those in the lowest quartile. Although the test for interaction was not significant, the odds of PA was substantially elevated for preeclamptics with the highest wGRS quartile (OR = 14.44, 95%CI: 6.62-31.53) compared to normotensive women in the lowest wGRS quartile.
  
  
  CONCLUSIONS
  Genetic variants in circadian rhythm genes may be associated with PA risk. Larger studies are needed to corroborate these findings and to further elucidate the pathogenesis of this important obstetrical complication.
authors.affiliation: Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA. Electronic address: Chun-fang.Qiu@Swedish.org.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Bizu
authors.initials: B
authors.lastname: Gelaye
authors.affiliation: UMR Amélioration Génétique et Adaptation des Plantes méditerranéennes et tropicales (AGAP), CIRAD, Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Denis
authors.affiliation: Department of Mathematics and Statistics, Georgetown University, Washington, DC, USA.
authors.forename: Mahlet G
authors.initials: MG
authors.lastname: Tadesse
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Luque Fernandez
authors.affiliation: Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Enquobahrie
authors.affiliation: Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Cande V
authors.initials: CV
authors.lastname: Ananth
authors.affiliation: Sección de Post Grado, Facultad de Medicina Humana, Universidad San Martín de Porres, Lima, Peru; A.C. PROESA, Lima, Peru; Department of Obstetrics and Gynecology, San Marcos University, Lima, Peru.
authors.forename: Sixto E
authors.initials: SE
authors.lastname: Sanchez
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Williams
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000037:Abruptio Placentae / Q000235:genetics*; D000328:Adult; D016022:Case-Control Studies; D057906:Circadian Clocks / Q000235:genetics; D056931:Cryptochromes / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C538966:CRY2 protein, human; D056931:Cryptochromes; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human
keywords: Circadian clock; Genetic risk score; Placental abruption; Pregnancy; SNPs