title: Genome-wide significance and replication of the chromosome 12p11.22 locus near the PTHLH gene for peripartum cardiomyopathy.
abstract: BACKGROUND
  Peripartum (PP) cardiomyopathy (CM) is a rare condition of unknown etiology that occurs in late pregnancy or early postpartum. Initial evidence suggests that genetic factors may influence PPCM. This study evaluated and replicated genome-wide association of single nucleotide polymorphisms with PPCM.
  
  
  RESULTS
  Genome-wide single nucleotide polymorphisms in women with verified PPCM diagnosis (n=41) were compared separately with local control subjects (n=49 postmenopausal age-discordant women with parity ≥1 and no heart failure) and iControls (n=654 women ages 30 to 84 years with unknown phenotypes). A replication study of independent population samples used new cases (PPCM2, n=30) compared with new age-discordant control subjects (local2, n=124) and with younger control subjects (n=89) and obstetric control subjects (n=90). A third case set of pregnancy-associated CM cases not meeting strict PPCM definitions (n=29) was also studied. In the genome-wide association study, 1 single nucleotide polymorphism (rs258415) met genome-wide significance for PPCM versus local control subjects (P=2.06×10(-8); odds ratio [OR], 5.96). This was verified versus iControls (P=7.92×10(-19); OR, 8.52). In the replication study for PPCM2 cases, rs258415 (ORs are per C allele) replicated at P=0.009 versus local2 control subjects (OR, 2.26). This replication was verified for PPCM2 versus younger control subjects (P=0.029; OR, 2.15) and versus obstetric control subjects (P=0.013; OR, 2.44). In pregnancy-associated cardiomyopathy cases, rs258415 had a similar effect versus local2 control subjects (P=0.06; OR, 1.79), younger control subjects (P=0.14; OR, 1.65), and obstetric control subjects (P=0.038; OR, 1.99).
  
  
  CONCLUSIONS
  Genome-wide association with PPCM was discovered and replicated for rs258415 at chromosome 12p11.22 near PTHLH. This study indicates a role of genetic factors in PPCM and provides a new locus for further pathophysiological and clinical investigation.
authors.affiliation: Cardiovascular Department, Intermountain Medical Center, Genetic Epidemiology Division, University of Utah, USA. benjamin.horne@imail.org
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Horne
authors.forename: Kismet D
authors.initials: KD
authors.lastname: Rasmusson
authors.forename: Rami
authors.initials: R
authors.lastname: Alharethi
authors.forename: Deborah
authors.initials: D
authors.lastname: Budge
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Brunisholz
authors.forename: Torri
authors.initials: T
authors.lastname: Metz
authors.forename: John F
authors.initials: JF
authors.lastname: Carlquist
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Connolly
authors.forename: T Flint
authors.initials: TF
authors.lastname: Porter
authors.forename: Donald L
authors.initials: DL
authors.lastname: Lappé
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Muhlestein
authors.forename: Robert
authors.initials: R
authors.lastname: Silver
authors.forename: Josef
authors.initials: J
authors.lastname: Stehlik
authors.forename: James J
authors.initials: JJ
authors.lastname: Park
authors.forename: Heidi T
authors.initials: HT
authors.lastname: May
authors.forename: Tami L
authors.initials: TL
authors.lastname: Bair
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
authors.forename: Dale G
authors.initials: DG
authors.lastname: Renlund
authors.forename: Abdallah G
authors.initials: AG
authors.lastname: Kfoury
mesh_terms: D000328:Adult; D009202:Cardiomyopathies / Q000235:genetics*; D016022:Case-Control Studies; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D058725:Peripartum Period; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000235:genetics*; D055815:Young Adult
chemical_list: C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein