1. Genome-wide significance and replication of the chromosome 12p11.22 locus near the PTHLH gene for peripartum cardiomyopathy.
- Author
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Horne BD, Rasmusson KD, Alharethi R, Budge D, Brunisholz KD, Metz T, Carlquist JF, Connolly JJ, Porter TF, Lappé DL, Muhlestein JB, Silver R, Stehlik J, Park JJ, May HT, Bair TL, Anderson JL, Renlund DG, and Kfoury AG
- Subjects
- Adult, Case-Control Studies, Female, Genome, Human, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Pregnancy, Young Adult, Cardiomyopathies genetics, Chromosomes, Human, Pair 12 genetics, Parathyroid Hormone-Related Protein genetics, Peripartum Period, Pregnancy Complications, Cardiovascular genetics
- 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., Methods and 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.
- Published
- 2011
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