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. 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.

A change of heart: case series: peripartum cardiomyopathy

“…Recurrence is common in subsequent pregnancy [4], and a genetic basis for the disease has been posited [5,6] and so has implications for family planning.…”

“…It has been shown to show some concordance in families, though this may simply be a first manifestation of familial dilated cardiomyopathy [5]. A genome-wide study has shown a strong association between a gene on chromosome 12 and PPCM [6].…”

A contemporary review of peripartum cardiomyopathy

“…7 There appears to be an association with the parathyroid hormone-like hormone ( PTHLH ) gene, which modulates vascular homeostasis via calcium channel agonisation. 8 Moreover, the TTN gene, which encodes the sarcomeric protein titin, has also been implicated in pathogenesis. 9 A novel hypothesis relates to excess prolactin production, which is associated with enhanced intravascular volumes, suppressed response to angiotensin and increased circulating erythropoietin levels.…”

Reversible Dilated Cardiomyopathy: Into the Thaumaturgy of the Heart - Part 2

“…Familial occurrence of PPCMP has been described and genetic association has been shown in mice and humans. 63,64 Recently, a large study on 172 PPCMP patients, showed a prevalence of truncating variants (especially in the Titin gene) similar to DCM patients, suggesting that these variants may predispose to the condition. 65 Myocarditis appears to be the main pathophysiological mechanism in PPCMP.…”