Replication of Genome-Wide Association of the PTHLH-KLHDC5 Locus with Peripartum Cardiomyopathy

Abstract

Introduction: Peripartum cardiomyopathy (PPCM) is a rare condition of unknown etiology, occurring late in pregnancy or early postpartum. Froma genome-wide association study (GWAS), we reported association of rs258415 with PPCMamong 41 cases and 49 age-discordant controls (C allele: odds ratio [OR]55.96, p = 2.1null10-8).Hypothesis: In an independent population, we tested the association of rs258415 and suggestive (p = 10-5 to 10-7) single nucleotide polymorphisms (SNPs) with PPCM. Methods: Using ourGWAS definitions, new PPCMcases (n=34) verified by strict definition (including EF (less-than or equal to)45%) were compared to older controls (n=124) by the Armitage test of trend. Older controls were post-menopausal age-discordant (ages 71-91 years) Caucasian females with no heart failure. PPCM were also compared to younger controls (n = 89, ages 20-44) and unconfirmed (non-strict defn) cases (n = 38). Results: PPCM cases averaged 33.6 (plus or minus) 6.9 years of age (range: 21-48). Rs258415 replicated for PPCMvs. older controls (minor allele frequency: 0.29 vs. 0.16; OR = 1.93 per allele, 95% CI = 1.02, 3.67; p = 0.041) and also predicted PPCM vs. younger controls (OR = 1.80, p = 0.10) but not vs. unconfirmed cases (OR = 1.06, p = 0.88). Rs258415 may predict unconfirmed cases vs. older controls (OR = 1.79, p = 0.053). Several suggestive SNPs also replicated (Table). (Table presented). Conclusion: GWAS-discovered association of the PTHLH-KLHDC5 locus (rs258415) with PPCM was independently replicated and other potential PPCM risk SNPs were identified. This confirms a genetic contribution to PPCM. Future studies will search for causal SNPs, explore clinical application, and study pathophysiological mechanisms.