Published Online
on September 28, 2009

A more recent version of this article appeared on November 1, 2009

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Original Article

Dysfunctional Corin I555 (P568) Allele is Associated with Impaired BNP Processing and Adverse Outcomes in African-Americans with Systolic Heart Failure: Results from the Genetic Risk Assessment in Heart Failure A-HeFT Sub-Study

J. Eduardo Rame¹; William Tam²; Dennis McNamara³; Manuel Worcel²; Michael L. Sabolinski²; Alan Wu¹ and Daniel L. Dries^4,5

¹ University of California San Francisco, San Francisco, CA;
² NitroMed Inc., Lexington, MA;
³ University of Pittsburgh Medical Center, Pittsburgh, PA;
⁴ Hospital of the University of Pennsylvania, Philadelphia, PA

^* Corresponding author; email: daniel.dries{at}uphs.upenn.edu

Background—Corin, a transmembrane serine protease expressed in cardiomyocytes, cleaves proANP and proBNP into biologically active peptide hormones. The minor corin I555(P568) allele, defined by the T555I and Q568P mutations, is common in persons of African ancestry and associated with increased risk for hypertension and cardiac concentric hypertrophy. The corin gene product containing the T555I and Q568P mutations has significantly reduced natriuretic peptide processing capacity . We hypothesized that the corin I555(P568) allele would be associated with adverse outcomes and impaired BNP processing in African-Americans with systolic heart failure.

Methods and Results—This is a retrospective study of 354 subjects in the African-America Heart Failure Trial (A-HeFT) Genetic Risk Assessment in Heart Failure (GRAHF) sub-study. In the corin variant group (N=50) compared to corin non-variant group (N=300), BNP-32 (amino acids 77-108) was lower (190pg/ml versus 340 pg/ml, p=0.007), but the ratio of unprocessed BNP _1-108/processed BNP-32 was significantly higher (P= 0.05). Stratified analyses were conducted because of evidence of significant interaction between the corin I555(P568) allele and treatment assignment. In the placebo arm, multivariable analysis demonstrated that the corin I555(P568) allele was associated with increased risk for death or heart failure hospitalization (RR 3.49; 95% CI 1.45-8.39; P=0.005); however, in the treatment arm (fixed-dose combination isosorbide-dinitrate/hydralazine), the corin I555(P568) allele was not associated with adverse outcomes.

Conclusions—We have identified a pharmacogenomic interaction in African-Americans with systolic heart failure. The corin I555(P568) allele is associated with an increased risk for death or heart failure hospitalization in patients receiving standard neurohormonal blockade, but the addition of fixed dose combination isosorbide-dinitrate/hydralazine (FDC I/H) ameliorates this risk. A plausible mechanism for this pharmacogenomic interaction is the impaired processing of BNP in carriers of the corin I555(P568) allele as compared to non-carriers.

Key Words: atrial natriuretic factor • epidemiology • genetics • heart failure • natriuretic peptides