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Original Articles

Dysfunctional Corin I555(P568) Allele Is Associated With Impaired Brain Natriuretic Peptide Processing and Adverse Outcomes in Blacks With Systolic Heart Failure

Results From the Genetic Risk Assessment in Heart Failure Substudy

J. Eduardo Rame, MD, MPhil; S. William Tam, PhD; Dennis McNamara, MD; Manuel Worcel, MD; Michael L. Sabolinski, MD; Alan H. Wu, PhD and Daniel L. Dries, MD, MPH

From the Division of Cardiology (J.E.R., A.H.W.), University of California San Francisco, San Francisco, Calif; NitroMed Inc (S.W.T., M.W., M.L.S.), Lexington, Mass; University of Pittsburgh Medical Center (D.M.), Pittsburgh, Pa; and Penn Cardiovascular Institute (D.L.D.), Heart Failure/Transplant Group, Hospital of the University of Pennsylvania, Philadelphia, Pa.

Correspondence to Daniel L. Dries, MD, MPH, Heart Failure/Transplant Program and the Penn Cardiovascular Institute, Cardiovascular Division, Hospital of the University of Pennsylvania, PCAM, 2nd Floor East Pavilion, Room 2-367, 3400 Civic Center Blvd, Philadelphia, PA 19104. E-mail daniel.dries{at}uphs.upenn.edu

Received March 19, 2009; accepted September 10, 2009.

Background— Corin, a transmembrane serine protease expressed in cardiomyocytes, cleaves pro–atrial natriuretic peptide and pro–brain natriuretic peptide (BNP) 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 blacks with systolic heart failure.

Methods and Results— This is a retrospective study of 354 subjects in the African American Heart Failure Trial Genetic Risk Assessment in Heart Failure substudy. In the corin variant group (n=50) compared with corin nonvariant group (n=300), BNP-32 (amino acids 77 to 108) was lower (190 pg/mL versus 340 pg/mL, P=0.007), but the ratio of unprocessed BNP_{1 to 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 (relative risk 3.49; 95% CI, 1.45 to 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 blacks 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 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 with noncarriers.

Key Words: genetics • epidemiology • heart failure • natriuretic peptides • pharmacology

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