Search

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Corin is a cardiac serine protease that acts as the pro-atrial natriuretic peptide (ANP) convertase. Recently, 2 single-nucleotide polymorphisms (SNPs) (T555I and Q568P) in the human corin gene have been identified in genetic epidemiological studies. The minor I555/P568 allele, which is more common in African Americans, is associated with hypertension and cardiac hypertrophy. In this study, we examined the effect of T555I and Q568P amino acid substitutions on corin function. We found that corin frizzled-like domain 2, where T555I/Q568P substitutions occur, was required for efficient pro-ANP processing in functional assays. Mutant corin lacking this domain had 30+/-5% (P<0.01) activity compared to that of wild type. Similarly, corin variant T555I/Q568P had a reduced (38+/-7%, P<0.01) pro-ANP processing activity compared to that of wild type. The variant also exhibited a low activity (44+/-15%, P<0.05) in processing pro-brain natriuretic peptide (BNP). We next examined the biochemical basis for the loss of activity in T555I/Q568P variant and found that the zymogen activation of the corin variant was impaired significantly, as indicated by the absence of the activated protease domain fragment. This finding was confirmed in human embryonic kidney (HEK)293 cells and murine HL-1 cardiomyocytes. Thus, our results show that the corin gene SNPs associated with hypertension and cardiac hypertrophy impair corin zymogen activation and natriuretic peptide processing activity. Our data suggest that corin deficiency may be an important mechanism in hypertensive and heart diseases.

Corin activates pro-A-type naturetic peptide and pro-B-type naturetic peptide into biologically active molecules. We recently identified a minor allele in the corin gene defined by 2 highly linked single nucleotide polymorphisms (T555I and Q568P), which was associated with hypertension in blacks. Because of the direct antihypertrophic effects of the natriuretic peptide system, we hypothesized that the minor corin I555(P568) allele would be associated with an enhanced hypertrophic response to pressure overload. The relationship between systolic blood pressure and indexed left ventricular mass, derived from cardiac MRI, was analyzed in the Dallas Heart Study as a function of corin allele status. The Multi-Ethnic Study of Atherosclerosis was used as a validation cohort. All of the analyses were limited to self-identified blacks without treatment for hypertension. In addition, we genotyped 2114 markers highly informative for African ancestry in the Dallas Heart Study and derived a covariate representing African ancestry for multivariate models. In adjusted analysis, the corin I555(P568) allele was an independent predictor of left-ventricular mass in subjects with elevated systolic blood pressure. Linear spline regression analysis confirmed a significant interaction (P=0.002) between the corin I555(P568) allele and systolic blood pressure as a predictor of left ventricular mass in subjects with systolic blood pressure >120 mm Hg, and this nonlinear interaction was replicated in the Multi-Ethnic Study of Atherosclerosis. In the Dallas Heart Study, the corin I555(P568) allele was also associated with an increased odds for prevalent left ventricular hypertrophy in the presence of untreated hypertension. These data suggest that the corin I555(P568) allele represents a cardiac hypertrophy-sensitizing genetic locus in systemic hypertension.

Background: The natriuretic peptide system contributes to blood pressure regulation. Atrial and brain natriuretic peptides are cleaved into smaller biologically active molecules by corin, a transmembrane serine protease expressed in cardiomyocytes., Method and Results: This genotype-phenotype genetic association study included replication samples and genomic control to correct for population stratification. Sequencing of the human corin gene identified 2 nonsynonymous, nonconservative single nucleotide polymorphisms (Q568P and T555I) in near-complete linkage disequilibrium, thus describing a single minor I555 (P568) corin gene allele. This allele was present in the heterozygote state in &12% of blacks but was extremely rare in whites (<0.5% were homozygous for the minor allele). In our primary population sample, the Dallas Heart Study, after adjustment for potential confounders, including population stratification, the corin I555 (P568) allele remained independently associated with increased risk for prevalent hypertension (odds ratio, 1.63; 95% CI, 1.11 to 2.38; P=0.013). The corin I555 (P568) allele also was associated with higher systolic blood pressure in subjects not using antihypertensive medication in unadjusted (133.7+/-20.7 versus 129.4+/-17.4 mm Hg; P=0.029) and adjusted (132.5+/-1.6 versus 128.9+/-0.6 mm Hg; P=0.029) analyses. The independent association of the minor corin allele with increased risk for prevalent hypertension was confirmed in the Multi-Ethnic Study of Atherosclerosis (odds ratio, 1.50; 95% CI, 1.09 to 2.06; P=0.014). In addition, the association of the minor corin I555 (P568) allele with higher systolic blood pressure was confirmed in adjusted analysis in the Chicago Genetics of Hypertension Study (125.8+/-1.9 versus 121.4+/-0.7 mm Hg; P=0.03)., Conclusions: The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension.

The progression from concentric left ventricular (LV) hypertrophy to heart failure has not been well defined. Of 159 predominantly hypertensive African-American patients with LV hypertrophy and a normal ejection fraction (EF), 28 (18%) developed a reduced EF after a median follow-up of approximately 4 years. Risk factors for this outcome included a history of coronary artery disease, pulmonary edema seen on a chest x-ray, or a subsequent myocardial infarction.