Corin Gene Minor Allele Defined by 2 Missense Mutations Is Common in Blacks and Associated With High Blood Pressure and Hypertension

Dries, Daniel L.; Victor, Ronald G.; Rame, J. Eduardo; Cooper, Richard S.; Wu, Xiaodong; Zhu, Xiaofeng; Léonard, David; Ho, Su Inn; Wu, Qingyu; Post, Wendy S.; Drazner, Mark H.

doi:10.1161/circulationaha.105.568881

Cited by 184 publications

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“…To control for hidden population stratification in the DHS, therefore, we entered a covariate of estimated African ancestry, derived from the genotyping of 2114 markers highly informative of African ancestry, for each subject in regression models as described previously. 10 These 2114 genomic markers were not ascertained in MESA; therefore, we could not adjust for population stratification in MESA. Table 1 demonstrates the genotype prevalences in the DHS and MESA according to self-identified race.…”

Section: Statistical Methodologymentioning

confidence: 99%

“…TaqMan 5Ј nuclease allelic discrimination assay 15 was used for genotyping of the corin polymorphisms as described. 10 Perlegen Sciences high-density oligonucleotide-hybridization array technology was used to genotype the DHS cohort for 2114 markers that are highly informative for African ancestry 16 as described previously. 10 The results of the corin sequencing project, including the nucleotide sequence defining and surrounding the T555I (threonine to isoleucine) and Q568P (glutamine to proline) polymorphisms in exon 11 of the human corin gene are available at pga@utsouthwestern.edu.…”

Section: Genotypingmentioning

confidence: 99%

“…8,9 We demonstrated recently that a minor allele in the human corin gene, defined by the presence of 2 single nucleotide polymorphisms (T555I and Q568) in near complete linkage disequilibrium, was enriched in black subjects and associated with higher blood pressure and an increased risk for prevalent hypertension. 10 Based on these data, we hypothesized that the corin I555(P568) allele was associated with impaired natriuretic peptide processing and, therefore, would be associated with an enhanced cardiac hypertrophic response to pressure overload. To test this hypothesis, we analyzed the relationship between systolic blood pressure (SBP) and indexed left ventricular mass, analyzed as a quantitative trait, in untreated blacks in our primary cohort, the Dallas Heart Study (DHS).…”

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Corin I555(P568) Allele Is Associated With Enhanced Cardiac Hypertrophic Response to Increased Systemic Afterload

et al. 2007

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Abstract-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 (Pϭ0.002) between the corin I555(P568) allele and systolic blood pressure as a predictor of left ventricular mass in subjects with systolic blood pressure Ͼ120 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. T he natriuretic peptide system functions as an autocrine and paracrine hormonal system within the heart that opposes the development of cardiac hypertrophy by mechanisms that are independent from the ability of the natriuretic peptides to lower blood pressure. [1][2][3][4][5][6] For example, mice with cardiomyocyte-restricted inactivation of the natriuretic peptide receptor (natriuretic peptide receptor type-A) have a lower blood pressure than control mice (because of higher systemic A-type naturetic peptide levels because of loss of the negative feedback), but have increased ventricular hypertrophy at baseline. Moreover, the differences between the knockout and control mice in terms of cardiomyocyte hypertrophy and activation of the hypertrophic gene cascade were enhanced after the application of pressure overload induced by aortic banding. 7 Corin is a type II transmembrane serine protease recently demonstrated to be the "pro-A-type naturetic peptide/pro-B-type naturetic peptide convertase" that uniquely processes the natriuretic peptide precursor molecules into biologically active molecules. 8,9 We demonstrated recently that a minor allele in the human corin gene, defined by...

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Section: Statistical Methodologymentioning

confidence: 99%

Section: Genotypingmentioning

confidence: 99%

mentioning

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Corin I555(P568) Allele Is Associated With Enhanced Cardiac Hypertrophic Response to Increased Systemic Afterload

et al. 2007

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“…Corin null mice develop hypertension, indicating the importance of corin in maintaining normal blood pressure in vivo (12). Most recently, nonsynonymous single nucleotide polymorphisms in a corin gene allele were found to be associated with an increased risk for hypertension in African-Americans (13). Patients with this gene allele also exhibited an enhanced cardiac hypertrophic response to high blood pressure, as indicated by a greater left ventricular mass that is disproportional to their systolic blood pressure (14,15).…”

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Role of Glycosylation in Corin Zymogen Activation

Liao

Wang

Chen

et al. 2007

Journal of Biological Chemistry

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The cardiac serine protease corin is the pro-atrial natriuretic peptide convertase. Corin is made as a zymogen, which is activated by proteolytic cleavage. Previous studies showed that recombinant human corin expressed in HEK 293 cells was biologically active, but activated corin fragments were not detectable, making it difficult to study corin activation. In this study, we showed that recombinant rat corin was activated in HEK 293 cells, murine HL-1 cardiomyocytes, and rat neonatal cardiomyocytes. In these cells, activated corin represented a small fraction of the total corin molecules. The activation of recombinant rat corin was inhibited by small molecule trypsin inhibitors but not inhibitors for matrix metalloproteinases or cysteine proteases, suggesting that a trypsin-like protease activated corin in these cells. Glycosidase digestion showed that rat and human corin proteins contained substantial N-glycans but little O-glycans. Treatment of HEK 293 cells expressing rat corin with tunicamycin prevented corin activation and inhibited its pro-atrial natriuretic peptide processing activity. Similar effects of tunicamycin on endogenous corin activity were found in HL-1 cells. Mutations altering the two N-glycosylation sites in the protease domain of rat corin prevented its activation in HEK 293 and HL-1 cells. Our results indicate that N-linked oligosaccharides play an important role in corin activation.

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“…The purified products (0.5 μL) were mixed with 9 μL of formamide and 0.5 μL of GeneScan-120 LIZ Size Standard (Applied Biosystems) and separated 15,16], and response to diuretic therapy [17]. In addition, the minor alleles of two highly linked polymorphisms (T555I/Q568P) in the Corin gene were reported to be associated with increased risk of hypertension and enhanced cardiac hypertrophic response to pressure overload in African Americans [18,19]. However, to date, few studies have investigated the relationship between gene variants of the natriuretic peptide system and cardiovascular phenotypes in Chinese [20,21], in which the dietary sodium intake is high and potassium intake is low, with a urinary Na + /K + ratio as high as 6 to 10 [22,23].…”

Section: Genotypingmentioning

confidence: 99%

Blood pressure and urinary sodium excretion in relation to 16 genetic polymorphisms in the natriuretic peptide system in Chinese

Liu

et al. 2014

Endocr J

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peptides. Corin is a recently identified transmembrane serine protease, is highly expressed in cardiomyocytes, and cleaves inactive proANP and proBNP into smaller biologically active molecules [3,4].It has been well documented that natriuretic peptides play important roles in the regulation of blood pressure through their diuretic, natriuretic, and vasodilatory properties [5]. In the transgenic mice, overexpression of ANP leads to decreased blood pressure levels [6,7], whereas in knockout mouse models, lack of ANP [8], NPRA [9], or Corin gene [10] contributes to the development of hypertension. In humans, the infusion of high doses of ANP significantly reduced mean blood pressure, with a marked increase in urinary sodium excretion [11]. In White populations, recent investigations revealed associations of several polymorphisms at the NPPA-NPPB locus with circulating natriuretic peptides [12][13][14], incident hypertension [12, 13, Blood pressure and urinary sodium excretion in relation to 16 genetic polymorphisms in the natriuretic peptide system in Chinese Abstract. We systematically investigated the association between single nucleotide polymorphisms (SNPs) in the natriuretic peptide system (NPPA, NPPB, NPPC, NPRA, NPRC, and Corin genes) and blood pressure in a Chinese population. The study population was recruited from a mountainous area 500 km south of Shanghai from 2003 to 2009. Using the ABI SNapShot method, we first genotyped 951 subjects enrolled in 2005 for 16 SNPs and then the remaining 1355 subjects as validation for 5 SNPs selected from the primary study. Overall, the association of the studied genetic polymorphisms with blood pressure and urinary excretion of cations was weak or non-significant. However, in the primary study, there was significant (P int =0.003) interaction between the rs198358 polymorphism and age in relation to diastolic blood pressure. After adjustment for covariates, diastolic blood pressure was significantly higher in the G allele carriers than AA homozygotes in 176 subjects aged 60 years or older (77.8±1.72 vs 73.9±1.54 mmHg, P=0.001). In the primary combined with validation studies, this interaction remained statistically significant (P int =0.02). The odds ratio of hypertension for carrying the G allele versus AA homozygotes was 1.25 (95% CI: 1.03-1.52; P=0.03) in all subjects, and 0.85 (0.51-1.41; P=0.53), 1.30 (0.98-1.73; P=0.06), and 1.45 (0.95-2.22; P=0.08) in the subjects younger than 40 years, 40-59 years, and 60 years or older, respectively. Some of the genetic polymorphisms in the natriuretic peptide system might be associated with blood pressure. However, not only the size, but also the direction of the association may change with age.Key words: Genetics, Natriuretic peptides, Blood pressure, Urinary sodium excretion, Population Original©The Japan Endocrine Society NATRIURETIC PEPTIDES are a family of hormones that include three known peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These three natr...

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Corin Gene Minor Allele Defined by 2 Missense Mutations Is Common in Blacks and Associated With High Blood Pressure and Hypertension

Cited by 184 publications

References 43 publications

Corin I555(P568) Allele Is Associated With Enhanced Cardiac Hypertrophic Response to Increased Systemic Afterload

Corin I555(P568) Allele Is Associated With Enhanced Cardiac Hypertrophic Response to Increased Systemic Afterload

Role of Glycosylation in Corin Zymogen Activation

Blood pressure and urinary sodium excretion in relation to 16 genetic polymorphisms in the natriuretic peptide system in Chinese

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