Genome-Wide Association Study on Plasma Levels of Midregional-Proadrenomedullin and C-Terminal-Pro-Endothelin-1

Verweij, Niek; Mahmud, Hasan; Boer, Rudolf A. de; Brouwers, Frank P.; Yu, Hongjuan; Asselbergs, Folkert W.; Struck, Joachim; Bakker, Stephan J. L.; Gansevoort, Ron T.; Munroe, Patricia B.; Hillege, Hans L.; Veldhuisen, Dirk J. van; Gilst, Wiek H. van; Silljé, Herman H W; Harst, Pim van der

doi:10.1161/hypertensionaha.111.203117

Cited by 34 publications

(28 citation statements)

References 31 publications

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“…Moreover, given that PK converts prorenin to renin, albeit in low pH [20] , this variant has been shown to be linked to disruption of enzymatic cascade events leading to a diminished formation of active renin [10] . Finally, this variant exhibits a strong association with pre-pro-endothelin-1 and prepro-adrenomedullin [21] , and with a reduced history of cardiovascular disease [11] . With regard to the functionality of the F12 -46C/T polymorphism, located in the promoter region of the F12 gene at nt46, it is known that it creates a new initiation codon (ATG) for transcription of the mRNA and a frameshift that produces a truncated protein.…”

Section: Discussionmentioning

confidence: 95%

Genetic Determinants of C1 Inhibitor Deficiency Angioedema Age of Onset

Gianni

Loules²,

Ζαμανάκου³

et al. 2017

Int Arch Allergy Immunol

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Background: In view of the large heterogeneity in the clinical presentation of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), great efforts are being made towards detecting measurable biological determinants of disease severity that can help to improve the management of the disease. Considering the central role that plasma kallikrein plays in bradykinin production, we investigated the contribution of the functional polymorphism KLKB1-428G/A to the disease phenotype. Methods: We studied 249 C1-INH-HAE patients from 114 European families, and we explored possible associations of C1-INH-HAE clinical features with carriage of KLKB1-428G/A, combined or not with that of the functional F12-46C/T polymorphism. Results: Carriers of the G allele of the KLKB1-428G/A polymorphism exhibited a significantly delayed disease onset (i.e., by 4.1 years [p < 0.001], depending on the zygocity status), while carriers of both the KLKB1-428G/A and the F12-46C/T polymorphism displayed an 8.8-year delay in disease onset (p < 0.001) and a 64% lower probability of needing long-term prophylactic treatment (p = 0.019). Conclusions: These findings support our initial hypothesis that functional alterations in genes of proteins involved in bradykinin metabolism and function affect the clinical phenotype and possibly contribute to the pathogenesis of C1-INH-HAE. Given that an earlier onset of symptoms is inversely correlated with the subsequent course of the disease and, eventually, the need for long-term prophylaxis, these polymorphisms may be helpful prognostic biomarkers of disease severity.

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Section: Discussionmentioning

confidence: 95%

Genetic Determinants of C1 Inhibitor Deficiency Angioedema Age of Onset

Gianni

Loules²,

Ζαμανάκου³

et al. 2017

Int Arch Allergy Immunol

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“…Rs4253238, which is in complete LD (r 2 =1.00) with rs3733402, was recently found to be associated with mid regional proadrenomedullin in individuals of European ancestry. 32 KLKB1 is known to encode plasma kallikrein, a serine protease synthesized in the liver as plasma prekallikrein, and when secreted into the blood it is converted into plasma kallikrein. 33 The plasma kallikrein controls the release of bradykinin and activates conversion of prorenin to renin.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Analysis of Plasma B–Type Natriuretic Peptide in Blacks

Musani¹,

Fox²,

Kraja³

et al. 2015

Circ Cardiovasc Genet

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Background Numerous experimental studies suggest that B-type natriuretic peptide (BNP) is cardioprotective, yet in clinical studies, higher plasma BNP concentrations have been associated with incident cardiovascular disease and higher left ventricular mass (LVM). Genetic association studies may allow us to determine the true causal directions without confounding by compensatory mechanisms. Methods and Results We performed meta-analysis of two genome-wide association (GWA) results from a total of 2,790 African Americans. We assumed an additive genetic model in association analysis of imputed 2.5 million SNP dosages with residuals generated from multivariable-adjusted logarithmically-transformed BNP controlling for relevant covariates and population stratification. Two loci were genome-wide significant, a candidate gene locus NPPB (rs198389, p-value=1.18×10−09) and novel missense variant in the KLKB1 locus (rs3733402, p-value=1.75×10−11) that explained 0.4% and 1.9% of variation in log BNP concentration, respectively. The observed increase in BNP concentration was proportional to the number of effect allele copies, an average of 8.1 pg/dl increase associated with two allele copies. SNPs in this loci were subsequently cross-checked with GWA results for the aldosterone-to-renin ratio in individuals of European ancestry, and only rs3733402 was genome-wide significant (p<5.0×10−8), suggesting possible shared genetic architecture for these two pathways. Other statistically significant relations for these SNPs included: rs198389 with systolic blood pressure in blacks (COGENT consortium) rs198389 and rs3733402 with LVM in whites (EchoGEN consortium). Conclusions These findings improve our knowledge of the genetic basis of BNP variation in African Americans, demonstrate possible shared allelic architecture for BNP with ARR and motivate further studies of underlying mechanisms.

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“…Venous blood was drawn into EDTA tubes; aliquots were made and stored at\ \80°C until analysis. The biomarkers tested were high-sensitive troponin-T (hs-TnT) [12], N-terminal pro-B-type natriuretic peptide (NT-proBNP) [13], mid-regional pro-A-type natriuretic peptide (MR-proANP) [14], C-terminal pro-endothelin-1 (CT-proET-1) [15], renin [9], aldosterone [9], C-terminal pro-arginine vasopressin (copeptin) [16], mid-regional pro-adrenomedullin (MR-proADM) [17], high-sensitive C-reactive protein (hs-CRP) [18], procalcitonin [19], plasminogen activator inhibitor-1 (PAI-1) [20], galectin-3 [21], urinary albumin excretion (UAE) [22], serum creatinine [17] and cystatin-C [17]. Details of the assays can be found in the data supplement.…”

Section: Methodsmentioning

confidence: 99%