Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population

Hong, Kyung‐Won; Jin, Hyun‐Seok; Lim, Ji‐Eun; Kim, Sang Soo; Go, Min Jin; Oh, Bermseok

doi:10.1038/jhg.2010.31

Cited by 76 publications

(52 citation statements)

References 26 publications

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“…Se han llevado a cabo numerosos estudios genéticos sobre estos sistemas; sin embargo, los resultados han sido incongruentes entre poblaciones, lo que evidencia la heterogeneidad de la hipertensión arterial en su etiología genética en las poblaciones continentales (45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58).…”

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Asociación y efectos de interacción en los genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2 sobre la hipertensión en población antioqueña

et al. 2013

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Asociación y efectos de interacción en los genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2 sobre la hipertensión en población antioqueña

et al. 2013

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“…However, none of the SNPs was replicated in the Korean population at the genomewide significance level in these analyses (Hong et al, 2009;2010a). Recently, Hong et al identified 10 SNPs associated with blood pressure and hypertension risk using the KARE data, composed of 8842 individuals, and replicated three SNPs-17249754 of the ATP2B1 gene, rs1378942 in the CSK gene, and rs12945290 in the ARSG gene-in the Health2 data on 7861 subjects (Hong et al, 2010b). …”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Association Analyses on Blood Pressure Using Three Different Phenotype Definitions

Park¹,

Uhmm²,

Shin³

et al. 2010

Genomics & Informatics

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Hypertension is the most prevalent disease worldwide and is itself a risk factor for cerebral, cardiac, and renal diseases. The inconsistency of candidate genes suggested by previous genomewide association studies (GWASs) may be due to not only differences in study design and genetic or environmental background but also the difference in the power of analysis between continuous traits and discrete traits. We analyzed 352,228 single nucleotide polymorphisms (SNPs) in 8842 unrelated Koreans obtained from Ansan and Ansung cohorts. We performed a series of GWA analyses using three different phenotype models; young hypertensive cases (278 subjects) versus elderly normotensive controls (680 subjects); the upper 25% (2211 hypertensive cases) versus the lower 25% of the SBP distribution (2211 hypotensive controls); and finally SBP and DBP as continuous traits (8842 subjects). The numbers of young hypertensive cases and elderly normotensive controls were not large enough to achieve genomewide significance. The model comparing the upper 25% subjects to the lower 25% of subjects showed a power that was approximate to that of QTL analysis. Two neighbor- ; DBP, p=6.41×10 ). However, we did not observe any gene variant attaining genomewide significance consistently in the three phenotype models except for the ATP2B1 gene variants. In general, the association signal with blood pressure was stronger in women than in men. Genes identified in GWASs are expected to open the way for prevention, early diagnosis, and personalized treatment of hypertension.

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“…Collectively, these findings provide the first functional evidence to our knowledge that Plekha7 modulates BP by mediating systemic vascular resistance in a hypertensive rat strain. Moreover, to our knowledge these are the first mechanistic data to support multiple GWAS that have nominated PLEKHA7 as a hypertension risk gene (5,6,8,21,22) but had yet to demonstrate causality.…”

Section: Discussionmentioning

confidence: 99%

“…A single-nucleotide polymorphism (SNP) (rs381815, minor allele frequency 0.26) in intron 1 of the pleckstrin homology domain containing family A member 7 (PLEKHA7) gene, was identified by five independent GWAS to be associated with elevated systolic blood pressure and hypertension in multiple populations (5,6,8,21,22). The associated locus contains only the PLEKHA7 gene (5); however, the genetic mechanism(s) underlying this locus have not yet been functionally characterized.…”

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confidence: 99%

“…Additionally, we have recently demonstrated multiple genes at a single hypertension GWAS-nominated locus (Agtrap-Plod1 locus) can have additive or subtractive effects on blood pressure and renal function when mutated in the SS rat (19). These previous studies highlight the utility of this model system for testing the roles of GWAS candidate human disease genes by disrupting their specific rat orthologs using ZFN technology (20).A single-nucleotide polymorphism (SNP) (rs381815, minor allele frequency 0.26) in intron 1 of the pleckstrin homology domain containing family A member 7 (PLEKHA7) gene, was identified by five independent GWAS to be associated with elevated systolic blood pressure and hypertension in multiple populations (5,6,8,21,22). The associated locus contains only the PLEKHA7 gene (5); however, the genetic mechanism(s) underlying this locus have not yet been functionally characterized.…”

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confidence: 99%

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Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat

Endres

Priestley²,

Palygin³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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PLEKHA7 (pleckstrin homology domain containing family A member 7) has been found in multiple studies as a candidate gene for human hypertension, yet functional data supporting this association are lacking. We investigated the contribution of this gene to the pathogenesis of salt-sensitive hypertension by mutating Plekha7 in the Dahl salt-sensitive (SS/JrHsdMcwi) rat using zincfinger nuclease technology. After four weeks on an 8% NaCl diet, homozygous mutant rats had lower mean arterial (149 ± 9 mmHg vs. 178 ± 7 mmHg; P < 0.05) and systolic (180 ± 7 mmHg vs. 213 ± 8 mmHg; P < 0.05) blood pressure compared with WT littermates. Albumin and protein excretion rates were also significantly lower in mutant rats, demonstrating a renoprotective effect of the mutation. Total peripheral resistance and perivascular fibrosis in the heart and kidney were significantly reduced in Plekha7 mutant animals, suggesting a potential role of the vasculature in the attenuation of hypertension. Indeed, both flow-mediated dilation and endothelium-dependent vasodilation in response to acetylcholine were improved in isolated mesenteric resistance arteries of Plekha7 mutant rats compared with WT. These vascular improvements were correlated with changes in intracellular calcium handling, resulting in increased nitric oxide bioavailability in mutant vessels. Collectively, these data provide the first functional evidence that Plekha7 may contribute to blood pressure regulation and cardiovascular function through its effects on the vasculature.H ypertension is a complex disease that is characterized by increased blood pressure, renal damage, and vascular dysfunction which collectively increase risk of atherosclerosis, stroke, heart disease, and renal failure in one-quarter of all adults worldwide (1-3). Because there is strong evidence of heritability in hypertension (2, 4, 5), considerable effort has been put toward identifying novel candidate genes and their molecular mechanisms. Genome-wide association studies (GWAS) have identified many potential hypertension loci, which shed light on the genetic complexity of this disease (5-8) but have provided little mechanistic insight. As such, validation and elucidation of the functional roles and disease mechanisms for these gene candidates are the next important challenges (4).Because hypertension is a complex disease (i.e., multiple variants of small effect sizes contributing to disease risk), we hypothesized candidate gene targeting on a genetically sensitized background would reveal functional role(s) of genetic disease modifiers. The Dahl salt-sensitive (SS) rat is an inbred genetic model of salt-sensitive hypertension that displays hypertensioninduced renal damage, cardiac hypertrophy and vascular dysfunction (9-11). These phenotypes are induced by exposing SS rats to a high-salt diet, which results in rapid induction of hypertensive phenotypes that closely resemble salt-induced hypertension seen in humans (12-15). Knockout of specific genes in this disease model using zinc-finger nuclease (ZFN...

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Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population

Cited by 76 publications

References 26 publications

Asociación y efectos de interacción en los genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2 sobre la hipertensión en población antioqueña

Asociación y efectos de interacción en los genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2 sobre la hipertensión en población antioqueña

Genome-Wide Association Analyses on Blood Pressure Using Three Different Phenotype Definitions

Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat

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