Large‐Scale Gene‐Centric Analysis Identifies Polymorphisms for Resistant Hypertension

Fontana, Vanessa; McDonough, Caitrin W.; Gong, Yan; Rouby, Nihal M. El; Sá, Ana Caroline Costa; Taylor, Kent D.; Chen, Y.‐D. Ida; Gums, John G.; Chapman, Arlene B.; Turner, Stephen T.; Pepine, Carl J.; Cooper‐DeHoff, Rhonda M.

doi:10.1161/jaha.114.001398

Cited by 35 publications

(37 citation statements)

References 47 publications

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“…A total of 178 SNPs were significantly associated with hypertension in GWAS, and 22 SNPs for 21 gene symbols including ATP2B1 and CSK, which were frequently investigated with blood pressure and hypertension [12,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64], were selected as tagging SNPs. The mutant allele of ATP2B1 rs11105368 was negatively associated with hypertension, but no significant interaction effects of urinary sodium were found in this study.…”

Section: Discussionmentioning

confidence: 99%

Interaction between Single Nucleotide Polymorphism and Urinary Sodium, Potassium, and Sodium-Potassium Ratio on the Risk of Hypertension in Korean Adults

et al. 2017

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Hypertension is a complex disease explained with diverse factors including environmental factors and genetic factors. The objectives of this study were to determine the interaction effects between gene variants and 24 h estimated urinary sodium and potassium excretion and sodium-potassium excretion ratios on the risk of hypertension. A total of 8839 participants were included in the genome-wide association study (GWAS) to find genetic factors associated with hypertension. Tanaka and Kawasaki formulas were applied to estimate 24 h urinary sodium and potassium excretion. A total of 4414 participants were included in interaction analyses to identify the interaction effects of gene variants according to 24 h estimated urinary factors on the risk of hypertension. CSK rs1378942 and CSK-MIR4513 rs3784789 were significantly modified by urinary sodium-potassium excretion ratio. In addition, MKLN rs1643270 with urinary potassium excretion, LOC101929750 rs7554672 with urinary sodium and potassium excretion, and TENM4 rs10466739 with urinary sodium-potassium excretion ratio showed significant interaction effects. The present study results indicated that the mutant alleles of CSK rs1378942 and CSK-MIR4513 rs3784789 had the strongest protective effects against hypertension in the middle group of 24 h estimated urinary sodium-potassium excretion ratio. Further studies are needed to replicate these analyses in other populations.

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Section: Discussionmentioning

confidence: 99%

Interaction between Single Nucleotide Polymorphism and Urinary Sodium, Potassium, and Sodium-Potassium Ratio on the Risk of Hypertension in Korean Adults

et al. 2017

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“…The association between ATP2B1 variants and BP variance and/or hypertension in human subjects (Cho et al, 2009;Levy et al, 2009;Hong et al, 2010;Takeuchi et al, 2010;Johnson et al, 2011) suggests that PMCA1 at least may play an important role in the genetic susceptibility to hypertension. Coupled with the recent observation reporting a genetic link between ATP2B1 and resistant hypertension (Fontana et al, 2014), there is thus increasing evidence to support PMCA1 as an attractive target for BP and resistance arterial modulation. It is worth noting that whilst effects of PMCA1 on modulation of BP, arterial structure and intracellular calcium have been demonstrated (Kobayashi et al, 2012) there remains a clear need for investigation into the effects of the protein on resistance arterial remodelling.…”

Section: Treatment Strategies and Future Directionsmentioning

confidence: 97%

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

Little

Cartwright

Neyses

et al. 2016

Pharmacology & Therapeutics

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The incidence of hypertension, the major modifiable risk factor for cardiovascular disease, is increasing. Thus, there is a pressing need for the development of new and more effective strategies to prevent and treat hypertension. Development of these relies on a continued evolution of our understanding of the mechanisms which control blood pressure (BP). Resistance arteries are important in the regulation of total peripheral resistance and BP; changes in their structure and function are strongly associated with hypertension. Anti-hypertensives which both reduce BP and reverse changes in resistance arterial structure reduce cardiovascular risk more than therapies which reduce BP alone. Hence, identification of novel potential vascular targets which modify BP is important. Hypertension is a multifactorial disorder which may include a genetic component. Genome wide association studies have identified ATP2B1, encoding the calcium pump plasma membrane calcium ATPase 1 (PMCA1), as having a strong association with BP and hypertension. Knockdown or reduced PMCA1 expression in mice has confirmed a physiological role for PMCA1 in BP and resistance arterial regulation. Altered expression or inhibition of PMCA4 has also been shown to modulate these parameters. The mechanisms whereby PMCA1 and 4 can modulate vascular function remain to be fully elucidated but may involve regulation of intracellular calcium homeostasis and/or comprise a structural role. However, clear physiological links between PMCA and BP, coupled with experimental studies directly linking PMCA1 and 4 to changes in BP and arterial function, suggest that they may be important targets for the development of new pharmacological modulators of BP.

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“…Missense mutations in PDE3A have been linked with autosomal dominant syndrome characterized by treatment-resistant hypertension and brachydactyly (38,39). SNPs in this locus have also shown suggestive associations with aortic root diameter (40), resistant hypertension (41) and SBP in a SNP-alcohol consumption interaction analysis (42).…”

Section: New Signals Near Known Bp Locimentioning

confidence: 99%

A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Sung

Fuentes

Winkler

et al. 2019

Human Molecular Genetics

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Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

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Large‐Scale Gene‐Centric Analysis Identifies Polymorphisms for Resistant Hypertension

Cited by 35 publications

References 47 publications

Interaction between Single Nucleotide Polymorphism and Urinary Sodium, Potassium, and Sodium-Potassium Ratio on the Risk of Hypertension in Korean Adults

Interaction between Single Nucleotide Polymorphism and Urinary Sodium, Potassium, and Sodium-Potassium Ratio on the Risk of Hypertension in Korean Adults

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

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