Genome-Wide Association Study Identifies CAMKID Variants Involved in Blood Pressure Response to Losartan: The Sophia Study

Frau, Francesca; Zaninello, Roberta; Salvi, Erika; Ortu, Maria Francesca; Braga, Daniele; Velayutham, Dinesh; Argiolas, Giuseppe; Fresu, Giovanni; Troffa, Chiara; Bulla, Emanuela; Bulla, Patrizia; Pitzoi, Silvia; Piras, Daniela; Glorioso, Valeria; Chittani, Martina; Bernini, Giampaolo; Bardini, Michele; Fallo, Francesco; Malatino, Lorenzo; Stancanelli, Benedetta; Regolisti, Giuseppe; Ferri, Claudio; Desideri, Giovambattista; Scioli, Giuseppe; Galletti, Ferruccio; Sciacqua, Angela; Perticone, Francesco; Esposti, Ezio Degli; Sturani, A; Semplicini, Andrea; Veglio, Franco; Mulatero, Paolo; Williams, Tracy Ann; Lanzani, Chiara; Hiltunen, Timo P.; Kontula, Kimmo; Boerwinkle, Eric; Turner, Stephen T.; Manunta, Paolo; Barlassina, Cristina; Cusi, Daniele; Glorioso, Nicola

doi:10.2217/pgs.14.119

Cited by 29 publications

(14 citation statements)

References 28 publications

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“…changes in diet, exercise, time-of-day, combinations of prescribed drugs, alcohol usage, etc .). Several PGx GWAS have reported variants in plausible genes associated with thiazide diuretics (Chittani et al, 2015; Turner et al, 2008; Turner et al, 2013), angiotensin II receptor blockers (Frau et al, 2014; Turner et al, 2012), and beta-blockers (Gong et al, 2015; Gong et al, 2016); yet, most of these studies involve relatively small discovery sample-sizes and are underpowered, as far as detecting associations having genome-wide significance ( i.e. P < 5 × 10 −8 ).…”

Section: Genetic Studies Of Pgx Traitsmentioning

confidence: 99%

Personalized medicine: Genetic risk prediction of drug response

Zhang

Nebert

2017

Pharmacology & Therapeutics

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Pharmacogenomics (PGx), a substantial component of “personalized medicine”, seeks to understand each individual's genetic composition to optimize drug therapy reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants. [b] Predominantly oligogenic traits represent variation largely influenced by a small number of major pharmacokinetic or pharmacodynamic genes. [c] Complex PGx traits resemble most multifactorial quantitative traits –– influenced by numerous small-effect variants, together with epigenetic effects and environmental factors. Prediction of monogenic drug responses is relatively simple, involving detection of underlying mutations; due to rarity of these events and incomplete penetrance, however, prospective tests based on genotype will have high false-positive rates, plus pharmacoeconomics will require justification. Prediction of predominantly oligogenic traits is slowly improving. Although a substantial fraction of variation can be explained by limited numbers of large-effect genetic variants, uncertainty in successful predictions and overall cost-benefit ratios will make such tests elusive for everyday clinical use. Prediction of complex PGx traits is almost impossible in the foreseeable future. Genome-wide association studies of large cohorts will continue to discover relevant genetic variants; however, these small-effect variants, combined, explain only a small fraction of phenotypic variance –– thus having limited predictive power and clinical utility.

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Section: Genetic Studies Of Pgx Traitsmentioning

confidence: 99%

Personalized medicine: Genetic risk prediction of drug response

Zhang

Nebert

2017

Pharmacology & Therapeutics

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“…Through a whole-genome approach, the authors identified a significant association between 4 SNPs on CAMK1D gene and BP response. CAMK1D encodes for a calcium-dependent kinase that modulates the transcription of factors NURR1, ARF1, ATF2 and CREB, involved in aldosterone production in the adrenal zona glomerulosa [75]. …”

Section: Pharmacogenomicsmentioning

confidence: 99%

Is There a Role for Genomics in the Management of Hypertension?

Burrello

Monticone

Buffolo

et al. 2017

IJMS

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Hypertension (HTN) affects about 1 billion people worldwide and the lack of a single identifiable cause complicates its treatment. Blood pressure (BP) levels are influenced by environmental factors, but there is a strong genetic component. Linkage analysis has identified several genes involved in Mendelian forms of HTN and the associated pathophysiological mechanisms have been unravelled, leading to targeted therapies. The majority of these syndromes are due to gain-of-function or loss-of-functions mutations, resulting in an alteration of mineralocorticoid, glucocorticoid, or sympathetic pathways. The diagnosis of monogenic forms of HTN has limited practical implications on the population and a systematic genetic screening is not justifiable. Genome-wide linkage and association studies (GWAS) have identified single nucleotide polymorphisms (SNPs), which influence BP. Forty-three variants have been described with each SNP affecting systolic and diastolic BP by 1.0 and 0.5 mmHg, respectively. Taken together Mendelian inheritance and all GWAS-identified HTN-associated variants explain 2–3% of BP variance. Epigenetic modifications, such as DNA methylation, histone modification and non-coding RNAs, have become increasingly recognized as important players in BP regulation and may justify a further part of missing heritability. In this review, we will discuss how genetics and genomics may assist clinicians in managing patients with HTN.

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“…The biological effect of these genes, as well as previously mentioned genes, can be found in Table 2. As part of the Study of the Pharmacogenomics in Italian hypertensive patients treated with the Angiotensin receptor blocker losartan (SOPHIA), a GWAS on BP response was performed in 372 hypertensives treated with losartan for 4 weeks [43•]. Four SNPs (rs10752271, rs10906202, rs4747995, and rs10737061) in the CAMK1D gene were significantly associated with SBP reduction response to losartan ( P <1×10 −5 ).…”

Section: Pharmacogenetics Of Antihypertensive Responsementioning

confidence: 99%

Pharmacogenomics of Hypertension and Heart Disease

2015

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Heart disease is a leading cause of death in the United States, and hypertension is a predominant risk factor. Thus, effective blood pressure control is important to prevent adverse sequelae of hypertension, including heart failure, coronary artery disease, atrial fibrillation, and ischemic stroke. Over half of Americans have uncontrolled blood pressure, which may in part be explained by interpatient variability in drug response secondary to genetic polymorphism. As such, pharmacogenetic testing may be a supplementary tool to guide treatment. This review highlights the pharmacogenetics of antihypertensive response and response to drugs that treat adverse hypertension-related sequelae, particularly coronary artery disease and atrial fibrillation. While pharmacogenetic evidence may be more robust for the latter with respect to clinical implementation, there is increasing evidence of genetic variants that may help predict antihypertensive response. However, additional research and validation are needed before clinical implementation guidelines for antihypertensive therapy can become a reality.

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Genome-Wide Association Study Identifies CAMKID Variants Involved in Blood Pressure Response to Losartan: The Sophia Study

Abstract: Using a genome-wide approach, we identified the CAMK1D gene as a novel locus associated with blood pressure response to losartan. CAMK1D gene characterization may represent a useful tool to personalize the treatment of essential hypertension.

Cited by 29 publications

References 28 publications

Personalized medicine: Genetic risk prediction of drug response

Personalized medicine: Genetic risk prediction of drug response

Is There a Role for Genomics in the Management of Hypertension?

Pharmacogenomics of Hypertension and Heart Disease

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