Integrated statistical and pathway approach to next-generation sequencing analysis: a family-based study of hypertension

Edwards, Jeremy S.; Atlas, Susan R.; Wilson, Susan M.; Cooper, Candice Frances; Luo, Li; Stidley, Christine A.

doi:10.1186/1753-6561-8-s1-s104

Cited by 7 publications

(9 citation statements)

References 21 publications

(22 reference statements)

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“…The three contributions that used simulated data [Almeida et al., ; Greco et al., ; Hu and Paterson, ] had the explicit knowledge of which genes were causal in the pathogenesis of hypertension; the other analyses relied on various proxy measures of causality. For example, both Dufresne et al [] and Edwards et al [] used only exonic variants, and all other analyses were restricted to variants that could be mapped to known genes. Aslibekyan et al [] explicitly compared variance contributions of SNVs within known blood pressure pathway genes with those of SNVs located within 50 kb upstream of the transcription start site and within 50 kb downstream of the stop codon; they found that genic regions played a more prominent role in the genetic architecture of hypertension than the flanking regions.…”

Section: Resultsmentioning

confidence: 99%

“…For example, both Dufresne et al [2014] and Edwards et al [2014] used only exonic variants, and all other analyses were restricted to variants that could be mapped to known genes. Aslibekyan et al [2014] explicitly compared variance contributions of SNVs within known blood pressure pathway genes with those of SNVs located within 50 kb upstream of the transcription start site and within 50 kb downstream of the stop codon; they found that genic regions played a more prominent role in the genetic architecture of hypertension than the flanking regions.…”

Section: S88mentioning

confidence: 99%

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Pathway Analysis Approaches for Rare and Common Variants: Insights From Genetic Analysis Workshop 18

Aslibekyan

Almeida

Tintle

2014

Genetic Epidemiology

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Pathway analysis, broadly defined as a group of methods incorporating a priori biological information from public databases, has emerged as a promising approach for analyzing high-dimensional genomic data. As part of Genetic Analysis Workshop 18 (GAW18), seven research groups applied pathway analysis techniques to whole genome sequence data from the San Antonio Family Study. Overall, the groups found that the potential of pathway analysis to improve detection of causal variants by lowering the multiple testing burden and incorporating biologic insight remains largely unrealized. Specifically, there is a lack of best practices at each stage of the pathway approach: annotation, analysis, interpretation, and follow-up. Annotation of genetic variants is inconsistent across databases, incomplete, and biased towards known genes. At the analysis stage, insufficient statistical power remains a major challenge. Analyses combining rare and common variants may have an inflated type 1 error rate and may not improve detection of causal genes. Inclusion of known causal genes may not improve statistical power, although the fraction of explained phenotypic variance may be a more appropriate metric. Interpretation of findings is further complicated by evidence in support of interactions between pathways as well as the lack of consensus on how to best incorporate functional information. Finally, all presented approaches warranted follow-up studies, both to reduce the likelihood of false positive findings and to identify specific causal variants within a given pathway. Despite the initial promise of pathway analysis for modeling biological complexity of disease phenotypes, many methodological challenges currently remain to be addressed.

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Section: Resultsmentioning

confidence: 99%

Section: S88mentioning

confidence: 99%

Pathway Analysis Approaches for Rare and Common Variants: Insights From Genetic Analysis Workshop 18

Aslibekyan

Almeida

Tintle

2014

Genetic Epidemiology

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“…The modulation of both plasma membrane Ca 2+ entry and endoplasmic reticulum (ER) Ca 2+ release is critical in EC function (21,22). Moreover, recent meta-analysis and genome-wide association studies in hypertensive individuals have linked type 1 1,4,5-trisphosphate receptor (IP3R1), a major [Ca 2+ ] i release channel (23,24), to high blood pressure (BP) (25,26). On these grounds, we sought to investigate in detail the functional role of the IP3R1/ Ca 2+ /calcineurin/nuclear factor of activated T cells (NFAT)/eNOS pathway in BP regulation.…”

mentioning

confidence: 99%

Maintenance of normal blood pressure is dependent on IP3R1-mediated regulation of eNOS

Yuan

Yang

Santulli

et al. 2016

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

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Endothelial cells (ECs) are critical mediators of blood pressure (BP) regulation, primarily via the generation and release of vasorelaxants, including nitric oxide (NO). NO is produced in ECs by endothelial NO synthase (eNOS), which is activated by both calcium (Ca 2+ )-dependent and independent pathways. Here, we report that intracellular Ca 2+ release from the endoplasmic reticulum (ER) via inositol 1,4,5-trisphosphate receptor (IP3R) is required for Ca 2+ -dependent eNOS activation. EC-specific type 1 1,4,5-trisphosphate receptor knockout (IP3R1 −/− ) mice are hypertensive and display blunted vasodilation in response to acetylcholine (ACh). Moreover, eNOS activity is reduced in both isolated IP3R1-deficient murine ECs and human ECs following IP3R1 knockdown. IP3R1 is upstream of calcineurin, a Ca 2+ /calmodulinactivated serine/threonine protein phosphatase. We show here that the calcineurin/nuclear factor of activated T cells (NFAT) pathway is less active and eNOS levels are decreased in IP3R1-deficient ECs. Furthermore, the calcineurin inhibitor cyclosporin A, whose use has been associated with the development of hypertension, reduces eNOS activity and vasodilation following ACh stimulation. Our results demonstrate that IP3R1 plays a crucial role in the ECmediated vasorelaxation and the maintenance of normal BP.is a major cause of morbidity and mortality affecting millions of adults worldwide (1, 2). Globally, among the ∼17 million deaths caused by cardiovascular diseases, nearly half can be attributed to complications of HTN (3-9). In addition, vasodilator drugs that activate nitric oxide (NO) production have been used to treat HTN for decades (4, 10). Calcineurin (also known as protein phosphatase 2B), is a Ca 2+ /calmodulin-activated serine/ threonine protein phosphatase. Calcineurin inhibitors are first-line immunosuppressants used in organ transplantation (11,12). However, calcineurin inhibition causes HTN in up to 70% of patients (13), and the exact underlying mechanisms are not fully understood.Vascular endothelial cells (ECs), located at the interface between the vessel wall and blood, release vasorelaxants that influence vascular smooth muscle tone in response to mechanical (e.g., shear stress) and biochemical stimuli (14, 15). These stimuli induce a rapid increase in intracellular Ca 2+ ([Ca 2+ ] i ) in ECs activating Ca 2+ -dependent signaling pathways, resulting in release of endothelium-derived relaxing factors, including NO (14,[16][17][18][19]. Mice lacking endothelial nitric oxide synthase (eNOS) develop severe HTN (20). However, how eNOS is regulated in vivo remains essentially unclear. The modulation of both plasma membrane Ca 2+ entry and endoplasmic reticulum (ER) Ca 2+ release is critical in EC function (21,22). Moreover, recent meta-analysis and genome-wide association studies in hypertensive individuals have linked type 1 1,4,5-trisphosphate receptor (IP3R1), a major [Ca 2+ ] i release channel (23,24), to high blood pressure (BP) (25,26). On these grounds, we sought to inve...

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“…The above examples underline the fundamental role played in PHC of the ability to process and analyze huge volumes of data, such as electronic medical records, in vivo imaging, genomics, and other "-omic" technologies [94,99]. Millions of genetic polymorphisms are identified with NGS technology; but in order to find an association between a polymorphism and a phenotype, a large number of statistical tests have to be performed and then require correction for multiple testing [100]. A methodology was recently proposed for unified analysis of NGS data.…”

Section: Bioinformaticsmentioning

confidence: 99%

Relevance of Personalized Health Care in Patients with Arterial Hypertension: Where are we now?

Binder¹,

Schäfer²,

Kaiser³

et al. 2016

Update on Essential Hypertension

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Personalized health care (PHC) or precision medicine is a new medical concept that aids in treatment decisions for patients by tailoring them to their individual needs. It often employs genetic testing to select appropriate and optimal therapies (pharmacogenomics). Although this concept is widely applied in oncology, the field of hypertension is still in the early stages and "personalization" is currently limited to tailoring antihypertensive treatment according to age, comorbidities, and ethnicity. Despite the fact that incomplete/lack of treatment response occurs in 10-30% of hypertensive patients for angiotensin-converting enzyme (ACE) inhibitors and in 15-25% for β-blockers, major continental guidelines still recommend the use of antihypertensive agents in a "onesize-fits-all" approach, neglecting the 1977 postulation of the Joint National Committee that "all patients must receive individualized therapy programs." The arrival of molecular testing offers new possibilities to differentiate monogenetic from polygenetic disorders and to identify associations between hypertension and drug response to corresponding genes. Up to 50% of the variation in blood pressure (BP) is attributable to genetic factors. Polymorphisms have been identified and studied in genes for BPmodifying receptors, such as ADBR (β-adrenergic receptors), and pharmacological pathways (GNB3, RAAS system). Approximately, one-quarter of the currently analyzed gene polymorphisms demonstrate significant pharmacogenetic effects (ADD1 Gly460Trp and the insertion/deletion [I/D] polymorphism in intron 16 of the ACE gene). Several large screening studies are currently ongoing to assess the impact on efficacy of antihypertensive medication of variants in hypertension-susceptibility genes. The GenHAT substudy of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) assessed the predictive validity of the ACE I/D genotype for coronary heart disease. The Family Blood Pressure Program included 11,079 participants to map genetic variants associated with hypertension. In this review chapter, we display the current body of knowledge regarding PHC in the treatment of hypertension. In particular, we highlight genetic variants associated with hyperten

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Integrated statistical and pathway approach to next-generation sequencing analysis: a family-based study of hypertension

Cited by 7 publications

References 21 publications

Pathway Analysis Approaches for Rare and Common Variants: Insights From Genetic Analysis Workshop 18

Pathway Analysis Approaches for Rare and Common Variants: Insights From Genetic Analysis Workshop 18

Maintenance of normal blood pressure is dependent on IP3R1-mediated regulation of eNOS

Relevance of Personalized Health Care in Patients with Arterial Hypertension: Where are we now?

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