GENETIC BASIS OF BLOOD PRESSURE AND HYPERTENSION

Abstract Epidemiologic and genomic studies have progressively improved our understanding of the causation of hypertension and the complex relationship with diet and environment. The majority of Mendelian forms of syndromic hypotension and hypertension (HTN) have all been linked to mutations in genes whose encoded proteins regulate salt–water balance in the kidney, supporting the primacy of the kidneys in blood pressure regulation. There are more than 1,477 single nucleotide polymorphisms associated with blood pressure and hypertension and the challenge is establishing a causal role for these variants. Hypertension is a complex multifactorial phenotype and it is likely to be influenced by multiple factors including interactions between diet and lifestyle factors, microbiome, and epigenetics. Given the finite genetic variability that is possible in humans, it is likely that incremental gains from single marker analyses have now plateaued and a greater leap in our understanding of the genetic basis of disease will come from integration of other omics and the interacting environmental factors. In this review, we focus on emerging results from the microbiome and metabolomics and discuss how leveraging these findings may facilitate a deeper understanding of the interrelationships between genomics, diet, and microbial ecology in humans in the causation of essential hypertension.

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Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure

10.1101/2020.05.29.123505 ◽

2020 ◽

Author(s):

Heming Wang ◽

Raymond Noordam ◽

Brian E Cade ◽

Karen Schwander ◽

Thomas W Winkler ◽

...

Keyword(s):

Blood Pressure ◽

Sleep Duration ◽

Genetic Basis ◽

Molecular Pathways ◽

Short Sleep Duration ◽

Short Sleep ◽

Genome Wide ◽

Long Sleep ◽

New Gene ◽

Stage 1

AbstractLong and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups using 1 degree of freedom (1df) interaction and 2df joint tests. Primary multi-ancestry analyses in 62,969 individuals in stage 1 identified 3 novel loci that were replicated in an additional 59,296 individuals in stage 2, including rs7955964 (FIGNL2/ANKRD33) showing significant 1df interactions with long sleep duration and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) showing significant 1df interactions with short sleep duration (Pint < 5×10−8). Secondary ancestry-specific two-stage analyses and combined stage 1 and 2 analyses additionally identified 23 novel loci that need external replication, including 3 and 5 loci showing significant 1df interactions with long and short sleep duration, respectively (Pint < 5×10−8). Multiple genes mapped to our 26 novel loci have known functions in sleep-wake regulation, nervous and cardiometabolic systems. We also identified new gene by long sleep interactions near five known BP loci (≤1Mb) including NME7, FAM208A, MKLN1, CEP164, and RGL3/ELAVL3 (Pint < 5×10−8). This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

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Genetic determinants of daytime napping and effects on cardiometabolic health

10.1101/2020.06.12.20129858 ◽

2020 ◽

Cited By ~ 1

Author(s):

Hassan S. Dashti ◽

Iyas Daghlas ◽

Jacqueline M. Lane ◽

Yunru Huang ◽

Miriam S. Udler ◽

...

Keyword(s):

Blood Pressure ◽

Drug Targets ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Cardiometabolic Health ◽

Genetic Determinants ◽

Genome Wide ◽

A Genome ◽

The Uk

AbstractDaytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remains unclear. Here, we performed a genome-wide association study of self-reported daytime napping in the UK Biobank (n=452,633) and identified 123 loci of which 60 replicated in 23andMe research participants (n=541,333). Findings included missense variants in established drug targets (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Signals were concordant with accelerometer-measured daytime inactivity duration and 33 signals colocalized with signals for other sleep phenotypes. Cluster analysis identified 3 clusters suggesting distinct nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization showed potential causal links between more frequent daytime napping and higher systolic blood pressure, diastolic blood pressure, and waist circumference.

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Genetic basis for altered vascular responses to ouabain and potassium-free solution in hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1986.251.6.h1276 ◽

1986 ◽

Vol 251 (6) ◽

pp. H1276-H1282 ◽

Cited By ~ 1

Author(s):

C. A. Bruner ◽

J. H. Myers ◽

C. F. Sing ◽

P. T. Jokelainen ◽

R. C. Webb

Keyword(s):

Blood Pressure ◽

Genetic Basis ◽

Genetic Factors ◽

Isometric Force ◽

Free Solution ◽

Half Time ◽

Spontaneously Hypertensive ◽

Wky Rats ◽

Wistar Kyoto ◽

F2 Progeny

Many properties intrinsic to vascular smooth muscle are altered in hypertension. It is unknown whether these abnormalities are primary traits that may contribute to the etiology of hypertension or whether these vascular differences between the hypertensive and normotensive strains are inherited independently of genetic factors that predispose to hypertension. To determine if genetic factors responsible for the predisposition for hypertension may be the same as or linked to genetic factors determining a specific vascular response, adult stroke-prone spontaneously hypertensive rats (SHRSP), normotensive Wistar-Kyoto (WKY) rats, and progeny of genetic crosses of SHRSP and WKY rats (F1, F2, F1 X WKY, F1 X SHRSP) were studied. Rats were killed and helical aortic strips were mounted in a tissue bath for isometric force recording. Contractile responses to 10(-3) M ouabain (expressed as a percent of force generated to a maximal depolarizing stimulus) were greater in aortas from SHRSP (90 +/- 9%) compared with aortas from WKY rats (38 +/- 5%, P less than 0.05). The half time for contraction in K+-free solution was more rapid in aortas from SHRSP (21 +/- 4 min) when compared with aortas from WKY rats (48 +/- 4 min, P less than 0.05). A significant positive correlation between blood pressure (tail-cuff method) and the contractile response to 10(-3) M ouabain was observed in the segregating F2 progeny. In contrast, no correlation between blood pressure and the half time for contraction in K+-free solution was observed in the segregating F2 progeny.(ABSTRACT TRUNCATED AT 250 WORDS)

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0016 Genetic Basis of Daytime Napping and Consequence on Cardiometabolic Health

SLEEP ◽

10.1093/sleep/zsaa056.015 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A7-A7

Author(s):

H S Dashti ◽

I Daghlas ◽

J Lane ◽

M Udler ◽

M Garaulet ◽

...

Keyword(s):

Blood Pressure ◽

Waist Circumference ◽

Health Outcomes ◽

Association Study ◽

Genetic Basis ◽

Biological Pathways ◽

European Ancestry ◽

Cardiometabolic Health ◽

Genome Wide ◽

Cardiometabolic Traits

Abstract Introduction Although daytime napping is a common, evolutionarily conserved behavior, its genetic basis is unknown. Elucidating its genetic basis may clarify relevant underlying biological pathways and determine causal links with cardiometabolic health. Methods We performed a genome-wide association study of self-reported daytime napping using linear regression in adults of European ancestry in the UK Biobank (n=452,633) and assessed robustness of signals with accelerometer-derived daytime inactivity duration (n=84,671). Next, we conducted a phenome-wide association study in a hospital-based clinical biobank (n=30,683) using napping genome-wide polygenic score (GPS), and Mendelian randomization (MR) with cardiometabolic traits. To deconstruct the napping genetic variants, we applied a novel “soft clustering” Bayesian nonnegative matrix factorization method and generated partitioned cluster-specific polygenic risk scores (PRS). Results We identified 121 distinct genome-wide significant loci for daytime napping, with lead signals at or near genes KSR2 (kinase-suppressor of ras 2), HCRTR1/HCRTR2 (hypocretin-receptor 1/2), SKOR2 (SKI family transcriptional-corepressor 2), and MAPT (microtubule-associated protein tau), among others. The loci associated with accelerometer-derived daytime inactivity duration. Gene enrichment analyses pointed to pathways involved in neurogenesis and others including nervous system development and opioid signaling. Genetic overlaps were evident in a clinical biobank where highest, compared to lowest, decile of napping GPS associated with 30%, 40%, and 50% higher odds for essential hypertension, obesity, and nonalcoholic liver disease, respectively (P<0.0001). In MR, potential causal links were identified with higher diastolic blood pressure (2.67 mmHg per napping category-increase, 95% CI 1.62–3.23, P=6.80e-07), systolic blood pressure (3.65mmHg, 1.86–5.44, P=6.40e-05), and waist circumference (0.28 SD-units, 0.11–0.45, P=0.0015). The clustering of variants identified 3 robust clusters (cluster-1: “higher sleep propensity”; cluster-2: “more fragmented/inefficient night sleep”; cluster-3: “early sleep timing”). Only clusters 2 and 3 PRSs were associated with worse cardiometabolic health outcomes, including higher BMI, waist circumference, CRP, and triglycerides (all P<0.05). Conclusion These findings expand our understanding of the genetic architecture of napping implicating multiple biological pathways, indicating possible genetic overlap and causal links to cardiometabolic traits, and suggesting distinct nap-promoting mechanisms with differential associations with health outcomes. Support This work is supported by grants NIH-F32DK102323, NIH-4T32HL007901, NIH-R01DK107859, NIH-R35HL135818, and MGH Research Scholar Fund.

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Genetic basis of blood pressure and hypertension

Trends in Genetics ◽

10.1016/j.tig.2012.04.001 ◽

2012 ◽

Vol 28 (8) ◽

pp. 397-408 ◽

Cited By ~ 90

Author(s):

Sandosh Padmanabhan ◽

Christopher Newton-Cheh ◽

Anna F. Dominiczak

Keyword(s):

Blood Pressure ◽

Genetic Basis

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Genetics of Essential Hypertension–Historical perspective and current concept

Acta geneticae medicae et gemellologiae ◽

10.1017/s1120962300012440 ◽

1968 ◽

Vol 17 (4) ◽

pp. 577-583 ◽

Cited By ~ 3

Author(s):

Julius Bauer

Keyword(s):

Metabolic Disease ◽

Blood Pressure ◽

Essential Hypertension ◽

Normal Level ◽

Historical Perspective ◽

Genetic Basis ◽

Diastolic Hypertension ◽

Specific Organ ◽

The Common ◽

Genetics Of Essential Hypertension

SummaryEssential hypertension was first recognized as morbid entity in 1911 and the word “essential” was substituted by “constitutional” in 1933. Diastolic hypertension may be constitutional or “symptomatic” if it belongs to the symptoms of a disease of specific organs (kidneys, endocrine, metabolic disease, cerebral or vascular disease). It is futile to search for such a diseased specific organ in constitutional hypertension (1933). Constitutional hypertension is a constitutional variant due to insufficient perfection of the homeostatic (feed-back) system maintaining the habitual blood pressure at a constant normal level. It is of multifactorial (polygenic) etiology (1960). It is a definite predisposition to actual diseases. It is a matter of semantics whether or not it should be called a disease of its own. The syntropy of constitutional hypertension and diabetes, obesity and arteriosclerosis is best explained by sharing various parts of polygenomes that are the common genetic basis of each of these morbid states.

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