Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension

Padmanabhan, Sandosh; Melander, Olle; Johnson, Toby; Blasio, Anna Maria Di; Lee, Wai Kwong; Gentilini, Davide; Hastie, Claire E.; Menni, Cristina; Monti, Maria Cristina; Delles, Christian; Laing, Stewart; Corso, Barbara; Navis, Gerjan; Kwakernaak, Arjan J.; Harst, Pim van der; Bochud, Murielle; Maillard, Marc; Burnier, Michel; Hedner, Thomas; Kjeldsen, Sverre E.; Wahlstrand, Björn; Sjögren, Marketa; Fava, Cristiano; Montagnana, Martina; Danese, Elisa; Torffvit, Ole; Hedblad, Bo; Snieder, Harold; Connell, John; Mj, Brown; Samani, Nilesh J.; Farrall, Martin; Cesana, Giancarlo; Mancia, Giuseppe; Signorini, Stefano; Grassı, Guıdo; Eyheramendy, S.; Wichmann, H‐Erich; Laan, Maris; Strachan, David P.; Sever, Peter; Shields, Denis C.; Stanton, Alice; Vollenweider, Péter; Teumer, Alexander; Völzke, Henry; Rettig, Rainer; Newton‐Cheh, Christopher; Arora, Pankaj; Zhang, Feng; Soranzo, Nicole; Spector, Timothy D.; Lucas, Gavin; Kathiresan, Sekar; Siscovick, David S.; Luan, Jian’an; Loos, Ruth J.F.; Wareham, Nicholas J.; Penninx, Brenda W. J. H.; Nolte, Ilja M.; McBride, Martin W.; Miller, William H.; Nicklin, Stuart A.; Baker, Andrew H.; Graham, Delyth; McDonald, Robert; Pell, Jill P.; Sattar, Naveed; Welsh, Paul; Munroe, Patricia B.; Caulfield, Mark; Zanchetti, Alberto; Dominiczak, Anna F.

doi:10.1371/journal.pgen.1001177

Cited by 336 publications

(284 citation statements)

References 41 publications

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“…The association of lower BP and increased sodium reabsorption appeared counterintuitive. 8 In our result, the minor G allele of rs13333226 was associated with higher DBP in a communitybased Chinese population; this result is opposite to those found with other cohorts. We therefore tested whether the UMOD gene correlated with renal sodium excretion.…”

Section: Discussioncontrasting

confidence: 99%

“…One study from the European cohorts found that the minor G allele of rs13333226 was associated with a lower risk of HTN. 8,25 However, in these cohorts, the minor G allele of rs13333226 is associated with lower urinary UMOD excretion and lower urinary sodium excretion. The association of lower BP and increased sodium reabsorption appeared counterintuitive.…”

Section: Discussionmentioning

confidence: 79%

“…7 Furthermore, in a genome-wide association study, one of the common variants of UMOD, rs13333226, is identified as being associated with HTN and cardiovascular risk in European cohorts. 8 We therefore systematically genotyped common variants across the UMOD gene in a community-based cohort and explored whether common variants of the UMOD gene are associated with BP.…”

Section: Introductionmentioning

confidence: 99%

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Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

et al. 2012

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Hypertension is an important risk factor for chronic kidney disease. The kidney, in turn, has an important role in the regulation of blood pressure (BP). On the basis of a genome-wide association study, single-nucleotide polymorphisms in the uromodulin (UMOD) promoter region had been considered to influence both renal sodium reabsorption and BP. In this study, we asked whether common variants across the UMOD gene influence BP in a community-based Chinese cohort. We screened seven common variants across the UMOD locus in a community-based population from Beijing, including 1000 individuals with 48% males and an average age of 63.7 ± 9.0 years. The urinary UMOD concentration was measured by enzyme-linked immunosorbent assay. We then analyzed the association of common variants of UMOD with BP. The UMOD promoter common variant rs13333226 G/A is associated with diastolic BP (DBP), and G allele carriers have higher DBP compared with A/A homozygotes (P ¼ 0.035). The variant rs6497476 C/T predicted the DBP level, with C homozygotes having a higher DBP compared with CT heterozygotes and T homozygotes (P ¼ 0.025). Urinary UMOD excretion was correlated with urinary sodium excretion (R ¼ 0.239, P ¼ 0.656*10 À13 ). We determined that common variants of UMOD are associated with DBP level in a community-based Chinese cohort.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

et al. 2012

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“…[34][35][36][37][38] On the contrary, heritability of hypertension and BP-related traits seems higher 18 and GWAS have reported different SNPs highly significantly associated with BP even if with quite low effect size in terms of mmHg. [19][20][21]39 This evidence could support the hypothesis that the genetic component of stroke susceptibility that is mediated by hypertension is quite diluted. Another hypothesis is that rarer variants in genes implicated in Mendelian forms of stroke may have larger effects.…”

Section: Discussionsupporting

confidence: 71%

A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case–control study

et al. 2014

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Genetic risk scores (GRS), summing up the total effect of several single-nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS based on 29 SNPs discovered by genome-wide association studies and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other 'traditional risk factors', also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Twenty-nine SNPs were genotyped in 3677 stroke cases and 2415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the combined sample, and separately for the three studies. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the combined sample (OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS P = 0.003) with similar trends in all three samples: LSR (1.050 (0.967-1.140); P = 0.25), MDC (1.168 (1.060-1.288); P = 0.002) and SAHLSIS (1.124 (0.997-1.267); P = 0.055). Measures of risk discrimination and reclassification improved marginally using the GRS. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension. INTRODUCTIONStroke is one of the leading causes of mortality, morbidity and disability worldwide. 1 Thanks to genome-wide association studies (GWAS), genetics of complex diseases has made dramatic steps forward in the last few years 2 but very few single-nucleotide polymorphisms (SNPs) have been invariantly associated with ischemic stroke. [3][4][5][6][7] Moreover, the relative risk conferred by individual genetic variants is usually low. Thus, in an attempt to estimate the aggregate effect of several gene variants, different genetic risk scores (GRS) have been constructed including a few studies on stroke with inconsistent results. [8][9][10][11][12][13][14][15] Interestingly, the selection of the SNPs to be included in GRS calculation have been based on different criteria: SNPs detected by GWAS either associated or not associated with known cardiovascular risk factors, as well as SNPs in candidate genes or pathways. [8][9][10][11][12][13][14][15] High blood pressure (BP) is the major risk factors for stroke and among the most important ones for other cardiovascular events. 16,17 Despite BP and hypertension being heritable traits, 18 the search for genetic variants associated with these traits has been more challenging compared with other cardiovascular risk factors. Only in recent years, GWAS have discovered several genetic variants which associate with BP-related ...

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“…This has already been apparent in the first large genome-wide association study by the Wellcome Trust Case-Control Consortium [87] where the study of all other complex diseases resulted in significant and plausible hits whereas not a single genetic variant achieved genome-wide significance for hypertension. Only with changes in study designs [88] and further increased sample sizes [89] have genomic studies in hypertension evolved into a success story.…”

Section: Precision Medicine and The Role Of Proteomics In Hypertensionmentioning

confidence: 99%

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

Delles

Carrick

Graham

et al. 2018

Expert Review of Proteomics

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Introduction: Hypertension is a complex and multifactorial cardiovascular disorder. With different mechanisms contributing to a different extent to an individual’s blood pressure, the discovery of novel pathogenetic principles of hypertension is challenging. However, there is an urgent and unmet clinical need to improve prevention, detection, and therapy of hypertension in order to reduce the global burden associated with hypertension-related cardiovascular diseases.Areas covered: Proteomic techniques have been applied in reductionist experimental models including angiotensin II infusion models in rodents and the spontaneously hypertensive rat in order to unravel mechanisms involved in blood pressure control and end organ damage. In humans proteomic studies mainly focus on prediction and detection of organ damage, particularly of heart failure and renal disease. While there are only few proteomic studies specifically addressing human primary hypertension, there are more data available in hypertensive disorders in pregnancy, such as preeclampsia. We will review these studies and discuss implications of proteomics on precision medicine approaches.Expert commentary: Despite the potential of proteomic studies in hypertension there has been moderate progress in this area of research. Standardized large-scale studies are required in order to make best use of the potential that proteomics offers in hypertension and other cardiovascular diseases.

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Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension

Cited by 336 publications

References 41 publications

Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case–control study

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

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