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

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

doi:10.1371/journal.pgen.1001177

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

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

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Abstract

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Original language	English
Article number	e1001177
Pages (from-to)	n/a
Number of pages	11
Journal	PL o S Genetics
Volume	6
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1001177
Publication status	Published - Oct 2010

Keywords

Aged
Alleles
Blood Pressure
Chromosomes, Human, Pair 16
Female
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Glomerular Filtration Rate
Humans
Hypertension
Linear Models
Male
Meta-Analysis as Topic
Middle Aged
Multivariate Analysis
Polymorphism, Single Nucleotide
Proportional Hazards Models
Risk Factors
Survival Analysis
Uromodulin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1001177

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Padmanabhan, S., Melander, O., Johnson, T., Di Blasio, A. M., Lee, W. K., Gentilini, D., Hastie, C. E., Menni, C., Monti, M. C., Delles, C., Laing, S., Corso, B., Navis, G., Kwakernaak, A. J., van der Harst, P., Bochud, M., Maillard, M., Burnier, M., Hedner, T., ... Dominiczak, A. F. (2010). Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension. PL o S Genetics, 6(10), n/a. Article e1001177. https://doi.org/10.1371/journal.pgen.1001177

@article{6f955f2228c1477a936be4460061c41e,

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

abstract = "Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.",

keywords = "Aged, Alleles, Blood Pressure, Chromosomes, Human, Pair 16, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glomerular Filtration Rate, Humans, Hypertension, Linear Models, Male, Meta-Analysis as Topic, Middle Aged, Multivariate Analysis, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Survival Analysis, Uromodulin",

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

year = "2010",

month = oct,

doi = "10.1371/journal.pgen.1001177",

language = "English",

volume = "6",

pages = "n/a",

journal = "PL o S Genetics",

issn = "1553-7404",

publisher = "Public Library of Science",

number = "10",

}

Padmanabhan, S, Melander, O, Johnson, T, Di Blasio, AM, Lee, WK, Gentilini, D, Hastie, CE, Menni, C, Monti, MC, Delles, C, Laing, S, Corso, B, Navis, G, Kwakernaak, AJ, van der Harst, P, Bochud, M, Maillard, M, Burnier, M, Hedner, T, Kjeldsen, S, Wahlstrand, B, Sjogren, M, Fava, C, Montagnana, M, Danese, E, Torffvit, O, Hedblad, B, Snieder, H, Connell, JMC, Brown, M, Samani, NJ, Farrall, M, Cesana, G, Mancia, G, Signorini, S, Grassi, G, Eyheramendy, S, Wichmann, HE, Laan, M, Strachan, DP, Sever, P, Shields, DC, Stanton, A, Vollenweider, P, Teumer, A, Voelzke, H, Rettig, R, Newton-Cheh, C, Arora, P, Zhang, F, Soranzo, N, Spector, TD, Lucas, G, Kathiresan, S, Siscovick, DS, Luan, J, Loos, RJF, Wareham, NJ, Penninx, BW, Nolte, IM, McBride, M, Miller, WH, Nicklin, SA, Baker, AH, Graham, D, McDonald, RA, Pell, JP, Sattar, N, Welsh, P, Munroe, P, Caulfield, MJ, Zanchetti, A & Dominiczak, AF 2010, 'Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension', PL o S Genetics, vol. 6, no. 10, e1001177, pp. n/a. https://doi.org/10.1371/journal.pgen.1001177

TY - JOUR

T1 - Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension

AU - Padmanabhan, Sandosh

AU - Melander, Olle

AU - Johnson, Toby

AU - Di Blasio, Anna Maria

AU - Lee, Wai K.

AU - Gentilini, Davide

AU - Hastie, Claire E.

AU - Menni, Cristina

AU - Monti, Maria Cristina

AU - Delles, Christian

AU - Laing, Stewart

AU - Corso, Barbara

AU - Navis, Gerjan

AU - Kwakernaak, Arjan J.

AU - van der Harst, Pim

AU - Bochud, Murielle

AU - Maillard, Marc

AU - Burnier, Michel

AU - Hedner, Thomas

AU - Kjeldsen, Sverre

AU - Wahlstrand, Bjorn

AU - Sjogren, Marketa

AU - Fava, Cristiano

AU - Montagnana, Martina

AU - Danese, Elisa

AU - Torffvit, Ole

AU - Hedblad, Bo

AU - Snieder, Harold

AU - Connell, John M. C.

AU - Brown, Morris

AU - Samani, Nilesh J.

AU - Farrall, Martin

AU - Cesana, Giancarlo

AU - Mancia, Giuseppe

AU - Signorini, Stefano

AU - Grassi, Guido

AU - Eyheramendy, Susana

AU - Wichmann, H. Erich

AU - Laan, Maris

AU - Strachan, David P.

AU - Sever, Peter

AU - Shields, Denis Colm

AU - Stanton, Alice

AU - Vollenweider, Peter

AU - Teumer, Alexander

AU - Voelzke, Henry

AU - Rettig, Rainer

AU - Newton-Cheh, Christopher

AU - Arora, Pankaj

AU - Zhang, Feng

AU - Soranzo, Nicole

AU - Spector, Timothy D.

AU - Lucas, Gavin

AU - Kathiresan, Sekar

AU - Siscovick, David S.

AU - Luan, Jian'an

AU - Loos, Ruth J. F.

AU - Wareham, Nicholas J.

AU - Penninx, Brenda W.

AU - Nolte, Ilja M.

AU - McBride, Martin

AU - Miller, William H.

AU - Nicklin, Stuart A.

AU - Baker, Andrew H.

AU - Graham, Delyth

AU - McDonald, Robert A.

AU - Pell, Jill P.

AU - Sattar, Naveed

AU - Welsh, Paul

AU - Munroe, Patricia

AU - Caulfield, Mark J.

AU - Zanchetti, Alberto

AU - Dominiczak, Anna F.

PY - 2010/10

Y1 - 2010/10

N2 - Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

AB - Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

KW - Aged

KW - Alleles

KW - Blood Pressure

KW - Chromosomes, Human, Pair 16

KW - Female

KW - Gene Frequency

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Glomerular Filtration Rate

KW - Humans

KW - Hypertension

KW - Linear Models

KW - Male

KW - Meta-Analysis as Topic

KW - Middle Aged

KW - Multivariate Analysis

KW - Polymorphism, Single Nucleotide

KW - Proportional Hazards Models

KW - Risk Factors

KW - Survival Analysis

KW - Uromodulin

U2 - 10.1371/journal.pgen.1001177

DO - 10.1371/journal.pgen.1001177

M3 - Article

C2 - 21082022

SN - 1553-7404

VL - 6

SP - n/a

JO - PL o S Genetics

JF - PL o S Genetics

IS - 10

M1 - e1001177

ER -

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

Abstract

Keywords

UN SDGs

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