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

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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 5′ region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10⁻¹¹). 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.

Vyšlo v časopise: Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near Associated with Hypertension. PLoS Genet 6(10): e32767. doi:10.1371/journal.pgen.1001177
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001177

Souhrn

Zdroje

1. EzzatiM

LopezAD

RodgersA

VanderHS

MurrayCJ

2002 Selected major risk factors and global and regional burden of disease. Lancet 360 1347 1360

2. KearneyPM

WheltonM

ReynoldsK

MuntnerP

WheltonPK

2005 Global burden of hypertension: analysis of worldwide data. Lancet 365 217 223

3. LewingtonS

ClarkeR

QizilbashN

PetoR

CollinsR

2002 Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360 1903 1913

4. ChobanianAV

BakrisGL

BlackHR

CushmanWC

GreenLA

2003 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289 2560 2572

5. ManciaG

De BackerG

DominiczakA

CifkovaR

FagardR

2007 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens 25 1751 1762

6. SegaR

FacchettiR

BombelliM

CesanaG

CorraoG

2005 Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 111 1777 1783

7. CutlerJA

SorliePD

WolzM

ThomT

FieldsLE

2008 Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988–1994 and 1999–2004. Hypertension 52 818 827

8. LevyD

EhretGB

RiceK

VerwoertGC

LaunerLJ

2009 Genome-wide association study of blood pressure and hypertension. Nat Genet 41 677 687

9. Newton-ChehC

JohnsonT

GatevaV

TobinMD

BochudM

2009 Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 41 666 676

10. The Wellcome Trust Case Control Consortium 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 678

11. SmithJG

PlatonovPG

HedbladB

EngstromG

MelanderO

2010 Atrial fibrillation in the Malmo diet and cancer study: a study of occurrence, risk factors and diagnostic validity. Eur J Epidemiol 25 2 95 102

12. IwaiN

KajimotoK

KokuboY

TomoikeH

2006 Extensive genetic analysis of 10 candidate genes for hypertension in Japanese. Hypertension 48 901 907

13. KottgenA

GlazerNL

DehghanA

HwangSJ

KatzR

2009 Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 41 712 717

14. BachmannS

MetzgerR

BunnemannB

1990 Tamm-Horsfall protein-mRNA synthesis is localized to the thick ascending limb of Henle's loop in rat kidney. Histochemistry and Cell Biology 94 517 523

15. MalagoliniN

CavalloneD

Serafini-CessiF

1997 Intracellular transport, cell-surface exposure and release of recombinant Tamm-Horsfall glycoprotein. Kidney Int 52 1340 1350

16. HartTC

GorryMC

HartPS

WoodardAS

ShihabiZ

2002 Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 39 882 892

17. RampoldiL

CaridiG

SantonD

BoarettoF

BernasconeI

2003 Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Hum Mol Genet 12 3369 3384

18. Vylet'alP

KublovaM

KalbacovaM

HodanovaK

BaresovaV

2006 Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int 70 1155 1169

19. TorffvitO

JorgensenPE

KamperAL

Holstein-RathlouNH

LeyssacPP

1998 Urinary excretion of Tamm-Horsfall protein and epidermal growth factor in chronic nephropathy. Nephron 79 167 172

20. ZurbigP

DecramerS

DaknaM

JantosJ

GoodDM

2009 The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease. Proteomics 9 2108 2117

21. DulawaJ

KokotF

KokotM

PanderH

1998 Urinary excretion of Tamm-Horsfall protein in normotensive and hypertensive elderly patients. J Hum Hypertens 12 635 637

22. TorffvitO

AgardhCD

ThulinT

1999 A study of Tamm-Horsfall protein excretion in hypertensive patients and type 1 diabetic patients. Scand J Urol Nephrol 33 187 191

23. LiftonRP

2004 Genetic dissection of human blood pressure variation: common pathways from rare phenotypes. Harvey Lect 100 71 101

24. JiW

FooJN

O'RoakBJ

ZhaoH

LarsonMG

2008 Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40 592 599

25. HanssonL

HednerT

Lund-JohansenP

KjeldsenSE

LindholmLH

2000 Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 356 359 365

26. BerglundG

ElmstahlS

JanzonL

LarssonSA

1993 The Malmo Diet and Cancer Study. Design and feasibility. J Intern Med 233 45 51

27. KathiresanS

MelanderO

AnevskiD

GuiducciC

BurttNP

2008 Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 358 1240 1249

28. FerrarioM

SegaR

CesanaGC

1991 Lessons from the MONICA Study in Northern Italy. J Hypertens 9 S7 S14

29. LyssenkoV

JonssonA

AlmgrenP

PulizziN

IsomaaB

2008 Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 359 2220 2232

30. LichtCM

de GeusEJ

SeldenrijkA

van HoutHP

ZitmanFG

2009 Depression is associated with decreased blood pressure, but antidepressant use increases the risk for hypertension. Hypertension 53 631 638

31. LeveyAS

BoschJP

LewisJB

GreeneT

RogersN

1999 A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130 461 470

32. CaulfieldM

MunroeP

PembrokeJ

SamaniN

DominiczakA

2003 Genome-wide mapping of human loci for essential hypertension. Lancet 361 2118 2123

33. VisserFW

MuntingaJH

DierckxRA

NavisG

2008 Feasibility and impact of the measurement of extracellular fluid volume simultaneous with GFR by 125I-iothalamate. Clin J Am Soc Nephrol 3 1308 1315

34. VisserFW

BoonstraAH

TitiaLA

BoomsmaF

NavisG

2008 Renal response to angiotensin II is blunted in sodium-sensitive normotensive men. Am J Hypertens 21 323 328

35. BochudM

BovetP

VollenweiderP

MaillardM

PaccaudF

2009 Association between white-coat effect and blunted dipping of nocturnal blood pressure. Am J Hypertens 22 1054 1061