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Association of Variants at with Chronic Kidney Disease and Kidney Stones—Role of Age and Comorbid Diseases


Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1×10−10). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3×10−23) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0×10−17) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0×10−6), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7×10−5).


Vyšlo v časopise: Association of Variants at with Chronic Kidney Disease and Kidney Stones—Role of Age and Comorbid Diseases. PLoS Genet 6(7): e32767. doi:10.1371/journal.pgen.1001039
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001039

Souhrn

Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1×10−10). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3×10−23) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0×10−17) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0×10−6), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7×10−5).


Zdroje

1. National Kidney Foundation. 2002 K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 39 S1 266

2. SarnakMJ

LeveyAS

SchoolwerthAC

CoreshJ

CulletonB

2003 Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108 2154 2169

3. LindemanRD

TobinJD

ShockNW

1984 Association between blood pressure and the rate of decline in renal function with age. Kidney Int 26 861 868

4. FliserD

FranekE

JoestM

BlockS

MutschlerE

1997 Renal function in the elderly: impact of hypertension and cardiac function. Kidney Int 51 1196 1204

5. FliserD

RitzE

1998 Relationship between hypertension and renal function and its therapeutic implications in the elderly. Gerontology 44 123 131

6. RibsteinJ

Du CailarG

MimranA

2001 Glucose tolerance and age-associated decline in renal function of hypertensive patients. J Hypertens 19 2257 2264

7. KasiskeBL

1987 Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int 31 1153 1159

8. BleyerAJ

ShemanskiLR

BurkeGL

HansenKJ

AppelRG

2000 Tobacco, hypertension, and vascular disease: risk factors for renal functional decline in an older population. Kidney Int 57 2072 2079

9. ViktorsdottirO

PalssonR

AndresdottirMB

AspelundT

GudnasonV

2005 Prevalence of chronic kidney disease based on estimated glomerular filtration rate and proteinuria in Icelandic adults. Nephrol Dial Transplant 20 1799 1807

10. CoreshJ

SelvinE

StevensLA

ManziJ

KusekJW

2007 Prevalence of chronic kidney disease in the United States. JAMA 298 2038 2047

11. LindemanRD

TobinJ

ShockNW

1985 Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 33 278 285

12. SmithDH

GullionCM

NicholsG

KeithDS

BrownJB

2004 Cost of medical care for chronic kidney disease and comorbidity among enrollees in a large HMO population. J Am Soc Nephrol 15 1300 1306

13. FoxCS

YangQ

CupplesLA

GuoCY

LarsonMG

2004 Genomewide linkage analysis to serum creatinine, GFR, and creatinine clearance in a community-based population: the Framingham Heart Study. J Am Soc Nephrol 15 2457 2461

14. KöttgenA

GlazerNL

DehghanA

HwangSJ

KatzR

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

15. The International HapMap Consortium 2005 A haplotype map of the human genome. Nature 437 1299 1320

16. BachmannS

Koeppen-HagemannI

KrizW

1985 Ultrastructural localization of Tamm-Horsfall glycoprotein (THP) in rat kidney as revealed by protein A-gold immunocytochemistry. Histochemistry 83 531 538

17. PeachRJ

DayWA

EllingsenPJ

McGivenAR

1988 Ultrastructural localization of Tamm-Horsfall protein in human kidney using immunogold electron microscopy. Histochem J 20 156 164

18. PookMA

JeremiahS

ScheinmanSJ

PoveyS

ThakkerRV

1993 Localization of the Tamm-Horsfall glycoprotein (uromodulin) gene to chromosome 16p12.3–16p13.11. Ann Hum Genet 57 285 290

19. DevuystO

DahanK

PirsonY

2005 Tamm-Horsfall protein or uromodulin: new ideas about an old molecule. Nephrol Dial Transplant 20 1290 1294

20. LeekerA

KreftB

SandmannJ

BatesJ

WasenauerG

1997 Tamm-Horsfall protein inhibits binding of S- and P-fimbriated Escherichia coli to human renal tubular epithelial cells. Exp Nephrol 5 38 46

21. HessB

NakagawaY

CoeFL

1989 Inhibition of calcium oxalate monohydrate crystal aggregation by urine proteins. Am J Physiol 257 F99 106

22. SaemannMD

WeichhartT

ZeydaM

StafflerG

SchunnM

2005 Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J Clin Invest 115 468 475

23. YuCL

TsaiCY

LinWM

LiaoTS

ChenHL

1993 Tamm-Horsfall urinary glycoprotein enhances monokine release and augments lymphocyte proliferation. Immunopharmacology 26 249 258

24. BachmannS

MutigK

BatesJ

WelkerP

GeistB

2005 Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice. Am J Physiol Renal Physiol 288 F559 567

25. BatesJM

RaffiHM

PrasadanK

MascarenhasR

LaszikZ

2004 Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int 65 791 797

26. MoL

HuangHY

ZhuXH

ShapiroE

HastyDL

2004 Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. Kidney Int 66 1159 1166

27. 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

28. 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

29. HelgadottirA

ThorleifssonG

ManolescuA

GretarsdottirS

BlondalT

2007 A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316 1491 1493

30. GretarsdottirS

ThorleifssonG

ManolescuA

StyrkarsdottirU

HelgadottirA

2008 Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann Neurol 64 402 409

31. SteinthorsdottirV

ThorleifssonG

ReynisdottirI

BenediktssonR

JonsdottirT

2007 A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39 770 775

32. GretarsdottirS

ThorleifssonG

ReynisdottirST

ManolescuA

JonsdottirS

2003 The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 35 131 138

33. WetzelsJF

KiemeneyLA

SwinkelsDW

WillemsHL

den HeijerM

2007 Age- and gender-specific reference values of estimated GFR in Caucasians: the Nijmegen Biomedical Study. Kidney Int 72 632 637

34. MarchiniJ

HowieB

MyersS

McVeanG

DonnellyP

2007 A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39 906 913

35. KutyavinIV

MilesiD

BelousovY

PodyminoginM

VorobievA

2006 A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res 34 e128

36. RiceJA

1995 Mathematical Statistics and Data Analysis Belmont, CA Wadsworth Inc

37. MantelN

HaenszelW

1959 Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22 719 748

38. HuberPJ

1981 Robust statistics New York Wiley 308

39. Team RDC 2009 R: A Language for Statistical Computing Vienna, Austria R Foundation for Statistical Computing

40. DevlinB

RoederK

1999 Genomic control for association studies. Biometrics 55 997 1004

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Genetika Reprodukčná medicína

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