Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor () Gene

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Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3×10^-37 is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1×10^-21), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02×10^-4). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.

Vyšlo v časopise: Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor () Gene. PLoS Genet 6(7): e32767. doi:10.1371/journal.pgen.1001035
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001035

Souhrn

Zdroje

1. CarafoliE

2004 Calcium-mediated cellular signals: a story of failures. Trends Biochem Sci 29 371 379

2. CarafoliE

2005 Calcium–a universal carrier of biological signals. Delivered on 3 July 2003 at the Special FEBS Meeting in Brussels. FEBS J 272 1073 1089

3. CarafoliE

2004 The ambivalent nature of the calcium signal. J Endocrinol Invest 27 134 136

4. WhitfieldJB

MartinNG

1984 The effects of inheritance on constituents of plasma: a twin study on some biochemical variables. Ann Clin Biochem 21 (Pt 3) 176 183

5. WilliamsPD

PuddeyIB

MartinNG

BeilinLJ

1992 Platelet cytosolic free calcium concentration, total plasma calcium concentration and blood pressure in human twins: a genetic analysis. Clin Sci (Lond) 82 493 504

6. LeifssonBG

AhrenB

1996 Serum calcium and survival in a large health screening program. J Clin Endocrinol Metab 81 2149 2153

7. LindL

SkarforsE

BerglundL

LithellH

LjunghallS

1997 Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol 50 967 973

8. DhingraR

SullivanLM

FoxCS

WangTJ

D'AgostinoRBSr

2007 Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 167 879 885

9. PalmerM

AdamiHO

BergstromR

JakobssonS

AkerstromG

1987 Survival and renal function in untreated hypercalcaemia. Population-based cohort study with 14 years of follow-up. Lancet 1 59 62

10. LundgrenE

LindL

PalmerM

JakobssonS

LjunghallS

2001 Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years. Surgery 130 978 985

11. WermersRA

KhoslaS

AtkinsonEJ

GrantCS

HodgsonSF

1998 Survival after the diagnosis of hyperparathyroidism: a population-based study. Am J Med 104 115 122

12. HeathHIII

OdelbergS

JacksonCE

TehBT

HaywardN

1996 Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. J Clin Endocrinol Metab 81 1312 1317

13. PollakMR

BrownEM

ChouYH

HebertSC

MarxSJ

1993 Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75 1297 1303

14. PollakMR

BrownEM

EstepHL

McLainePN

KiforO

1994 Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet 8 303 307

15. ColeDE

PeltekovaVD

RubinLA

HawkerGA

ViethR

1999 A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations. Lancet 353 112 115

16. ColeDE

ViethR

TrangHM

WongBY

HendyGN

2001 Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene. Mol Genet Metab 72 168 174

17. FirmannM

MayorV

Marques-VidalPM

BochudM

PecoudA

2008 The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome. BMC Cardiovasc Disord

18. RodondiN

CornuzJ

Marques-VidalP

ButlerJ

HayozD

2008 Aspirin use for the primary prevention of coronary heart disease: A population-based study in Switzerland. Prev Med 46 137 144

19. ChambersJC

ElliottP

ZabanehD

ZhangW

LiY

2008 Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet 40 716 718

20. KoonerJS

ChambersJC

Aguilar-SalinasCA

HindsDA

HydeCL

2008 Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet 40 149 151

21. MelzerD

PerryJR

HernandezD

CorsiAM

StevensK

2008 A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 4 e1000072 doi:10.1371/journal.pgen.1000072

22. SchockNW

GreulichRC

AndresR

ArenbergD

CostaPT

1984 Normal Human Aging: The Baltimore Longitudinal Study of Aging. Washington D.C

23. ScillitaniA

GuarnieriV

DeGS

MuscarellaLA

BattistaC

2004 Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor. J Clin Endocrinol Metab 89 5634 5638

24. StyrkarsdottirU

HalldorssonBV

GretarsdottirS

GudbjartssonDF

WaltersGB

2009 New sequence variants associated with bone mineral density. Nat Genet 41 15 17

25. StyrkarsdottirU

HalldorssonBV

GretarsdottirS

GudbjartssonDF

WaltersGB

2008 Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358 2355 2365

26. GudbjartssonDF

WaltersGB

ThorleifssonG

StefanssonH

HalldorssonBV

2008 Many sequence variants affecting diversity of adult human height. Nat Genet 40 609 615

27. LettreG

JacksonAU

GiegerC

SchumacherFR

BerndtSI

2008 Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40 584 591

28. WeedonMN

LettreG

FreathyRM

LindgrenCM

VoightBF

2007 A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet 39 1245 1250

29. WeedonMN

LangoH

LindgrenCM

WallaceC

EvansDM

2008 Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 40 575 583

30. FraylingTM

TimpsonNJ

WeedonMN

ZegginiE

FreathyRM

2007 A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316 889 894

31. LoosRJ

LindgrenCM

LiS

WheelerE

ZhaoJH

2008 Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40 768 775

32. DoringA

GiegerC

MehtaD

GohlkeH

ProkischH

2008 SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet 40 430 436

33. LiS

SannaS

MaschioA

BusoneroF

UsalaG

2007 The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet 3 e194 doi:10.1371/journal.pgen.0030194

34. WallaceC

NewhouseSJ

BraundP

ZhangF

TobinM

2008 Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet 82 139 149

35. SandhuMS

WaterworthDM

DebenhamSL

WheelerE

PapadakisK

2008 LDL-cholesterol concentrations: a genome-wide association study. Lancet 371 483 491

36. WillerCJ

SannaS

JacksonAU

ScuteriA

BonnycastleLL

2008 Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40 161 169

37. GoldsteinDB

2009 Common genetic variation and human traits. N Engl J Med 360 1696 1698

38. MaherB

2008 Personal genomes: The case of the missing heritability. Nature 456 18 21

39. BaiM

TrivediS

BrownEM

1998 Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J Biol Chem 273 23605 23610

40. BaiM

TrivediS

LaneCR

YangY

QuinnSJ

1998 Protein kinase C phosphorylation of threonine at position 888 in Ca2+o-sensing receptor (CaR) inhibits coupling to Ca2+ store release. J Biol Chem 273 21267 21275

41. GamaL

BreitwieserGE

1998 A carboxyl-terminal domain controls the cooperativity for extracellular Ca2+ activation of the human calcium sensing receptor. A study with receptor-green fluorescent protein fusions. J Biol Chem 273 29712 29718

42. VezzoliG

TerranegraA

ArcidiaconoT

BiasionR

CovielloD

2007 R990G polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria. Kidney Int 71 1155 1162

43. HardingB

CurleyAJ

HannanFM

ChristiePT

BowlMR

2006 Functional characterization of calcium sensing receptor polymorphisms and absence of association with indices of calcium homeostasis and bone mineral density. Clin Endocrinol (Oxf) 65 598 605

44. KellyC

GunnIR

GaffneyD

DevgunMS

2006 Serum calcium, urine calcium and polymorphisms of the calcium sensing receptor gene. Ann Clin Biochem 43 503 506

45. LaaksonenMM

OutilaTA

KarkkainenMU

KemiVE

RitaHJ

2009 Associations of vitamin D receptor, calcium-sensing receptor and parathyroid hormone gene polymorphisms with calcium homeostasis and peripheral bone density in adult Finns. J NutrigenetNutrigenomics 2 55 63

46. BollerslevJ

WilsonSG

DickIM

DevineA

DhaliwalSS

2004 Calcium-sensing receptor gene polymorphism A986S does not predict serum calcium level, bone mineral density, calcaneal ultrasound indices, or fracture rate in a large cohort of elderly women. Calcif Tissue Int 74 12 17

47. CetaniF

BorsariS

VignaliE

PardiE

PiconeA

2002 Calcium-sensing receptor gene polymorphisms in primary hyperparathyroidism. J Endocrinol Invest 25 614 619

48. YamauchiM

SugimotoT

YamaguchiT

YanoS

KanzawaM

2001 Association of polymorphic alleles of the calcium-sensing receptor gene with the clinical severity of primary hyperparathyroidism. Clin Endocrinol (Oxf) 55 373 379

49. RotheHM

ShapiroWB

SunWY

ChouSY

2005 Calcium-sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl. Pharmacogenet Genomics 15 29 34

50. ScillitaniA

GuarnieriV

BattistaC

DeGS

MuscarellaLA

2007 Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor. J Clin Endocrinol Metab 92 277 283

51. MiedlichS

LameschP

MuellerA

PaschkeR

2001 Frequency of the calcium-sensing receptor variant A986S in patients with primary hyperparathyroidism. Eur J Endocrinol 145 421 427

52. VezzoliG

TaniniA

FerrucciL

SoldatiL

BianchinC

2002 Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients. J Am Soc Nephrol 13 2517 2523

53. KimKS

KimGS

HwangJY

LeeHJ

ParkMH

2007 Single nucleotide polymorphisms in bone turnover-related genes in Koreans: ethnic differences in linkage disequilibrium and haplotype. BMC Med Genet 8 70

54. MarzW

SeelhorstU

WellnitzB

TiranB

Obermayer-PietschB

2007 Alanine to serine polymorphism at position 986 of the calcium-sensing receptor associated with coronary heart disease, myocardial infarction, all-cause, and cardiovascular mortality. J Clin Endocrinol Metab 92 2363 2369

55. RichardsJB

KavvouraFK

RivadeneiraF

StyrkarsdottirU

EstradaK

2009 Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med 151 528 537

56. BjörkmanMP

SorvaAJ

TilvisRS

1979 Calculated serum calcium is an insufficient surrogate for measured ionized calcium. Archives of Gerontology and Geriatrics 49 348 350

57. RobertsonWG

MarshallRW

1979 Calcium measurements in serum and plasma–total and ionized. CRC Crit Rev Clin Lab Sci 11 271 304

58. LadensonJH

LewisJW

BoydJC

1978 Failure of total calcium corrected for protein, albumin, and pH to correctly assess free calcium status. J Clin Endocrinol Metab 46 986 993

59. ChambersJC

ZhangW

LiY

SehmiJ

WassMN

2009 Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nature Genetics

60. FerrucciL

BandinelliS

BenvenutiE

Di IorioA

MacchiC

2000 Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study. J Am Geriatr Soc 48 1618 1625

61. ShockNW

GreulichRC

ArenbergD

CostaPT

LakattaEG

1984 Normal Human Aging: The Baltimore Longitudinal Study of Aging. Washington, D.C. National Institutes of Health

62. RussoCR

LauretaniF

BandinelliS

BartaliB

Di IorioA

2003 Aging bone in men and women: beyond changes in bone mineral density. Osteoporos Int 14 531 538