Common genetic variants associate with serum phosphorus concentration.
Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.
Kestenbaum
Bryan
B
Division of Nephrology, Department of Medicine, University of Washington, Kidney Research Institute, Seattle, Washington 98104-2499, USA. brk@u.washington.edu
Glazer
Nicole L
NL
Köttgen
Anna
A
Felix
Janine F
JF
Hwang
Shih-Jen
SJ
Liu
Yongmei
Y
Lohman
Kurt
K
Kritchevsky
Stephen B
SB
Hausman
Dorothy B
DB
Petersen
Ann-Kristin
AK
Gieger
Christian
C
Ried
Janina S
JS
Meitinger
Thomas
T
Strom
Tim M
TM
Wichmann
H Erich
HE
Campbell
Harry
H
Hayward
Caroline
C
Rudan
Igor
I
de Boer
Ian H
IH
Psaty
Bruce M
BM
Rice
Kenneth M
KM
Chen
Yii-Der Ida
YD
Li
Man
M
Arking
Dan E
DE
Boerwinkle
Eric
E
Coresh
Josef
J
Yang
Qiong
Q
Levy
Daniel
D
van Rooij
Frank J A
FJ
Dehghan
Abbas
A
Rivadeneira
Fernando
F
Uitterlinden
André G
AG
Hofman
Albert
A
van Duijn
Cornelia M
CM
Shlipak
Michael G
MG
Kao
W H Linda
WH
Witteman
Jacqueline C M
JC
Siscovick
David S
DS
Fox
Caroline S
CS
D000328:Adult; D000368:Aged; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D007668:Kidney / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010758:Phosphorus / Q000097:blood*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D012737:Sex Factors; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics; D044465:White People
C095550:CASR protein, human; C000717427:FGF23 protein, human; D044169:Receptors, Calcium-Sensing; C493554:SLC34A1 protein, human; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23