Risk of nephrolithiasis in primary hyperparathyroidism is associated with two polymorphisms of the calcium-sensing receptor gene.
OBJECTIVE
Two single-nucleotide polymorphisms (SNPs) at the calcium-sensing receptor (CASR) gene were previously associated with kidney stones in patients with primary hyperparathyroidism (PHPT): rs1501899, likely associated with a decrease in CASR expression, and Arg990Gly, causing a gain of CASR function. To evaluate the interaction of these two SNPs in the stone risk, we tested the association of stones with the genotype at both SNPs in PHPT patients and the association of rs1501899 with CASR expression as messenger RNA (mRNA) in human kidney samples.


RESULTS
Two hundred and ninety-six PHPT patients were genotyped at the rs1501899 and Arg990Gly SNPs. Minor allele frequency at tested SNPs was higher in PHPT stone formers relative to non-stone forming patients. PHPT patients carrying one or two copies of the minor allele at both rs1501899 and Arg990Gly (n = 16) had the maximal risk of stones (odds ratio, OR 8.3) and higher serum ionized calcium compared with homozygous patients for the wild-type allele at both SNPs. CASR expression as mRNA was measured by real time polymerase chain reaction (PCR) in normal kidney medulla samples from 109 subjects. CASR mRNA was significantly lower in medulla samples from homozygotes for the minor allele at rs1501899 than in subjects with other genotypes.


CONCLUSIONS
We conclude that the simultaneous presence of the minor allele at rs1501899 and Arg990Gly may amplify the kidney stone risk in PHPT patients, despite their apparently opposite effects on CASR function in the kidney.
Nephrology and Dialysis Unit, Postgraduate School of Nephrology, San Raffaele Scientific Institute, Vita Salute University, via Olgettina 60, 20132, Milan, Italy, vezzoli.giuseppe@hsr.it.
Giuseppe
G
Vezzoli
Alfredo
A
Scillitani
Sabrina
S
Corbetta
Annalisa
A
Terranegra
Elena
E
Dogliotti
Vito
V
Guarnieri
Teresa
T
Arcidiacono
Lorenza
L
Macrina
Alessandra
A
Mingione
Caterina
C
Brasacchio
Cristina
C
Eller-Vainicher
Daniele
D
Cusi
Anna
A
Spada
David E C
DE
Cole
Geoffrey N
GN
Hendy
Donatella
D
Spotti
Laura
L
Soldati
D000483:Alleles; D002118:Calcium / Q000097:blood; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000097:blood / Q000150:complications / Q000235:genetics*; D007679:Kidney Medulla / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D053040:Nephrolithiasis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D012307:Risk Factors
C095550:CASR protein, human; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D002118:Calcium