The Calcium-Sensing Receptor Gene Polymorphism rs1801725 and Calcium-Related Phenotypes in Hemodialysis Patients.
BACKGROUND/AIMS
The calcium-sensing receptor gene (CASR) rs1801725 variant is responsible for a non-conservative amino-acid change (A986S) in the calcium-sensing receptor cytoplasmic tail. We hypothesized that rs1801725 polymorphism might be helpful in understanding Ca-related abnormalities in HD patients.


METHODS
In 1215 subjects (245 on cinacalcet), we determined the associations of rs1801725 with secondary hyperparathyroidism (sHPT)-related laboratory parameters, PTH-decreasing effect of cinacalcet hydrochloride, coronary artery disease (CAD), myocardial infarction (MI), nephrolithiasis-related ESRD, and mortality. CASR rs7652589(A<G)_rs1801725(G>T) haplotypes and rs1801725 epistatic interactions with vitamin D signaling pathway genes were examined for associations with selected phenotypes.


RESULTS
The rs1801725 variant allele showed an increasing independent effect on plasma PTH (Pcorrected = 0.009). CASR rs7652589_rs1801725 AT haplotype was associated with 1.7-fold higher frequency of PTH levels over 437 pg/mL than the reference haplotype GG (P = 0.001). CASR rs7652589_rs1801725 AG haplotype was 1.5-fold more frequent in nephrolithiasis-related ESRD than the GG haplotype (P = 0.004). There were no significant associations between rs1801725, CAD, MI, and response to cinacalcet. Variant homozygosity of rs1801725 correlated independently with higher infection-related mortality compared with heterozygosity (HR 7.95, 95%CI 2.15 - 29.37, P = 0.003) and major homozygosity (HR 5.89, 95%CI 1.69 - 20.55, P = 0.040). CASR rs1801725 did not show epistatic interactions with vitamin D signaling pathway genes concerning tested associations.


CONCLUSION
The variant allele of CASR rs1801725 solely and together with the variant allele of rs7652589 increases risk of more advanced sHPT. Homozygosity of the rs1801725 variant allele contributes to infection-related mortality in HD patients.
['Grzegorzewska|Alicja E|AE|', 'Bednarski|Dariusz|D|', 'Świderska|Monika|M|', 'Mostowska|Adrianna|A|', 'Jagodziński|Paweł P|PP|']
D002118:Calcium D000069449:Cinacalcet D003324:Coronary Artery Disease D005260:Female D006801:Humans D006962:Hyperparathyroidism, Secondary D007239:Infections D007676:Kidney Failure, Chronic D008297:Male D008875:Middle Aged D010281:Parathyroid Hormone D010641:Phenotype D020641:Polymorphism, Single Nucleotide D044169:Receptors, Calcium-Sensing D006435:Renal Dialysis D014807:Vitamin D
Calcium-sensing receptor gene Hemodialysis Cinacalcet Calcium Nephrolithiasis Parathyroid hormone Phosphorus Survival Vitamin D pathway genes