| Introduction and ObjectiveNon-surgical hypoparathyroidism(Ns-HypoPT)is a rare disorder characterized by hypocalcemia and hyperphosphatemia with low or inappropriately normal parathyroid hormone(PTH)levels,of which pathogenesis remains unknown.In recent years,many studies were carried out to investigate the association between single nucleotide polymorphisms(SNPs)and primary hyperparathyroidism,while the researches between SNPs and adult-onset Ns-HypoPT were sparse.Only two studies analyzed the association of Ns-HypoPT pathogenesis and clinical characteristics with few SNPs in PTH and VDR genes.The study aims to first extensively explore the association between SNPs in genes,which were known as disease-causing genes,with adult-onset Ns-HypoPT susceptibility and clinical phenotypes.MethodsWe screened SNPs in the functional regions of all Ns-HypoPT candicate genes that were found by PubMed database,including CASR?GNA11?PTH?TBX1?AIRE?GATA3?GCM2?TBCE?FAM111A?SOX3?VDR?LDN16 and TRPM6.We identified the SNPs with a minor allele frequency>5%in Chinese Han population based on NCBI dbSNP database,1000 Genomes browser and HapMap database.Several miRNA target prediction softwares and transcription factor(TF)binding sites prediction softwares were used to investigate SNPs in target binding sites for miRNAs and TFs.These softwares included SNP Function Prediction,miRDB?microRNA,TargetScan 7.0,PolymiRTS,PROMO and TFBind.We also included ten TagSNPs of GNA11 because we found the significantly different distribution of the SNPs in its functional regions.Genotyping of SNPs was performed with MassARRAY in 203 Ns-HypoPT patients and 209 healthy controls.Direct sequencing was performed to confirm the accuracy of genotyping results.Chi square and logistic regression analysis were used to analyze the association between SNPs above with Ns-HypoPT susceptibility and its clinical charateristics.Results1.A total of 37 SNPs were selected from 13 candicate genes,and all SNPs were in the Hardy-Weinberg equilibrium in the control subjects and had 100%accuracy confirmed by Sanger sequencing.2.Only SNPs in GNA11 gene were differently distributed in cases and controls.The risk allele of rs 11084997 reduced the risk of Ns-HypoPT both in additive and dominant models(OR=0.382 and 0.647,respectively),while rs308060 was associated with increased risk of Ns-HypoPT in additive,dominant,and recessive models(OR=3.269,2.864 and 2.727,respectively).3.In the cases,the frequency of CC halotype composed of the minor alleles of rsl 1084997 and rs4806907 was lower than in the controls(P<0.05),while the frequency of TTCGCC halotype composed of the minor alleles of rs308060 and other TagSNPs was higher than in the controls.4.The correlation between SNPs and clinical phenotypes1)Compared with patients without risk allele C of rs308049,the patients who carried it had lower serum calcium level(P<0.05).We also found out that CCGGCT halotype with this allele was associated with PTH level(P<0.05).2)The patients carried with risk allele G of it had lower accurence of intracranial calcification(P<0.05).3)In femal patients,genotypes of rs385443,rs3746069,rs308033,and rs308039 were assocatied with bone mineral desity(BMD)and Z score(P<0.05).However,only rs17828831 was related to BMD and Z score in male patients(P<0.05).4)The risk alleles of rs4806907(C)and rs385443(G)were associated with increased risk of hypercalciuria,while CC and CG haplotypes consisted of risk allele C of rs4806907 also were the risk fators for hypercalciuria in Ns-HypoPT patients.5.Spearman analysis found that the genotypes of rs739837 in VDR gene was positively related with serum calcium level.The risk alleles of this SNP and rs2228570 incresed the risk of hypercalciuria in Ns-HypoPT patients.Conclusions1.The present study found that rs110844997 and rs308060 in GNA11 gene may be associated with Ns-HypoPT susceptibility.The former SNP was showed as a protective factor,while the latter SNP was showed as a risk factor.2.The genotypes of rs308049,rs7803011,rs385443,rs3746069,rs308033,rs308039,and rs4806907 may be associated with several characteristics of Ns-HypoPT.3.rs739837 and rs2228570 of VDR gene may be related with the different response to vitamin D analog treatment.Introduction and ObjectiveThe areal bone mineral density(aBMD)tested by DXA is abnormally high in non-surgical hypoparathyroidism(Ns-HypoPT)patients.Different types of pseudohypoparathyroidism(PHP)have different characteristics in bone metabolism.However,there is few studies carried out to assess their bone mass and microstructure.High resolution peripheral quantitative CT(HRpQCT)is a new imaging technique that can separately assess trabecular and cortical bone microstructure of the radius and tibia in vivo.Only two studies used HRpQCT to assess Ns-HypoPT and PHP bone quality.This study aims to evaluate and compare the bone structural features of Ns-HypoPT,PHP1A and PHP1B patients in a Chinese population.MethodsIn 40 patients with Ns-HypoPT,11 patients with PHP1A and 31 patients with PHP1B,the distal radius and tibia were imaged using HR-pQCT.Clinical data including areal bone mineral density(aBMD)assessed by Dual-energy X-ray absorptiometry(DXA)were collected.Results1.Compared with Ns-HypoPT,PHP1B patients had higher level of ?-CTX and ALP,which were positively correlated with PTH level(r=0.720,P=0.008;r=0.718,P=0.001).2.Only 3 PHP1A patients finished the DXA,therefore we only compared the aBMD and its Z score of femoral neck,total hip and L2-L4 in Ns-HypoPT and PHP1B patients.Ns-HypoPT patients had abnormally high level of aBMD and Z score in all sites.After adjusting for age,gender and BMI,the aBMD and Z score in all sites of PHP1B patients were lower than Ns-HypoPT.3.Comparison of HRpQCT parameters in three goups of patients and healthy controls:1)Ns-HypoPT and healthy controls:Patients had higher trabecular volume bone density(Tb.vBMD)and trabecular number(Tb.N)than controls(P<0.05),while they had lower trabecular separation(Tb.Sp)and inhomogeneity of network(Tb.1/N.SD)in the tibia(P<0.001).2)Ns-HypoPT and PHPIA:Most HRpQCT parameters were similar in these patients except that Tb.l/N.SD of the tibia was higher in PHP1A patients than Ns-HypoPT(P=0.027).3)Ns-HypoPT and PHP1B:Tb.vBMD,trabecular bone volume fraction(Tb.BV/TV)and thickness(Tb.Th)of radius was lower in PHPIB patients(P<0.05),while cortical porosity(Ct.Po)of the radius(P=0.030),Tb.Sp and Tb.l/N.SD of tibia was higher(P<0.05).4)PHP1A,PHP1B and controls:There was no significant difference in HRpQCT test between PHP1A and controls,so as the PHP1B patients and controls.However,PHP1B patients had lower Tb.vBMD,Tb.BV/TV and Tb.Th of radius than PHP1A.4.The association between aBMD,HRpQCT and clinical characteristics:1)The disease duration of Ns-HypoPT was positively related to L2-L4 aBMD and its Z score,Ct.vBMD,Tb.vBMD,Tb.BV/TV,Tb.N and Tb.l/N.SD of radius,but was negatively correlated with Tb.Sp and Ct.Po.2)The disease duration of PHP1B was negatively related to Tb.BV/TV,Tb.N and Tb.Th,but was positively correlated with Tb.Sp and Tb.l/N.SD.PTH level was negatively correlated with Tb.N,while positively correlated with Tb.Sp.ConclusionsThe median level of bone turnover in Ns-HypoPT patients was in the lower section of normal range.The bone turnover level was higher in PHP1B patients than Ns-HypoPT,and it was positively correlated with PTH level.The aBMD and Z score in all sites of Ns-HypoPT patients were abnormally high,while PHP1B patients were lower than them.Moreover,Ns-HypoPT patients had higher trabecular vBMD and lower separation than healthy controls.While several parameters of trabecular bone were significantly different between PHP1B and Ns-HypoPT patients,and same with PHP1A and PHP1B.The disease duration of Ns-HypoPT patients were positively correlated with L2-L4 aBMD,vBMD and bone microstructure,while it was negatively correlated with trabecular separation and cortical porosity.The PTH level of PHP1B patients was negatively correlated with femoral neck aBMD,radius corical bone vBMD and trabecular number,but was positively related to trabecular separation.Diease duration was negatively correlated with vBMD and bone microstructure. |
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