The Association Study Of GALNT3Polymorphisms And Phenotypes Of Osteoporosis

Part1:The Association Study of GALNT3Polymorphisms and Phenotypes of Osteoporosis in Chinese Postmenopausal WomenObjective:GALNT3gene encodes UDP-N-acetyl-α-D-galactosamine-polypeptide:polypeptide N-acetylgalactosaminyltransferase-3(ppGalNacT3), responsible for initiating the O-glycosylation of fibroblast growth factor23(FGF23), important in phosphorous regulation. Inactivating mutations of the GALNT3gene can cause familial tumoral calcinosis. The aim of present study is to investigate the association of GALNT3polymorphisms with osteoporosis phenotypes in Chinese postmenopausal women.Methodology:A total of1353postmenopausal women were collected. Dual energy X-ray absorptiometry (DXA) was used for bone mineral density (BMD) measurements. Vertebral fracture phenotypes were ascertained by vertebral X-ray reading. Osteoporotic fracture phenotypes were obtained from questionnaires. Single nucleotide polymorphisms (SNP) of GALNT3were determined by TaqMan allelic discrimination assay. Differences of BMD, serum phosphorus or serum calcium in diverse genotypes or haplotypes were analyzed by General linear model-analysis of covariance (GLM-ANCOVA). Linear regression or logistic regression was used for association analysis of different osteoporosis phenotypes, phosphrous or calcium. Partial correlation was used to investigate the relationship between phosphorus or calcium and BMD.Results:1. GALNT3polymorphisms were associated with BMD:Polymorphisms of rsl863196, rs6710518and rsl3429321were significantly associated with femoral neck (FN) BMD and total hip (TH) BMD (P value0.002-0.005). The minor alleles of the three loci (G, T and T, respectively) were associated with increased risk of osteoporosis; polymorphisms of rs4667492and rs6721582were associated with TH BMD (P value0.037and0.014, respectively). Haplotype-1additive model and dominant model were found to be associated with TH BMD (p-value0.035and0.024, respectively). The minor allels of the two loci (C and T, respectively) were protective factors of TH BMD.2. GALNT3polymorphisms were associated with bone turnover markers (BTM): Polymorphisms of rs1863196, rs6710518and rs13429321were associated with cross linked C-telopeptide of type1collagen (β-CTX) and amino-terminal procollagen of type1collagen (P1NP)(P value0.006-0.044). The minor alleles of the three loci (G, T and T, respectively) were associated with the increase of β-CTX or P1NP.3. GALNT3polymorphisms were associated with serum calcium and phosphrous levels:Polymorphism of rs6721582associated with serum calcium at marginal significant level (P=0.048); Polymorphisms of rs1863196and rsl3429321were associated with serum phosphrous (P value0.016and0.037, respectively). The minor alleles of the two loci (G and T, respectively) were associated with the decrease of serum phosphrous.4. Haplotypes of GALNT3were associated with BMD:Haplotype-1(ACCAAA) was a protective factor for TH BMD;Haplotype-2(GTTATG) was risk factor for FN BMD and TH BMD.5. Haplotypes of GALNT3were associated with BTM:Haplotype-2(GTTATG) was associated with the increase of β-CTX and P1NP.6. Serum phosphrous was associated with BMD:Serum phosphrous had a positive correlation of LS BMD and TH BMD (P value0.020and0.018, respectively).7. GALNT3SNP or haplotypes were not associated with LS BMD or fracture risk. GALNT3haplotypes were not associated with serum calcium or phosphrous.Conclusions:GALNT3may play a role in the genetic susceptibility to osteoporosis among Chinese postmenopausal women. Part2:Genetic Analysis of an Acrodysostosis CaseBackgroud:Acrodysostosis (ACRDYS) is a rare skeletal dysplasia, some of which have multiple hormone resistance. PRKAR1A gene, which encodes the type I-alpha regulatory subunits (R I a) of cAMP-dependent protein kinase (PKA), has been found to be associated with ACRDYS.Objective:To investigate the clinical manifestation and genetic background of a Chinese girl of ACRDYS with multiple hormone resistance.Methods:A12-year-old Chinese girl, presenting with features of acrodysostosis, was included in our analysis. Laboratory analysis and X-ray were used for diagonosis of ACRDYS. Polymerase chain reaction (PCR) and direct sequencing were used for genetic analysis.Results:The patient was such as round face,"pug-nose" and brachydactyly. She also had elevated serum parathyroid hormone (PTH) and thyroid stimulating hormone (TSH) values. Leukocytic DNA was sequenced for GNAS gene and PRKAR1A gene mutation. No abnormality was detected in GNAS. A de novo heterozygous missense mutation (c.866G>A/p.G289E) was identified in PRKAR1A gene.Conclusions:Our findings confirm that c.866G>A/p.G289E mutation in PRKAR1A may cause ACRDYS with multiple hormone resistance.