GALNT3基因多态性与绝经后妇女骨质疏松表型的关联研究
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摘要
第一部分
GALNT3基因多态性与绝经后妇女骨质疏松表型的关联研究
目的：GALNT3基因编码的UDP-N-乙酰-α-D-半乳糖氨基转移酶3(UDP-N-acetyl-α-D-galactosamine-polypeptide:polypeptide N-acetylgalactosamin-yltransferase-3,ppGalNacT3)是催化成纤维细胞生长因子23(fibroblast growth factor23, FGF23) O-糖基化的起始酶,在骨骼矿化过程中起重要作用。本研究的目的是探讨GALNT3基因多态性与北京地区汉族绝经后妇女骨质疏松表型的关系。
方法：研究对象源自北京地区椎体骨折(Peking Vertebral Fracture, PK-VF)研究,采用分层随机抽样的方法从北京7个区收集,本研究共纳入1353名绝经后妇女,以双能X线吸收仪(dual energy X-ray absorptiometry, DXA)检测腰椎(lumbar spine, LS)、股骨颈(femoral neck, FN)和全髋(total hip, TH)的骨密度(bone mineral density, BMD),通过阅读胸腰椎X线片确定椎体骨折表型,通过问卷调查确定脆性骨折表型。使用TaqMan基因分型技术检测GALNT3基因9个标签单核苷酸多态性(tag single nucleotide polymorphisms, tagSNP)位点,采用协方差分析、多元线性回归、logistic回归、偏相关分析等统计学方法分析各SNP位点基因型和单体型与各骨质疏松表型的关系及血钙磷与BMD间的关系。
结果：
1. GALNT3基因多态性与BMD相关：rsl863196, rs6710518和rs13429321位点的多态性与FN BMD及TH BMD密切相关(P值0.002-0.005),该三个位点的罕见等位基因(分别为G、T、T)是股骨颈及髋部骨质疏松的危险因子；rs4667492和rs6721582位点的多态性与THBMD密切相关(P值分别为0.037,0.014),该两个位点的罕见等位基因(分别为C和A)是髋部骨质疏松的保护因子。
2. GALNT3基因多态性与骨转换标志物(bone turnover markers, BTM)相关：rs1863196,rs6710518和rs13429321位点的多态性与BTM相关(P值0.006-0.044),这三个位点的罕见等位基因(分别为G、T、T)携带者具有1型胶原交联C-末端肽(cross linked C-telopeptide of type1collagen,β-CTX)或1型原胶原N-端前肽(amino-terminal procollagen of type1collagen, P1NP)升高的趋势。
3. GALNT3基因多态性与血钙磷水平相关：rs6721582位点多态性与血钙相关性达到统计学上显著性的临界值(P=0.048)；rs1863196和rs13429321位点的多态性与血磷相关(P值分别为0.016或0.037),该两个位点的罕见等位基因(G和T)携带者具有血磷降低的趋势,但影响不显著(相关系数分别为-0.021和0.017)。
4. GALNT3基因单倍体型与BMD相关：由rs1863196, rs6710518, rs4667492rs1425000,rs13429321和rs6721582组成的单倍体型ACCAAA(单倍体型-1)是髋部骨质疏松的保护因子；GTTATG (单倍体型-2)是股骨颈及髋部骨质疏松的危险因子。
5. GALNT3基因单倍体型与BTM相关：单倍体型GTTATG(单倍体型-2)与β-CTX和P1NP明显相关,携带该单倍体型者β-CTX和PINP明显升高。
6.血磷水平与BMD相关：血磷水平与LS BMD及TH BMD呈正相关(P值分别为0.020和0.018,偏相关系数分别为0.068和0.083)。
7.未发现GALNT3基因多态性及单倍体型与LS BMD.椎体骨折及脆性骨折之问的关联；未发现单倍体型与血钙磷间的关联。
结论：本研究结果提示GALNT3基因多态性与骨质疏松表型明显相关,GALNT3基因多态性与骨质疏松的关系可能与其对血磷的调控相关,GALNT3基因可能是中国绝经后妇女骨质疏松的易感基因。该结论有待在其他人群和更大样本中进一步验证。
第二部分一例肢端发育不良患者基因突变分析
背景：肢端发育不良(Acrodysostosis, ACRDYS)是一种罕见的骨骼发育不良性疾病,患者常伴有多种激素抵抗。编码环磷酸腺苷依赖的蛋白激酶Iα亚型调节亚基的PRKAR1A基因,是该病的致病基因之一。
目的：本研究对一例肢端发育不良伴多种激素抵抗的患者进行基因分析,试探讨其基因突变位点及类型。
方法：研究对象为一例12岁中国女童,经实验室检查及放射学诊断为ACRDYS.采用聚合酶链反应(polymerase chain reaction, PCR)和直接测序的方法对患者及其父母进行基因突变分析。
结果：患者脸圆、鼻梁塌陷,有明显的短指(趾)畸形,血清甲状旁腺激素(parathyroid hormone, PTH)、促甲状腺激素(thyroid stimulating hormone, TSH)水平明显升高,提示可能存在多种激素抵抗。PRKAR1A基因发现c.866G>A/p.G289E新生突变,是中国人群中发现的首个ACRDYS患者的突变。患者父母均是该位点的杂合子。
结论：本研究是国内首次在ACRDYS患者中发现PRKAR1A基因突变,研究结果证实了PRKAR1A基因p.G289E突变会导致ACRDYS伴多种激素抵抗。
Part1:The Association Study of GALNT3Polymorphisms and Phenotypes of Osteoporosis in Chinese Postmenopausal Women
Objective: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 Case
Backgroud: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.
GALNT3基因多态性与绝经后妇女骨质疏松表型的关联研究
目的：GALNT3基因编码的UDP-N-乙酰-α-D-半乳糖氨基转移酶3(UDP-N-acetyl-α-D-galactosamine-polypeptide:polypeptide N-acetylgalactosamin-yltransferase-3,ppGalNacT3)是催化成纤维细胞生长因子23(fibroblast growth factor23, FGF23) O-糖基化的起始酶,在骨骼矿化过程中起重要作用。本研究的目的是探讨GALNT3基因多态性与北京地区汉族绝经后妇女骨质疏松表型的关系。
方法：研究对象源自北京地区椎体骨折(Peking Vertebral Fracture, PK-VF)研究,采用分层随机抽样的方法从北京7个区收集,本研究共纳入1353名绝经后妇女,以双能X线吸收仪(dual energy X-ray absorptiometry, DXA)检测腰椎(lumbar spine, LS)、股骨颈(femoral neck, FN)和全髋(total hip, TH)的骨密度(bone mineral density, BMD),通过阅读胸腰椎X线片确定椎体骨折表型,通过问卷调查确定脆性骨折表型。使用TaqMan基因分型技术检测GALNT3基因9个标签单核苷酸多态性(tag single nucleotide polymorphisms, tagSNP)位点,采用协方差分析、多元线性回归、logistic回归、偏相关分析等统计学方法分析各SNP位点基因型和单体型与各骨质疏松表型的关系及血钙磷与BMD间的关系。
结果：
1. GALNT3基因多态性与BMD相关：rsl863196, rs6710518和rs13429321位点的多态性与FN BMD及TH BMD密切相关(P值0.002-0.005),该三个位点的罕见等位基因(分别为G、T、T)是股骨颈及髋部骨质疏松的危险因子；rs4667492和rs6721582位点的多态性与THBMD密切相关(P值分别为0.037,0.014),该两个位点的罕见等位基因(分别为C和A)是髋部骨质疏松的保护因子。
2. GALNT3基因多态性与骨转换标志物(bone turnover markers, BTM)相关：rs1863196,rs6710518和rs13429321位点的多态性与BTM相关(P值0.006-0.044),这三个位点的罕见等位基因(分别为G、T、T)携带者具有1型胶原交联C-末端肽(cross linked C-telopeptide of type1collagen,β-CTX)或1型原胶原N-端前肽(amino-terminal procollagen of type1collagen, P1NP)升高的趋势。
3. GALNT3基因多态性与血钙磷水平相关：rs6721582位点多态性与血钙相关性达到统计学上显著性的临界值(P=0.048)；rs1863196和rs13429321位点的多态性与血磷相关(P值分别为0.016或0.037),该两个位点的罕见等位基因(G和T)携带者具有血磷降低的趋势,但影响不显著(相关系数分别为-0.021和0.017)。
4. GALNT3基因单倍体型与BMD相关：由rs1863196, rs6710518, rs4667492rs1425000,rs13429321和rs6721582组成的单倍体型ACCAAA(单倍体型-1)是髋部骨质疏松的保护因子；GTTATG (单倍体型-2)是股骨颈及髋部骨质疏松的危险因子。
5. GALNT3基因单倍体型与BTM相关：单倍体型GTTATG(单倍体型-2)与β-CTX和P1NP明显相关,携带该单倍体型者β-CTX和PINP明显升高。
6.血磷水平与BMD相关：血磷水平与LS BMD及TH BMD呈正相关(P值分别为0.020和0.018,偏相关系数分别为0.068和0.083)。
7.未发现GALNT3基因多态性及单倍体型与LS BMD.椎体骨折及脆性骨折之问的关联；未发现单倍体型与血钙磷间的关联。
结论：本研究结果提示GALNT3基因多态性与骨质疏松表型明显相关,GALNT3基因多态性与骨质疏松的关系可能与其对血磷的调控相关,GALNT3基因可能是中国绝经后妇女骨质疏松的易感基因。该结论有待在其他人群和更大样本中进一步验证。
第二部分一例肢端发育不良患者基因突变分析
背景：肢端发育不良(Acrodysostosis, ACRDYS)是一种罕见的骨骼发育不良性疾病,患者常伴有多种激素抵抗。编码环磷酸腺苷依赖的蛋白激酶Iα亚型调节亚基的PRKAR1A基因,是该病的致病基因之一。
目的：本研究对一例肢端发育不良伴多种激素抵抗的患者进行基因分析,试探讨其基因突变位点及类型。
方法：研究对象为一例12岁中国女童,经实验室检查及放射学诊断为ACRDYS.采用聚合酶链反应(polymerase chain reaction, PCR)和直接测序的方法对患者及其父母进行基因突变分析。
结果：患者脸圆、鼻梁塌陷,有明显的短指(趾)畸形,血清甲状旁腺激素(parathyroid hormone, PTH)、促甲状腺激素(thyroid stimulating hormone, TSH)水平明显升高,提示可能存在多种激素抵抗。PRKAR1A基因发现c.866G>A/p.G289E新生突变,是中国人群中发现的首个ACRDYS患者的突变。患者父母均是该位点的杂合子。
结论：本研究是国内首次在ACRDYS患者中发现PRKAR1A基因突变,研究结果证实了PRKAR1A基因p.G289E突变会导致ACRDYS伴多种激素抵抗。
Part1:The Association Study of GALNT3Polymorphisms and Phenotypes of Osteoporosis in Chinese Postmenopausal Women
Objective: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 Case
Backgroud: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.
引文
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[46]Maroteaux P, Malamut G. [Acrodysostosis][J]. Presse Med.1968,76(46): 2189-2192.
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[2]Robinow M, Pfeiffer R A, Gorlin R J, et al. Acrodysostosis. A syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation[J]. Am J Dis Child. 1971,121(3):195-203.
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[5]Linglart A, Menguy C, Couvineau A, et al. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance[J]. N Engl J Med.2011,364(23):2218-2226.
[6]Michot C, Le Goff C, Goldenberg A, et al. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis[J]. Am J Hum Genet.2012,90(4): 740-745.
[7]Lee H, Graham J J, Rimoin D L, et al. Exome sequencing identifies PDE4D mutations in acrodysostosis[J]. Am J Hum Genet.2012,90(4):746-751.
[8]Nii E, Urawa M, Nshimura T, et al. Acrodysostosis with unusual iridal color changing with age[J]. Am J Med Genet B Neuropsychiatr Genet.2007,144B(6): 824-825.
[9]Matsuo M. Acrodysostosis [J]. Ryoikibetsu Shokogun Shirizu.2001(33):126-127.
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