维生素D受体基因多态性与婴幼儿佝偻病易感性的研究
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摘要
目的研究维生素D受体(VDR)基因ApaⅠ、BsmⅠ位点多态性与婴幼儿佝偻病的相关性,探讨其遗传易感性,为临床探索一条新的诊治途径提供理论依据。
方法采用病例对照研究,选择确诊的佝偻病患儿56例(病例组)和正常婴幼儿76例(对照组)作为研究对象。应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析检测VDR基因ApaⅠ、BsmⅠ位点的多态性,比较两组之间的VDR基因型和等位基因频率,并用SHEsis软件分析ApaⅠ、BsmⅠ连锁不平衡及单倍型频率。
结果病例组和对照组婴幼儿VDR基因ApaⅠ位点基因型分布频率分别为:AA(14.3%),Aa(46.4%),aa(39.3%)和AA(13.3%),Aa(50%),aa(36.8%),两组之间的差异无统计学意义(x~2=0.166,P＞0.05);病例组和对照组婴幼儿的VDR基因ApaⅠ位点等位基因分布频率分别为A(37.5%),a(62.5%),A(38.2%),a(61.8%),两组之间的差异无统计学意义(x~2=0.12,P＞0.05);婴幼儿佝偻病患儿和对照组婴幼儿VDR基因BsmⅠ位点基因型分布频率分别为:BB(3.6%),Bb(21.4%),bb(75.0%)和BB(1.3%),Bb(18.4%),bb(80.3%),两组之间的差异无统计学意义(x~2=0.521,P＞0.05);佝偻病患儿和对照组婴幼儿的VDR基因BsmⅠ位点等位基因分布频率分别为B(14.3%),b(85.7%)和B(10.5%),b(89.5%),两组之间差异无统计学意义(x~2=0.783,P＞0.05)。ApaⅠ与BsmⅠ二位点D′为0.230,r~2为0.010。D′＜0.7,两位点之间不存在连锁不平衡。单倍型分析显示在病例组和对照组中的分布频率差异无统计学意义(P＞0.05)。
结论VDR基因ApaⅠ、BsmⅠ位点的多态性可能与婴幼儿佝偻病遗传易感性无关。
Objective To study the association between vitamin D receptor(VDR) gene polymorphism and vitamin D deficiency rickets in Infants and to explore the genetic susceptibility of its.
Methods Case-control study was adapted. Choose confirmed 56 cases of infants with rickets(case group) and 76 cases of normal infants (control group) as the subjects. VDR gene ApaI and BsmI polymorphisms were determined by PCR-RFLP technology. The frequencies of the VDR genotype and allele were compared between the two groups. Frequency of haplotypes and linkage disequilibrium of ApaI and BsmI polymorphism in two groups were analysis by the SHEsis programs.
Results Frequencies of AA, Aa and aa genotypes were 14.3%, 46.4% and 39.3% in the rickets group, and 13.3%, 50% and 36.8% in the control group respectively, frequencies of A, a alleles were 37.5%, 62.5% in the rickets group and 38.2%, 61.8% in the control group respectively. Frequencies of BB, Bb and bb genotypes were 3.6%, 21.4% and 75.0% in the rickets group, and 1.3%, 18.4% and 80.3% in the control group respectively, frequencies of B, b alleles were 14.3%, 85.7% in the rickets group and 10.5%, 89.5% in the control group respectively. No significant difference was found in either the frequency distribution of this VDR genotype or this allele (A or a; B or b) between two groups. Two polymorphisms didn't show linkage disequilibrium and D' and r~2 is respectively 0.230, 0.010. The haplotype analysis revealed that there was not different in Frequency of haplotypes between two groups.
Conclusion The ApaI and BsmI polymorphism of VDR gene might be not associated with vitamin D deficiency rickets in infants.
方法采用病例对照研究,选择确诊的佝偻病患儿56例(病例组)和正常婴幼儿76例(对照组)作为研究对象。应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析检测VDR基因ApaⅠ、BsmⅠ位点的多态性,比较两组之间的VDR基因型和等位基因频率,并用SHEsis软件分析ApaⅠ、BsmⅠ连锁不平衡及单倍型频率。
结果病例组和对照组婴幼儿VDR基因ApaⅠ位点基因型分布频率分别为:AA(14.3%),Aa(46.4%),aa(39.3%)和AA(13.3%),Aa(50%),aa(36.8%),两组之间的差异无统计学意义(x~2=0.166,P＞0.05);病例组和对照组婴幼儿的VDR基因ApaⅠ位点等位基因分布频率分别为A(37.5%),a(62.5%),A(38.2%),a(61.8%),两组之间的差异无统计学意义(x~2=0.12,P＞0.05);婴幼儿佝偻病患儿和对照组婴幼儿VDR基因BsmⅠ位点基因型分布频率分别为:BB(3.6%),Bb(21.4%),bb(75.0%)和BB(1.3%),Bb(18.4%),bb(80.3%),两组之间的差异无统计学意义(x~2=0.521,P＞0.05);佝偻病患儿和对照组婴幼儿的VDR基因BsmⅠ位点等位基因分布频率分别为B(14.3%),b(85.7%)和B(10.5%),b(89.5%),两组之间差异无统计学意义(x~2=0.783,P＞0.05)。ApaⅠ与BsmⅠ二位点D′为0.230,r~2为0.010。D′＜0.7,两位点之间不存在连锁不平衡。单倍型分析显示在病例组和对照组中的分布频率差异无统计学意义(P＞0.05)。
结论VDR基因ApaⅠ、BsmⅠ位点的多态性可能与婴幼儿佝偻病遗传易感性无关。
Objective To study the association between vitamin D receptor(VDR) gene polymorphism and vitamin D deficiency rickets in Infants and to explore the genetic susceptibility of its.
Methods Case-control study was adapted. Choose confirmed 56 cases of infants with rickets(case group) and 76 cases of normal infants (control group) as the subjects. VDR gene ApaI and BsmI polymorphisms were determined by PCR-RFLP technology. The frequencies of the VDR genotype and allele were compared between the two groups. Frequency of haplotypes and linkage disequilibrium of ApaI and BsmI polymorphism in two groups were analysis by the SHEsis programs.
Results Frequencies of AA, Aa and aa genotypes were 14.3%, 46.4% and 39.3% in the rickets group, and 13.3%, 50% and 36.8% in the control group respectively, frequencies of A, a alleles were 37.5%, 62.5% in the rickets group and 38.2%, 61.8% in the control group respectively. Frequencies of BB, Bb and bb genotypes were 3.6%, 21.4% and 75.0% in the rickets group, and 1.3%, 18.4% and 80.3% in the control group respectively, frequencies of B, b alleles were 14.3%, 85.7% in the rickets group and 10.5%, 89.5% in the control group respectively. No significant difference was found in either the frequency distribution of this VDR genotype or this allele (A or a; B or b) between two groups. Two polymorphisms didn't show linkage disequilibrium and D' and r~2 is respectively 0.230, 0.010. The haplotype analysis revealed that there was not different in Frequency of haplotypes between two groups.
Conclusion The ApaI and BsmI polymorphism of VDR gene might be not associated with vitamin D deficiency rickets in infants.
引文
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[2] Holick MF. Resurrection of Vitamin D deficiency and rickets[J]. J Clin Invest,2006,116(8): 2062-2072.
[3] Taymans SE, Pack S, Pak E, et al. The human Vitamin D receptor gene is localized to region 12cen-q12 by fluorescent in situ hybridization and radiation hybrid mapping:genetic and physical VDR map[J]. J Bone Miner Res. 1999, 14:1163-1166.
[4] Grofts LA, Hancock MS, Morrision NA, et al. Multiple promoters direct the tissue-specific expression of novel N-terminal variant human vitamin D receptor gene transcripts[J]. Proc Natl Acad Sci. 1998, 95: 10529-10534.
[5] Brown MA, Haughton MA, Grant SF, et al. Genetic control of bone density and turnover: role of the collagen 1 alpha 1,estrogen receptor, and vitamin D receptor genes[J]. J Bone Miner Res, 2001, 16: 758-764.
[6] Ongphiphadhanakul B, Rajatanavin R, Chanprasertyothin S, et al. Vitamin D receptor gene polymorphism is associated with urinary calcium excretion but not with bone mineral density in postmenopausal women[J]. Journal of Endocrinological Investigation. 1997, 20: 592-596.
[7] Kruabayashi T, Tomita M, Matsushita H, et al, Association of vitamin D and estrogen receptor gene polymorphism with the effect of hoemone replacement therapy on bone mineral density in Japanese women[J], Am J Obstet Gynecol.1999,180: 1115-1120.
[8] Riggs BL, Nguyen TV, Melton Lj, et al. The contribution of vitamin D receptor gene alleles to the determination of bone mineral density innormal and ostrporatic women[J]. J Bone Miner Res, 1995, 10: 991-996.
[9]Zmuda JM,Cauley JA,Ferrell RE.Vitamin D receptorgene variants and osteoporosis[J].Epidemiol Rev 2000,22:203-217.
[10]Carling T,Ridefelt P,Hellman P,et al.Vitamin D receptor polymorphisms correlate to parathyroidcell function in primary hyperparathyroidism[J].J Clin Endocrinol Metab 1997,82:1772-1775.
[11]席卫平,杨建平,李连青,等.维生素D受体基因ApaI位点多态性与维生素D缺乏性佝偻病的研究[J].中华儿科杂志,2005,43(7):514-515.
[12]Kaneko A,Urnaa V,Nakamura K et al.Vitamin D receptor polymorphism among rickets children in Mongolia[J].JEpidemiol,2007,17(1):25-98.
[13]Fischer PR,Thacher TD,PettiforJ M,et al.VitaminD receptor polymorphhisms and nutritional rickets in Nigerian children[J].J Bone MinerRes,2000,15:2206-22.
[14]李海林,龚晓辉,黄永坤等.维生素D受体基因ApaI多态性与维生素D缺乏性佝偻病易感性研究[J].中华医学遗传学杂志,2005,22(1):105-107.
[15]李筠,孙琼.VDR基因多态性与营养性佝偻病的关联研究[J].浙江医学,1999,21(2):69-70.
[16]杨建平,席卫平,李连青,等。维生素D受体基因BsmI多态性与儿童佝偻病的关系研究[J].中国实用儿科杂志,2006,21(1):61-62.
[17]王光,孙利炜,等.佝偻病患儿维生素D受体基因多态性的研究[J]中华儿科杂志,2004,42(10):788-789.
[18]胡亚美,江载芳,主编.诸福棠实用儿科学[M],第七版,北京:人民卫生出版社,2002,536-542.
[19]吴胜虎,余晓丹,颜崇淮,等.维生素D缺乏性佝偻病遗传易感性的研究[J].中国妇幼保健,2006,21:3088-3091.
[20]Vuppututi MR,Goswamir,Gupta N,et al.Prevalence and functional significance of 25-hydroxyvitamin D deficiency and vitamin D receptor gene polymorphisms in Asian Indians[J].Am J Clin Nutr,2006,83(6):1411-1419.
[21]Shi YY,He L.SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci[J].Cell Res,2005,15(2):97-98.
[22]Vogel Motulsky.人类遗传学[M].罗会元,译.第3版.北京:人民卫生出版社,1999,749-750.
[23]Malloy PJ,Pike JW,Feldman D.The vitamin D receptor and the syndrome of hereditary 1.25-dihydroxy vitamin D resistant rickets[J].Endocr Rev,1999,20:156-188.
[24]Haussler MR,Whitfield GK,Hausseler CA.The nuclear vitamin D receptor:biological molecular regulatory properties revealed[J].J bone Miner Res,1998,13:325-349.
[25]Gong G,Stern HS,Cheng SC,et al.The association of bone mineral density with vitamin D receptor gene polymorphisms[J].Osteoporos Int,1999,9:55-64.
[26]Morrison NA,Qi JC,Tokita A,et al.Prediction of bone density from vitamin D receptor alleles[J].Nature,1994,367(6460):284-287.
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