佝偻病患儿维生素D受体基因BsmI和FokI位点多态性与骨密度相关性研究
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摘要
目的分析佝偻病患儿维生素D受体(VDR)基因Bsml和Fokl位点多态性与骨密度(BMD)的相关性。方法选取2017年1—12月于烟台市烟台山医院儿科就诊的佝偻病患儿50例作为研究组,另选择同期在医院体检的健康婴儿50例作为健康对照组,采用聚合酶链反应(PCR)和基因测序法检测VDR基因BsmI和FokI位点多态性,采用BMD-1000A超声波骨密度仪检测左胫骨中段骨密度,自动生化分析仪检测血清钙和磷,酶联免疫法检测血清25-(OH)D_3水平,采用全血干化学法检测骨碱性磷酸酶(B-ALP)。结果研究组血钙、骨密度以及25-(OH)D_3明显低于健康对照组,而血磷和B-ALP明显高于健康对照组,差异具有统计学意义(t/P=6. 578/0. 000,8. 489/0. 000,4.489/0.000,2.936/0.004,5.358/0.000);研究组和健康对照组在FokI位点上的基因型ff、Ff以及FF差异具有统计学意义(χ~2=6.979,P=0.031),而在BsmI位点上基因型BB和bb+Bb分布上无统计学意义(χ~2=0. 102,P=0.749);FokI位点携带FF基因型个体的佝偻病发生风险高于携带ff+Ff基因型个体,差异具有统计学意义(OR=3.918,95%CI 1. 174～8.918,P=0.045),而BsmI位点基因型BB与bb+Bb个体相比,佝偻病发病风险差异无统计学意义(P>0.05);2组骨密度和25-(OH)D_3在不同基因型个体间差异均具有统计学意义(P<0.05),而不同基因型间血钙、血磷以及B-ALP差异无统计学意义(P>0.05)。两两比较结果显示FF基因型个体骨密度和25-(OH)D_3水平均明显低于携带Ff和ff基因型个体(P<0.05)。结论婴幼儿佝偻病VDR基因FokI位点多态性与骨密度、25-(OH)D_3水平密切相关,FF基因型可能是佝偻病发生的遗传危险因素。
Objective To analyze the correlation between BsmI and FokI polymorphisms of vitamin D receptor(VDR) gene and bone mineral density( BMD) in children with rickets. Methods Fifty cases of rickets in Yantaishan Hospital from January to December 2017 were selected as the study group, and 50 healthy infants in the same period were selected as the control group. Polymerase chain reaction( PCR) and gene sequencing were used to detect the polymorphism of BsmI and FokI loci of VDR gene. BMD-1000 A ultrasound bone densitometer was used to detect the bone mineral density in the middle segment of left tibia. Serum calcium and phosphorus were detected by analyzer, serum 25-(OH) D_3 was detected by ELISA, and bone alkaline phosphatase( B-ALP) was detected by whole blood dry chemistry. Results The serum calcium,bone mineral density and 25-( OH) D_3 of the study group were significantly lower than those of the healthy control group, and the serum phosphorus and B-ALP were significantly higher than the healthy control group. The difference was statistically significant(t/P = 6.578/0.000, t/P = 8.489/0.000, t/P = 4.489/0.000, t/P = 2.936/0.004,t/P = 5.358/0.000); differences in genotypes ff, Ff and FF at the FokI locus between the study and healthy controls Statistically significant(χ~2 =6.979,P =0.031), but there was no statistically significant difference in genotype BB and bb + Bb distribution at BsmI locus(χ~2 =0. 102,P =0.749); FokI locus carries FF genotype The risk of rickets was higher in individuals than in those carrying ff + Ff genotypes. The difference was statistically significant(OR=3.918, 95% CI 1.174-8.918, P=0.045), while BsmI genotype BB and bb + Bb individuals There was no significant difference in the risk of rickets(P >0.05). There were significant differences in bone mineral density and 25-( OH) D3 between the two genotypes( P < 0. 05), and blood between different genotypes. There was no significant difference in calcium, blood phosphorus and B-ALP(P>0.05). The results of pairwise comparison showed that the bone mineral density and 25-(OH) D3 level of FF genotype were significantly lower than those of Ff and ff genotypes(P < 0. 05). Conclusion FokI polymorphism of VDR gene in infants and young children with rickets is closely related to bone mineral density and 25-(OH) D3 level. FF genotype may be a genetic risk factor for rickets.
Objective To analyze the correlation between BsmI and FokI polymorphisms of vitamin D receptor(VDR) gene and bone mineral density( BMD) in children with rickets. Methods Fifty cases of rickets in Yantaishan Hospital from January to December 2017 were selected as the study group, and 50 healthy infants in the same period were selected as the control group. Polymerase chain reaction( PCR) and gene sequencing were used to detect the polymorphism of BsmI and FokI loci of VDR gene. BMD-1000 A ultrasound bone densitometer was used to detect the bone mineral density in the middle segment of left tibia. Serum calcium and phosphorus were detected by analyzer, serum 25-(OH) D_3 was detected by ELISA, and bone alkaline phosphatase( B-ALP) was detected by whole blood dry chemistry. Results The serum calcium,bone mineral density and 25-( OH) D_3 of the study group were significantly lower than those of the healthy control group, and the serum phosphorus and B-ALP were significantly higher than the healthy control group. The difference was statistically significant(t/P = 6.578/0.000, t/P = 8.489/0.000, t/P = 4.489/0.000, t/P = 2.936/0.004,t/P = 5.358/0.000); differences in genotypes ff, Ff and FF at the FokI locus between the study and healthy controls Statistically significant(χ~2 =6.979,P =0.031), but there was no statistically significant difference in genotype BB and bb + Bb distribution at BsmI locus(χ~2 =0. 102,P =0.749); FokI locus carries FF genotype The risk of rickets was higher in individuals than in those carrying ff + Ff genotypes. The difference was statistically significant(OR=3.918, 95% CI 1.174-8.918, P=0.045), while BsmI genotype BB and bb + Bb individuals There was no significant difference in the risk of rickets(P >0.05). There were significant differences in bone mineral density and 25-( OH) D3 between the two genotypes( P < 0. 05), and blood between different genotypes. There was no significant difference in calcium, blood phosphorus and B-ALP(P>0.05). The results of pairwise comparison showed that the bone mineral density and 25-(OH) D3 level of FF genotype were significantly lower than those of Ff and ff genotypes(P < 0. 05). Conclusion FokI polymorphism of VDR gene in infants and young children with rickets is closely related to bone mineral density and 25-(OH) D3 level. FF genotype may be a genetic risk factor for rickets.
引文
[1]Biljana V, Slavica M, Zoran I, et al. Case report of an infant with severe vitamin D deficiency rickets manifested as hypocalcemic seizures[J]. Srpski Arhiv Za Celokupno Lekarstvo, 2016, 144(1-2):90-93. DOI:10.2298/SARH1602090V.
[2] Haimi M, Kremer R. Vitamin D deficiency/insufficiency from childhood to adulthood:Insights from a sunny country[J]. World Journal of Clinical Pediatrics, 2017, 6(1):1-9. DOI:10. 5409/wjcp. v6.i1. 1.
[3] Heublein S, Mayr D, Meindl A, et al. Vitamin D receptor, Retinoid X receptor and peroxisome proliferator-activated receptorγare overexpressed in BRCA1 mutated breast cancer and predict prognosis[J]. J Exp Clin Cancer Res, 2017, 36(1):57. DOI:10. 1186/s13046-017-0517-1.
[4] Wang J, Thingholm LB, Skieceviciene J, et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota[J]. Nature Genetics,2016, 48(11):1396-1406. DOI:10.1038/ng.3695.
[5] Abd-Allah SH, Pasha HF, Hagrass HA, et al. Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1diabetes in Egyptian children[J]. Gene, 2014, 536(2):430-434.DOI:10. 1016/j. gene. 2013. 12.032.
[6]中华儿科杂志编辑委员会,中华医学会儿科学分会儿童保健学组,全国佝偻病防治科研协作组.维生素D缺乏性佝偻病防治建议[J].中华儿科杂志,2008, 46(3):190-191.
[7]阿娜尔·阿依甫汗.小儿社区佝偻病的临床调查及病因总结分析[J].中国卫生产业,2017,14(1):173-175. DOI:10.16659/j.cnki. 1672-5654.2017.01.173.
[8] Zhu K, Oddy WH, Holt P, et al. Tracking of vitamin D status from childhood to early adulthood and its association with peak bone mass[J]. American Journal of Clinical Nutrition, 2017, 106(1):276-283. DOI:10.3945/ajcn. 116.150524.
[9] Alraddadi R, Bahijri S, Borai A, et al. Prevalence of lifestyle practices that might affect bone health in relation to vitamin D status a-mong female Saudi adolescents[J]. Nutrition, 2018, 45(1):108-113. DOI:10.1016/j. nut. 2017.07.015.
[10] Biljana V, Slavica M, Zoran I, et al. Case report of an infant with severe vitamin D deficiency rickets manifested as hypocalcemic seizures[J]. Srpski Arhiv Za Celokupno Lekarstvo, 2016, 144(1-2):90-93. DOI:10.2298/SARH1602090V.
[11] Kiess W, Bae YJ, Penke M, et al. Vitamin D in health and disease:the global threat of vitamin D deficient rickets[J]. J Pediatr Endocrinol Metab, 2016, 29(4):391-393. DOI:10. 1515/jpem-2016-0054.
[12] Koek WN, Zillikens MC, Bc VDE, et al. Novel Compound Heterozygous Mutations in the CYP27B1 Gene Lead to Pseudovitamin DDeficient Rickets[J]. Calcified Tissue International, 2016,99(3):326-331. DOI:10.1007/s00223-016-0165-z.
[13] Kdj J, Hachmeister CU, Khasira M, et al. Vitamin D deficiency causes rickets in an urban informal settlement in Kenya and is associated with malnutrition[J]. Maternal&Child Nutrition, 2017, 14(5):e12452. DOI:10.1111/mcn. 12452.
[14] Ghazi AA, Hosseinpanah F, Ardakani EM, et al. Effects of differ-ent doses of oral cholecalciferol on serum 25(OH)D, PTH, calcium and bone markers during fall and winter in schoolchildren[J].European Journal of Clinical Nutrition, 2010, 64(12):1415-1422.DOI:1038/ejcn.2010.169.
[15] Mahjoubi I, Kallel A, Sba MH, et al. Lack of association between FokI polymorphism in vitamin D receptor gene(VDR)&type 2 diabetes mellitus in the Tunisian population[J]. Indian Journal of Medical Research, 2016, 144(1):46-51. DOI:10. 4103/0971-5916.193282.
[16] Elhoseiny SM, Morgan DS, Rabie AM, et al. Vitamin D Receptor(VDR)Gene Polymorphisms(FokI, BsmI)and their Relation to Vitamin D Status in Pediatricsβeta Thalassemia Major[J]. Indian J Hematol Blood Transfus, 2016, 32(2):228-238. DOI:10. 1007/s12288-015-0552-z.
[17]王宝珍,孙永静,哈丽君,等.银川地区汉族儿童维生素D受体基因BsmI位点和FokI位点单核苷酸多态性与维生素D缺乏性佝楼病的相关性研究[J].宁夏医学杂志,2015, 37(12):1071-1073. DOI:10.13621/j. 1001-5949.2015.12.1071.
[2] Haimi M, Kremer R. Vitamin D deficiency/insufficiency from childhood to adulthood:Insights from a sunny country[J]. World Journal of Clinical Pediatrics, 2017, 6(1):1-9. DOI:10. 5409/wjcp. v6.i1. 1.
[3] Heublein S, Mayr D, Meindl A, et al. Vitamin D receptor, Retinoid X receptor and peroxisome proliferator-activated receptorγare overexpressed in BRCA1 mutated breast cancer and predict prognosis[J]. J Exp Clin Cancer Res, 2017, 36(1):57. DOI:10. 1186/s13046-017-0517-1.
[4] Wang J, Thingholm LB, Skieceviciene J, et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota[J]. Nature Genetics,2016, 48(11):1396-1406. DOI:10.1038/ng.3695.
[5] Abd-Allah SH, Pasha HF, Hagrass HA, et al. Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1diabetes in Egyptian children[J]. Gene, 2014, 536(2):430-434.DOI:10. 1016/j. gene. 2013. 12.032.
[6]中华儿科杂志编辑委员会,中华医学会儿科学分会儿童保健学组,全国佝偻病防治科研协作组.维生素D缺乏性佝偻病防治建议[J].中华儿科杂志,2008, 46(3):190-191.
[7]阿娜尔·阿依甫汗.小儿社区佝偻病的临床调查及病因总结分析[J].中国卫生产业,2017,14(1):173-175. DOI:10.16659/j.cnki. 1672-5654.2017.01.173.
[8] Zhu K, Oddy WH, Holt P, et al. Tracking of vitamin D status from childhood to early adulthood and its association with peak bone mass[J]. American Journal of Clinical Nutrition, 2017, 106(1):276-283. DOI:10.3945/ajcn. 116.150524.
[9] Alraddadi R, Bahijri S, Borai A, et al. Prevalence of lifestyle practices that might affect bone health in relation to vitamin D status a-mong female Saudi adolescents[J]. Nutrition, 2018, 45(1):108-113. DOI:10.1016/j. nut. 2017.07.015.
[10] Biljana V, Slavica M, Zoran I, et al. Case report of an infant with severe vitamin D deficiency rickets manifested as hypocalcemic seizures[J]. Srpski Arhiv Za Celokupno Lekarstvo, 2016, 144(1-2):90-93. DOI:10.2298/SARH1602090V.
[11] Kiess W, Bae YJ, Penke M, et al. Vitamin D in health and disease:the global threat of vitamin D deficient rickets[J]. J Pediatr Endocrinol Metab, 2016, 29(4):391-393. DOI:10. 1515/jpem-2016-0054.
[12] Koek WN, Zillikens MC, Bc VDE, et al. Novel Compound Heterozygous Mutations in the CYP27B1 Gene Lead to Pseudovitamin DDeficient Rickets[J]. Calcified Tissue International, 2016,99(3):326-331. DOI:10.1007/s00223-016-0165-z.
[13] Kdj J, Hachmeister CU, Khasira M, et al. Vitamin D deficiency causes rickets in an urban informal settlement in Kenya and is associated with malnutrition[J]. Maternal&Child Nutrition, 2017, 14(5):e12452. DOI:10.1111/mcn. 12452.
[14] Ghazi AA, Hosseinpanah F, Ardakani EM, et al. Effects of differ-ent doses of oral cholecalciferol on serum 25(OH)D, PTH, calcium and bone markers during fall and winter in schoolchildren[J].European Journal of Clinical Nutrition, 2010, 64(12):1415-1422.DOI:1038/ejcn.2010.169.
[15] Mahjoubi I, Kallel A, Sba MH, et al. Lack of association between FokI polymorphism in vitamin D receptor gene(VDR)&type 2 diabetes mellitus in the Tunisian population[J]. Indian Journal of Medical Research, 2016, 144(1):46-51. DOI:10. 4103/0971-5916.193282.
[16] Elhoseiny SM, Morgan DS, Rabie AM, et al. Vitamin D Receptor(VDR)Gene Polymorphisms(FokI, BsmI)and their Relation to Vitamin D Status in Pediatricsβeta Thalassemia Major[J]. Indian J Hematol Blood Transfus, 2016, 32(2):228-238. DOI:10. 1007/s12288-015-0552-z.
[17]王宝珍,孙永静,哈丽君,等.银川地区汉族儿童维生素D受体基因BsmI位点和FokI位点单核苷酸多态性与维生素D缺乏性佝楼病的相关性研究[J].宁夏医学杂志,2015, 37(12):1071-1073. DOI:10.13621/j. 1001-5949.2015.12.1071.