GC、CYP2R1基因多态性与北京汉族绝经后妇女血清维生素D水平的关系
摘要
目的：维生素D缺乏是一个普遍而重要的健康问题,近期研究发现遗传因素对血清25(OH)D水平有一定影响。本研究的目的是探讨GC及CYP2R1基因多态性与维生素D水平的关系,并探讨GC基因多态性与骨密度、骨转换标志物及骨量异常、骨折、椎体骨折的关系。
方法：以北京地区随机抽样的1494名汉族绝经后妇女为研究对象,通过问卷调查和胸腰椎X线检查确定自报骨折及椎体骨折表型。以双能X线吸收仪检测腰椎(L2-4)、股骨颈和全髋三个部位的骨密度,用罗氏自动检测仪通过电化学发光免疫测定法检测样本血清的β-CTX、P1NP和25(OH)D水平。通过TaqMan基因分型技术获得GC和CYP2R1基因6个SNP位点的基因型。采用线性回归、二元logistic回归等统计学方法分析各SNP位点基因型和单体型与血清25(OH)D水平、骨密度、骨转换标志物及骨量异常、骨折、椎体骨折的关系。
结果：
1.本研究的1494例研究对象中有维生素D缺乏的1338人,维生素D相对不足的146人,分别占总研究对象的89.6%和9.8%。
2.GC基因rs222020位点(P=0.003)和rs2298849位点(P＝3.73e-4)的多态性与血清25(OH)D水平显著相关,并且这种显著性经过对多重检验的校正后仍然存在。rs222020的少见等位基因C和rs2298849的少见等位基因G可能是血清25(OH)D水平的保护性等位基因。rs222020-rs2298849的单体型CG对应升高的血清25(OH)D水平(p=0.138,P＝0.001),单体型TA对应降低的血清25(OH)D水平(β=-0.118,P＝0.002)。
3. CYP2R1基因多态性与血清25(OH)D水平无显著相关性。
4.GC基因多态性与β-CTX、P1NP和腰椎L2-4、股骨颈、全髋各部位骨密度及骨量异常风险、脆性骨折风险、有X证据的椎体骨折风险无显著相关性。CYP2R1基因多态性与β-CTX、P1NP水平有显著相关性,与上述各部位骨密度及骨量异常风险、骨折风险无显著相关性。
结论：在北京汉族绝经后妇女群体中,GC基因的多态性与血清25(OH)D水平显著相关,CYP2R1基因多态性与血清25(OH)D水平无显著相关性。CYP2R1基因与β-CTX、P1NP水平的相关性需要进一步验证。
Objective:Vitamin D deficiency is a common and important healthy problem. Recently people have found some genetic factors that may influence serum25(OH)D concentration. The aim of our study is to determine if GC and CYP2R1genetic variants have association with serum25(OH)D level and to explore if there is association between GC variants and bone mineral density (BMD), bone turnover markers, fracture, or vertebral fracture in postmenopausal women.
Methods:We randomly selected a population of1494postmenopausal women of Han ethnic group from7communities in Beijing. Main information was acquired as follows: Osteoporotic fracture and vertebral fracture phenotypes:questionnaire and vertebral X-ray reading; BMD of lumbar spine (L2-4), femoral neck (FN) and total hip:dual energy X-ray absorptiometry (DXA); Serum bone turnover markers and25(OH)D: automated Roche electrochemiluminescence system; Genotyping:TaqMan pre-designed SNP genotyping assays in real-time PCR System. Linear regression and binary logistic regression were used to test the associations of SNP genotypes, haplotypes and serum25(OH)D level, BMD, bone turnover markers, and low bone mass, fracture, and vertebral fracture.
Results:
1. In our sample1338women have vitamin D deficiency and another146women have vitamin D insufficiency, occupying89.6%and9.8%of total sample, respectively.
2. The variants of rs222020(P=0.003) and rs2298849(P=3.73e-4) at GC are significantly associated with serum25(OH)D level. This association is still significant after10000times max(T) permutation test. Allele C of rs222020and allele G of rs2298849might be protective for serum25(OH)D level. Among the haplotypes of rs222020-rs2298849, CG (β=0.138,P=0.001) and TA (β=-0.118,P=0.002) correspond to increasing and decreasing serum25(OH)D concentrations, respectively. We didn't find significant association between CYP2R1polymorphisms and serum25(OH)D level.
3. No significant association were found between GC polymorphisms and BMD of L2-4, FN, and total hip, β-CTX, P1NP, and the risk of having abnormal BMD, fracture, or vertebral fracture. CYP2R1polymorphisms had similar results except its significant association with p-CTX and P1NP.
Conclusion:GC variants have significant association with serum25(OH)D level among postmenopausal women of Han ethnic group in Beijing while CYP2R1variants weren't found significant. Association of CYP2R1genetic variants with β-CTX and P1NP needs to be proven.
方法：以北京地区随机抽样的1494名汉族绝经后妇女为研究对象,通过问卷调查和胸腰椎X线检查确定自报骨折及椎体骨折表型。以双能X线吸收仪检测腰椎(L2-4)、股骨颈和全髋三个部位的骨密度,用罗氏自动检测仪通过电化学发光免疫测定法检测样本血清的β-CTX、P1NP和25(OH)D水平。通过TaqMan基因分型技术获得GC和CYP2R1基因6个SNP位点的基因型。采用线性回归、二元logistic回归等统计学方法分析各SNP位点基因型和单体型与血清25(OH)D水平、骨密度、骨转换标志物及骨量异常、骨折、椎体骨折的关系。
结果：
1.本研究的1494例研究对象中有维生素D缺乏的1338人,维生素D相对不足的146人,分别占总研究对象的89.6%和9.8%。
2.GC基因rs222020位点(P=0.003)和rs2298849位点(P＝3.73e-4)的多态性与血清25(OH)D水平显著相关,并且这种显著性经过对多重检验的校正后仍然存在。rs222020的少见等位基因C和rs2298849的少见等位基因G可能是血清25(OH)D水平的保护性等位基因。rs222020-rs2298849的单体型CG对应升高的血清25(OH)D水平(p=0.138,P＝0.001),单体型TA对应降低的血清25(OH)D水平(β=-0.118,P＝0.002)。
3. CYP2R1基因多态性与血清25(OH)D水平无显著相关性。
4.GC基因多态性与β-CTX、P1NP和腰椎L2-4、股骨颈、全髋各部位骨密度及骨量异常风险、脆性骨折风险、有X证据的椎体骨折风险无显著相关性。CYP2R1基因多态性与β-CTX、P1NP水平有显著相关性,与上述各部位骨密度及骨量异常风险、骨折风险无显著相关性。
结论：在北京汉族绝经后妇女群体中,GC基因的多态性与血清25(OH)D水平显著相关,CYP2R1基因多态性与血清25(OH)D水平无显著相关性。CYP2R1基因与β-CTX、P1NP水平的相关性需要进一步验证。
Objective:Vitamin D deficiency is a common and important healthy problem. Recently people have found some genetic factors that may influence serum25(OH)D concentration. The aim of our study is to determine if GC and CYP2R1genetic variants have association with serum25(OH)D level and to explore if there is association between GC variants and bone mineral density (BMD), bone turnover markers, fracture, or vertebral fracture in postmenopausal women.
Methods:We randomly selected a population of1494postmenopausal women of Han ethnic group from7communities in Beijing. Main information was acquired as follows: Osteoporotic fracture and vertebral fracture phenotypes:questionnaire and vertebral X-ray reading; BMD of lumbar spine (L2-4), femoral neck (FN) and total hip:dual energy X-ray absorptiometry (DXA); Serum bone turnover markers and25(OH)D: automated Roche electrochemiluminescence system; Genotyping:TaqMan pre-designed SNP genotyping assays in real-time PCR System. Linear regression and binary logistic regression were used to test the associations of SNP genotypes, haplotypes and serum25(OH)D level, BMD, bone turnover markers, and low bone mass, fracture, and vertebral fracture.
Results:
1. In our sample1338women have vitamin D deficiency and another146women have vitamin D insufficiency, occupying89.6%and9.8%of total sample, respectively.
2. The variants of rs222020(P=0.003) and rs2298849(P=3.73e-4) at GC are significantly associated with serum25(OH)D level. This association is still significant after10000times max(T) permutation test. Allele C of rs222020and allele G of rs2298849might be protective for serum25(OH)D level. Among the haplotypes of rs222020-rs2298849, CG (β=0.138,P=0.001) and TA (β=-0.118,P=0.002) correspond to increasing and decreasing serum25(OH)D concentrations, respectively. We didn't find significant association between CYP2R1polymorphisms and serum25(OH)D level.
3. No significant association were found between GC polymorphisms and BMD of L2-4, FN, and total hip, β-CTX, P1NP, and the risk of having abnormal BMD, fracture, or vertebral fracture. CYP2R1polymorphisms had similar results except its significant association with p-CTX and P1NP.
Conclusion:GC variants have significant association with serum25(OH)D level among postmenopausal women of Han ethnic group in Beijing while CYP2R1variants weren't found significant. Association of CYP2R1genetic variants with β-CTX and P1NP needs to be proven.
引文
[1]Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet[J]. Lancet 1989;2:1104-5.
[2]Holick MF. Vitamin D:a d-lightful solution for health[J]. J Investig Med 2011;59:872-80.
[3]Holick MF. Vitamin D deficiency [J]. N Engl J Med 2007;357:266-81.
[4]Lu L, Yu Z, Pan A, et al. Plasma 25-hydroxyvitamin D concentration and metabolic syndrome among middle-aged and elderly Chinese individuals[J]. Diabetes Care 2009;32:1278-83.
[5]Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes[J]. Am J Clin Nutr 2006;84:18-28.
[6]El-Hajj Fuleihan G, Nabulsi M, Tamim H, et al. Effect of vitamin D replacement on musculoskeletal parameters in school children:a randomized controlled trial [J]. J Clin Endocrinol Metab 2006;91:405-12.
[7]Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D:a meta-analysis of randomised controlled trials[J]. BMJ 2009;339:b3692.
[8]Broe KE, Chen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel DP. A higher dose of vitamin d reduces the risk of falls in nursing home residents:a randomized, multiple-dose study [J]. J Am Geriatr Soc 2007;55:234-9.
[9]Reddy Vanga S, Good M, Howard PA, Vacek JL. Role of vitamin D in cardiovascular health[J]. Am J Cardiol 2010;106:798-805.
[10]Stechschulte SA, Kirsner RS, Federman DG. Vitamin D:bone and beyond, rationale and recommendations for supplementation[J]. Am J Med 2009; 122:793-802.
[11]Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults[J]. Diabetes Care 2005;28:1228-30.
[12]Baynes KC, Boucher BJ, Feskens EJ, Kromhout D. Vitamin D, glucose tolerance and insulinaemia in elderly men[J]. Diabetologia 1997;40:344-7.
[13]Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey[J]. Am J Hypertens 2007;20:713-9.
[14]Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension[J]. Hypertension 2007;49:1063-9.
[15]Zeeb H, Greinert R. The role of vitamin D in cancer prevention:does UV protection conflict with the need to raise low levels of vitamin D[J]? Dtsch Arztebl Int 2010;107:638-43.
[16]Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Meta-analysis of vitamin D, calcium and the prevention of breast cancer[J]. Breast Cancer Res Treat 2010;121:469-77.
[17]Luscombe CJ, Fryer AA, French ME, et al. Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer[J]. Lancet 2001;358:641-2.
[18]Ben-Zvi I, Aranow C, Mackay M, et al. The impact of vitamin D on dendritic cell function in patients with systemic lupus erythematosus[J]. PLoS One 2010;5:e9193.
[19]Hanwell HE, Banwell B. Assessment of evidence for a protective role of vitamin D in multiple sclerosis[J]. Biochim Biophys Acta 2011;1812:202-12.
[20]Grant WB. Epidemiology of disease risks in relation to vitamin D insufficiency[J]. Prog Biophys Mol Biol 2006;92:65-79.
[21]Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction[J]. Am J Clin Nutr 2004;79:820-5.
[22]Matsuoka LY, Ide L, Wortsman J, MacLaughlin JA, Holick MF. Sunscreens suppress cutaneous vitamin D3 synthesis[J]. J Clin Endocrinol Metab 1987;64:1165-8.
[23]Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3[J]. Lancet 1982; 1:74-6.
[24]Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity[J]. Am J Clin Nutr 2000;72:690-3.
[25]Grober U, Holick MF, Kisters K. Vitamin D and drugs[J]. Med Monatsschr Pharm 2011;34:377-87.
[26]Arguelles LM, Langman CB, Ariza AJ, et al. Heritability and environmental factors affecting vitamin D status in rural Chinese adolescent twins[J]. J Clin Endocrinol Metab 2009;94:3273-81.
[27]Shea MK, Benjamin EJ, Dupuis J, et al. Genetic and non-genetic correlates of vitamins K and D[J]. Eur J Clin Nutr 2009;63:458-64.
[28]Snellman G, Melhus H, Gedeborg R, et al. Seasonal genetic influence on serum 25-hydroxyvitamin D levels:a twin study[J]. PLoS One 2009;4:e7747.
[29]Roberts R, Wells GA, Stewart AF, Dandona S, Chen L. The genome-wide association study--a new era for common poly genic disorders[J]. J Cardiovasc Transl Res 2010;3:173-82.
[30]Ahn J, Yu K, Stolzenberg-Solomon R, et al. Genome-wide association study of circulating vitamin D levels[J]. Hum Mol Genet 2010;19:2739-45.
[31]Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency:a genome-wide association study[J]. Lancet 2010;376:180-8.
[32]Bu FX, Armas L, Lappe J, et al. Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects[J]. Hum Genet 2010;128:549-56.
[33]Lu L, Sheng H, Li H, et al. Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans[J]. Hum Genet 2012;131:505-12.
[34]张智海,沈建雄,刘忠厚.DXA骨密度仪在国内标一化回顾性研究[J].中国骨质疏松杂志2005；11(2)：133-45.
[35]Genant HK, Wu CY, Kuijk C, C M. Vertebral fracture assessment using a semiquantitative technique[J]. J Bone Miner Res 1993;8(9):1137-48.
[36]Abbas S, Linseisen J, Slanger T, et al. The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status[J]. Cancer Epidemiol Biomarkers Prev 2008;17:1339-43.
[37]Fang Y, van Meurs JB, Arp P, et al. Vitamin D binding protein genotype and osteoporosis[J]. Calcif Tissue Int 2009;85:85-93.
[38]Lauridsen AL, Vestergaard P, Hermann AP, et al. Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein):a cross-sectional study on 595 early postmenopausal women[J]. Calcif Tissue Int 2005;77:15-22.
[39]Lauridsen AL, Vestergaard P, Nexo E. Mean serum concentration of vitamin D-binding protein (Gc globulin) is related to the Gc phenotype in women[J]. Clin Chem 2001;47:753-6.
[40]Kawakami M, Blum CB, Ramakrishnan R, Dell RB, Goodman DS. Turnover of the plasma binding protein for vitamin D and its metabolites in normal human subjects[J]. J Clin Endocrinol Metab 1981;53:1110-6.
[41]Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP) [J]. Hum Genet 1993;92:183-8.
[42]Trummer O, Schwetz V, Walter-Finell D, et al. Allelic Determinants of Vitamin D Insufficiency, Bone Mineral Density, and Bone Fractures[J]. J Clin Endocrinol Metab 2012.
[43]Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park HW. Structural analysis of CYP2R1 in complex with vitamin D3[J]. J Mol Biol 2008;380:95-106.
[44]Zhao J, Xia W, Nie M, et al. The levels of bone turnover markers in Chinese postmenopausal women:Peking Vertebral Fracture study [J]. Menopause 2011;18:1237-43.
[45]Al-oanzi ZH, Tuck SP, Mastana SS, et al. Vitamin D-binding protein gene microsatellite polymorphism influences BMD and risk of fractures in men[J]. Osteoporos Int 2008;19:951-60.
[46]Lauridsen AL, Vestergaard P, Hermann AP, Moller HJ, Mosekilde L, Nexo E. Female premenopausal fracture risk is associated with gc phenotype[J]. J Bone Miner Res 2004; 19:875-81.
[47]Ezura Y, Nakajima T, Kajita M, et al. Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density[J]. J Bone Miner Res 2003; 18:1642-9.
[48]Powe CE, Ricciardi C, Berg AH, et al. Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship[J]. J Bone Miner Res 2011;26:1609-16.
[1]Chun RF. New perspectives on the vitamin D binding protein[J]. Cell Biochem Funct 2012.
[2]Wood AM, Bassford C, Webster D, et al. Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages[J]. Thorax 2011;66:205-10.
[3]Cooke NE, Willard HF, David EV, George DL. Direct regional assignment of the gene for vitamin D binding protein (Gc-globulin) to human chromosome 4q11-q13 and identification of an associated DNA polymorphism[J]. Hum Genet 1986;73:225-9.
[4]Song YH, Ray K, Liebhaber SA, Cooke NE. Vitamin D-binding protein gene transcription is regulated by the relative abundance of hepatocyte nuclear factors 1alpha and 1beta[J]. J Biol Chem 1998;273:28408-18.
[5]McLeod JF, Cooke NE. The vitamin D-binding protein, alpha-fetoprotein, albumin multigene family:detection of transcripts in multiple tissues[J]. J Biol Chem 1989;264:21760-9.
[6]Cooke NE, David EV. Serum vitamin D-binding protein is a third member of the albumin and alpha fetoprotein gene family[J]. J Clin Invest 1985;76:2420-4.
[7]Yang F, Brune JL, Naylor SL, Cupples RL, Naberhaus KH, Bowman BH. Human group-specific component (Gc) is a member of the albumin family [J]. Proc Natl Acad Sci U S A 1985;82:7994-8.
[8]Svasti J, Kurosky A, Bennett A, Bowman BH. Molecular basis for the three major forms of human serum vitamin D binding protein (group-specific component) [J]. Biochemistry 1979;18:1611-7.
[9]Borges CR, Jarvis JW, Oran PE, Nelson RW. Population studies of Vitamin D Binding Protein microheterogeneity by mass spectrometry lead to characterization of its genotype-dependent O-glycosylation patterns[J]. J Proteome Res 2008;7:4143-53.
[10]Verboven CC, De Bondt HL, De Ranter C, Bouillon R, Van Baelen H. Crystallization and X-ray investigation of vitamin D-binding protein from human serum. Identification of the crystal content[J]. J Steroid Biochem Mol Biol 1995;54:11-4.
[11]Verboven C, Rabijns A, De Maeyer M, Van Baelen H, Bouillon R, De Ranter C. A structural basis for the unique binding features of the human vitamin D-binding protein[J]. Nat Struct Biol 2002;9:131-6.
[12]Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG. Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein[J]. J Clin Endocrinol Metab 1986;63:954-9.
[13]Bikle DD, Siiteri PK, Ryzen E, Haddad JG. Serum protein binding of 1,25-dihydroxyvitamin D:a reevaluation by direct measurement of free metabolite levels[J]. J Clin Endocrinol Metab 1985;61:969-75.
[14]Speeckaert M, Huang G, Delanghe JR, Taes YE. Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism[J]. Clin Chim Acta 2006;372:33-42.
[15]Mc Leod JF, Kowalski MA, Haddad JG, Jr. Interactions among serum vitamin D binding protein, monomeric actin, profilin, and profilactin[J]. J Biol Chem 1989;264:1260-7.
[16]Calvo M, Ena JM. Relations between vitamin D and fatty acid binding properties of vitamin D-binding protein[J]. Biochem Biophys Res Commun 1989; 163:14-7.
[17]Vieth R, Kessler MJ, Pritzker KP. Species differences in the binding kinetics of 25-hydroxyvitamin D3 to vitamin D binding protein[J]. Can J Physiol Pharmacol 1990;68:1368-71.
[18]Fang Y, van Meurs JB, Arp P, et al. Vitamin D binding protein genotype and osteoporosis[J]. Calcif Tissue Int 2009;85:85-93.
[19]Safadi FF, Thornton P, Magiera H, et al. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein[J]. J Clin Invest 1999;103:239-51.
[20]Vavrusa B, Cleve H, Constans J. A deficiency mutant of the Gc system[J]. Hum Genet 1983;65:102-7.
[21]Ahn J, Yu K, Stolzenberg-Solomon R, et al. Genome-wide association study of circulating vitamin D levels[J]. Hum Mol Genet 2010;19:2739-45.
[22]Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency:a genome-wide association study[J]. Lancet 2010;376:180-8.
[23]Bu FX, Armas L, Lappe J, et al. Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects[J]. Hum Genet 2010;128:549-56.
[24]Lu L, Sheng H, Li H, et al. Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans[J]. Hum Genet 2012;131:505-12.
[25]Abbas S, Linseisen J, Slanger T, et al. The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status[J]. Cancer Epidemiol Biomarkers Prev 2008;17:1339-43.
[26]Lauridsen AL, Vestergaard P, Hermann AP, et al. Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein):a cross-sectional study on 595 early postmenopausal women[J]. Calcif Tissue Int 2005;77:15-22.
[27]Lauridsen AL, Vestergaard P, Nexo E. Mean serum concentration of vitamin D-binding protein (Gc globulin) is related to the Gc phenotype in women[J]. Clin Chem 2001;47:753-6.
[28]Kawakami M, Blum CB, Ramakrishnan R, Dell RB, Goodman DS. Turnover of the plasma binding protein for vitamin D and its metabolites in normal human subjects[J]. J Clin Endocrinol Metab 1981;53:1110-6.
[29]Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP) [J]. Hum Genet 1993;92:183-8.
[30]Al-oanzi ZH, Tuck SP, Mastana SS, et al. Vitamin D-binding protein gene microsatellite polymorphism influences BMD and risk of fractures in men[J]. Osteoporos Int 2008; 19:951-60.
[31]Lauridsen AL, Vestergaard P, Hermann AP, Moller HJ, Mosekilde L, Nexo E. Female premenopausal fracture risk is associated with gc phenotype [J]. J Bone Miner Res 2004; 19:875-81.
[32]Ezura Y, Nakajima T, Kajita M, et al. Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density[J]. J Bone Miner Res 2003; 18:1642-9.
[33]Powe CE, Ricciardi C, Berg AH, et al. Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship[J]. J Bone Miner Res 2011;26:1609-16.
[34]Bakke PS, Zhu G, Gulsvik A, et al. Candidate genes for COPD in two large data sets[J]. Eur Respir J 2011;37:255-63,
[35]Wilk JB, Walter RE, Laramie JM, Gottlieb DJ, O'Connor GT. Framingham Heart Study genome-wide association:results for pulmonary function measures[J]. BMC Med Genet 2007;8 Suppl 1:S8.
[36]Shen LH, Zhang XM, Su DJ, et al. Association of vitamin D binding protein variants with susceptibility to chronic obstructive pulmonary disease [J]. J Int Med Res 2010;38:1093-8.
[37]Martineau AR, Leandro AC, Anderson ST, et al. Association between Gc genotype and susceptibility to TB is dependent on vitamin D status[J]. Eur Respir J 2010;35:1106-12.
[38]Leandro AC, Rocha MA, Cardoso CS, Bonecini-Almeida MG Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-gamma genes and its association with susceptibility to tuberculosis[J]. Braz J Med Biol Res 2009;42:312-22.
[39]Li F, Jiang L, Willis-Owen SA, Zhang Y, Gao J. Vitamin D binding protein variants associate with asthma susceptibility in the Chinese Han population[J]. BMC Med Genet 2011;12:103.
[40]Gressner OA, Gao C, Siluschek M, Kim P, Gressner AM. Inverse association between serum concentrations of actin-free vitamin D-binding protein and the histopathological extent of fibrogenic liver disease or hepatocellular carcinoma[J]. Eur J Gastroenterol Hepatol 2009;21:990-5.
[41]Weinstein SJ, Stolzenberg-Solomon RZ, Kopp W, Rager H, Virtamo J, Albanes D. Impact of circulating vitamin D binding protein levels on the association between 25-hydroxyvitamin D and pancreatic cancer risk:a nested case-control study [J]. Cancer Res 2012;72:1190-8.
[42]Poynter JN, Jacobs ET, Figueiredo JC, et al. Genetic variation in the vitamin D receptor (VDR) and the vitamin D-binding protein (GC) and risk for colorectal cancer: results from the Colon Cancer Family Registry [J]. Cancer Epidemiol Biomarkers Prev 2010;19:525-36.
[43]Blanton D, Han Z, Bierschenk L, et al. Reduced serum vitamin D-binding protein levels are associated with type 1 diabetes[J]. Diabetes 2011;60:2566-70.
[44]Orton SM, Ramagopalan SV, Para AE, et al. Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians[J]. J Neurol Sci 2011;305:116-20.
[45]Eloranta JJ, Wenger C, Mwinyi J, et al. Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease [J]. Pharmacogenet Genomics 2011;21:559-64.
[46]Jiang H, Xiong DH, Guo YF, et al. Association analysis of vitamin D-binding protein gene polymorphisms with variations of obesity-related traits in Caucasian nuclear families[J]. Int J Obes (Lond) 2007;31:1319-24.
[2]Holick MF. Vitamin D:a d-lightful solution for health[J]. J Investig Med 2011;59:872-80.
[3]Holick MF. Vitamin D deficiency [J]. N Engl J Med 2007;357:266-81.
[4]Lu L, Yu Z, Pan A, et al. Plasma 25-hydroxyvitamin D concentration and metabolic syndrome among middle-aged and elderly Chinese individuals[J]. Diabetes Care 2009;32:1278-83.
[5]Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes[J]. Am J Clin Nutr 2006;84:18-28.
[6]El-Hajj Fuleihan G, Nabulsi M, Tamim H, et al. Effect of vitamin D replacement on musculoskeletal parameters in school children:a randomized controlled trial [J]. J Clin Endocrinol Metab 2006;91:405-12.
[7]Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D:a meta-analysis of randomised controlled trials[J]. BMJ 2009;339:b3692.
[8]Broe KE, Chen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel DP. A higher dose of vitamin d reduces the risk of falls in nursing home residents:a randomized, multiple-dose study [J]. J Am Geriatr Soc 2007;55:234-9.
[9]Reddy Vanga S, Good M, Howard PA, Vacek JL. Role of vitamin D in cardiovascular health[J]. Am J Cardiol 2010;106:798-805.
[10]Stechschulte SA, Kirsner RS, Federman DG. Vitamin D:bone and beyond, rationale and recommendations for supplementation[J]. Am J Med 2009; 122:793-802.
[11]Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults[J]. Diabetes Care 2005;28:1228-30.
[12]Baynes KC, Boucher BJ, Feskens EJ, Kromhout D. Vitamin D, glucose tolerance and insulinaemia in elderly men[J]. Diabetologia 1997;40:344-7.
[13]Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey[J]. Am J Hypertens 2007;20:713-9.
[14]Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension[J]. Hypertension 2007;49:1063-9.
[15]Zeeb H, Greinert R. The role of vitamin D in cancer prevention:does UV protection conflict with the need to raise low levels of vitamin D[J]? Dtsch Arztebl Int 2010;107:638-43.
[16]Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Meta-analysis of vitamin D, calcium and the prevention of breast cancer[J]. Breast Cancer Res Treat 2010;121:469-77.
[17]Luscombe CJ, Fryer AA, French ME, et al. Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer[J]. Lancet 2001;358:641-2.
[18]Ben-Zvi I, Aranow C, Mackay M, et al. The impact of vitamin D on dendritic cell function in patients with systemic lupus erythematosus[J]. PLoS One 2010;5:e9193.
[19]Hanwell HE, Banwell B. Assessment of evidence for a protective role of vitamin D in multiple sclerosis[J]. Biochim Biophys Acta 2011;1812:202-12.
[20]Grant WB. Epidemiology of disease risks in relation to vitamin D insufficiency[J]. Prog Biophys Mol Biol 2006;92:65-79.
[21]Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction[J]. Am J Clin Nutr 2004;79:820-5.
[22]Matsuoka LY, Ide L, Wortsman J, MacLaughlin JA, Holick MF. Sunscreens suppress cutaneous vitamin D3 synthesis[J]. J Clin Endocrinol Metab 1987;64:1165-8.
[23]Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3[J]. Lancet 1982; 1:74-6.
[24]Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity[J]. Am J Clin Nutr 2000;72:690-3.
[25]Grober U, Holick MF, Kisters K. Vitamin D and drugs[J]. Med Monatsschr Pharm 2011;34:377-87.
[26]Arguelles LM, Langman CB, Ariza AJ, et al. Heritability and environmental factors affecting vitamin D status in rural Chinese adolescent twins[J]. J Clin Endocrinol Metab 2009;94:3273-81.
[27]Shea MK, Benjamin EJ, Dupuis J, et al. Genetic and non-genetic correlates of vitamins K and D[J]. Eur J Clin Nutr 2009;63:458-64.
[28]Snellman G, Melhus H, Gedeborg R, et al. Seasonal genetic influence on serum 25-hydroxyvitamin D levels:a twin study[J]. PLoS One 2009;4:e7747.
[29]Roberts R, Wells GA, Stewart AF, Dandona S, Chen L. The genome-wide association study--a new era for common poly genic disorders[J]. J Cardiovasc Transl Res 2010;3:173-82.
[30]Ahn J, Yu K, Stolzenberg-Solomon R, et al. Genome-wide association study of circulating vitamin D levels[J]. Hum Mol Genet 2010;19:2739-45.
[31]Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency:a genome-wide association study[J]. Lancet 2010;376:180-8.
[32]Bu FX, Armas L, Lappe J, et al. Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects[J]. Hum Genet 2010;128:549-56.
[33]Lu L, Sheng H, Li H, et al. Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans[J]. Hum Genet 2012;131:505-12.
[34]张智海,沈建雄,刘忠厚.DXA骨密度仪在国内标一化回顾性研究[J].中国骨质疏松杂志2005；11(2)：133-45.
[35]Genant HK, Wu CY, Kuijk C, C M. Vertebral fracture assessment using a semiquantitative technique[J]. J Bone Miner Res 1993;8(9):1137-48.
[36]Abbas S, Linseisen J, Slanger T, et al. The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status[J]. Cancer Epidemiol Biomarkers Prev 2008;17:1339-43.
[37]Fang Y, van Meurs JB, Arp P, et al. Vitamin D binding protein genotype and osteoporosis[J]. Calcif Tissue Int 2009;85:85-93.
[38]Lauridsen AL, Vestergaard P, Hermann AP, et al. Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein):a cross-sectional study on 595 early postmenopausal women[J]. Calcif Tissue Int 2005;77:15-22.
[39]Lauridsen AL, Vestergaard P, Nexo E. Mean serum concentration of vitamin D-binding protein (Gc globulin) is related to the Gc phenotype in women[J]. Clin Chem 2001;47:753-6.
[40]Kawakami M, Blum CB, Ramakrishnan R, Dell RB, Goodman DS. Turnover of the plasma binding protein for vitamin D and its metabolites in normal human subjects[J]. J Clin Endocrinol Metab 1981;53:1110-6.
[41]Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP) [J]. Hum Genet 1993;92:183-8.
[42]Trummer O, Schwetz V, Walter-Finell D, et al. Allelic Determinants of Vitamin D Insufficiency, Bone Mineral Density, and Bone Fractures[J]. J Clin Endocrinol Metab 2012.
[43]Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park HW. Structural analysis of CYP2R1 in complex with vitamin D3[J]. J Mol Biol 2008;380:95-106.
[44]Zhao J, Xia W, Nie M, et al. The levels of bone turnover markers in Chinese postmenopausal women:Peking Vertebral Fracture study [J]. Menopause 2011;18:1237-43.
[45]Al-oanzi ZH, Tuck SP, Mastana SS, et al. Vitamin D-binding protein gene microsatellite polymorphism influences BMD and risk of fractures in men[J]. Osteoporos Int 2008;19:951-60.
[46]Lauridsen AL, Vestergaard P, Hermann AP, Moller HJ, Mosekilde L, Nexo E. Female premenopausal fracture risk is associated with gc phenotype[J]. J Bone Miner Res 2004; 19:875-81.
[47]Ezura Y, Nakajima T, Kajita M, et al. Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density[J]. J Bone Miner Res 2003; 18:1642-9.
[48]Powe CE, Ricciardi C, Berg AH, et al. Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship[J]. J Bone Miner Res 2011;26:1609-16.
[1]Chun RF. New perspectives on the vitamin D binding protein[J]. Cell Biochem Funct 2012.
[2]Wood AM, Bassford C, Webster D, et al. Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages[J]. Thorax 2011;66:205-10.
[3]Cooke NE, Willard HF, David EV, George DL. Direct regional assignment of the gene for vitamin D binding protein (Gc-globulin) to human chromosome 4q11-q13 and identification of an associated DNA polymorphism[J]. Hum Genet 1986;73:225-9.
[4]Song YH, Ray K, Liebhaber SA, Cooke NE. Vitamin D-binding protein gene transcription is regulated by the relative abundance of hepatocyte nuclear factors 1alpha and 1beta[J]. J Biol Chem 1998;273:28408-18.
[5]McLeod JF, Cooke NE. The vitamin D-binding protein, alpha-fetoprotein, albumin multigene family:detection of transcripts in multiple tissues[J]. J Biol Chem 1989;264:21760-9.
[6]Cooke NE, David EV. Serum vitamin D-binding protein is a third member of the albumin and alpha fetoprotein gene family[J]. J Clin Invest 1985;76:2420-4.
[7]Yang F, Brune JL, Naylor SL, Cupples RL, Naberhaus KH, Bowman BH. Human group-specific component (Gc) is a member of the albumin family [J]. Proc Natl Acad Sci U S A 1985;82:7994-8.
[8]Svasti J, Kurosky A, Bennett A, Bowman BH. Molecular basis for the three major forms of human serum vitamin D binding protein (group-specific component) [J]. Biochemistry 1979;18:1611-7.
[9]Borges CR, Jarvis JW, Oran PE, Nelson RW. Population studies of Vitamin D Binding Protein microheterogeneity by mass spectrometry lead to characterization of its genotype-dependent O-glycosylation patterns[J]. J Proteome Res 2008;7:4143-53.
[10]Verboven CC, De Bondt HL, De Ranter C, Bouillon R, Van Baelen H. Crystallization and X-ray investigation of vitamin D-binding protein from human serum. Identification of the crystal content[J]. J Steroid Biochem Mol Biol 1995;54:11-4.
[11]Verboven C, Rabijns A, De Maeyer M, Van Baelen H, Bouillon R, De Ranter C. A structural basis for the unique binding features of the human vitamin D-binding protein[J]. Nat Struct Biol 2002;9:131-6.
[12]Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG. Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein[J]. J Clin Endocrinol Metab 1986;63:954-9.
[13]Bikle DD, Siiteri PK, Ryzen E, Haddad JG. Serum protein binding of 1,25-dihydroxyvitamin D:a reevaluation by direct measurement of free metabolite levels[J]. J Clin Endocrinol Metab 1985;61:969-75.
[14]Speeckaert M, Huang G, Delanghe JR, Taes YE. Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism[J]. Clin Chim Acta 2006;372:33-42.
[15]Mc Leod JF, Kowalski MA, Haddad JG, Jr. Interactions among serum vitamin D binding protein, monomeric actin, profilin, and profilactin[J]. J Biol Chem 1989;264:1260-7.
[16]Calvo M, Ena JM. Relations between vitamin D and fatty acid binding properties of vitamin D-binding protein[J]. Biochem Biophys Res Commun 1989; 163:14-7.
[17]Vieth R, Kessler MJ, Pritzker KP. Species differences in the binding kinetics of 25-hydroxyvitamin D3 to vitamin D binding protein[J]. Can J Physiol Pharmacol 1990;68:1368-71.
[18]Fang Y, van Meurs JB, Arp P, et al. Vitamin D binding protein genotype and osteoporosis[J]. Calcif Tissue Int 2009;85:85-93.
[19]Safadi FF, Thornton P, Magiera H, et al. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein[J]. J Clin Invest 1999;103:239-51.
[20]Vavrusa B, Cleve H, Constans J. A deficiency mutant of the Gc system[J]. Hum Genet 1983;65:102-7.
[21]Ahn J, Yu K, Stolzenberg-Solomon R, et al. Genome-wide association study of circulating vitamin D levels[J]. Hum Mol Genet 2010;19:2739-45.
[22]Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency:a genome-wide association study[J]. Lancet 2010;376:180-8.
[23]Bu FX, Armas L, Lappe J, et al. Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects[J]. Hum Genet 2010;128:549-56.
[24]Lu L, Sheng H, Li H, et al. Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans[J]. Hum Genet 2012;131:505-12.
[25]Abbas S, Linseisen J, Slanger T, et al. The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status[J]. Cancer Epidemiol Biomarkers Prev 2008;17:1339-43.
[26]Lauridsen AL, Vestergaard P, Hermann AP, et al. Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein):a cross-sectional study on 595 early postmenopausal women[J]. Calcif Tissue Int 2005;77:15-22.
[27]Lauridsen AL, Vestergaard P, Nexo E. Mean serum concentration of vitamin D-binding protein (Gc globulin) is related to the Gc phenotype in women[J]. Clin Chem 2001;47:753-6.
[28]Kawakami M, Blum CB, Ramakrishnan R, Dell RB, Goodman DS. Turnover of the plasma binding protein for vitamin D and its metabolites in normal human subjects[J]. J Clin Endocrinol Metab 1981;53:1110-6.
[29]Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP) [J]. Hum Genet 1993;92:183-8.
[30]Al-oanzi ZH, Tuck SP, Mastana SS, et al. Vitamin D-binding protein gene microsatellite polymorphism influences BMD and risk of fractures in men[J]. Osteoporos Int 2008; 19:951-60.
[31]Lauridsen AL, Vestergaard P, Hermann AP, Moller HJ, Mosekilde L, Nexo E. Female premenopausal fracture risk is associated with gc phenotype [J]. J Bone Miner Res 2004; 19:875-81.
[32]Ezura Y, Nakajima T, Kajita M, et al. Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density[J]. J Bone Miner Res 2003; 18:1642-9.
[33]Powe CE, Ricciardi C, Berg AH, et al. Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship[J]. J Bone Miner Res 2011;26:1609-16.
[34]Bakke PS, Zhu G, Gulsvik A, et al. Candidate genes for COPD in two large data sets[J]. Eur Respir J 2011;37:255-63,
[35]Wilk JB, Walter RE, Laramie JM, Gottlieb DJ, O'Connor GT. Framingham Heart Study genome-wide association:results for pulmonary function measures[J]. BMC Med Genet 2007;8 Suppl 1:S8.
[36]Shen LH, Zhang XM, Su DJ, et al. Association of vitamin D binding protein variants with susceptibility to chronic obstructive pulmonary disease [J]. J Int Med Res 2010;38:1093-8.
[37]Martineau AR, Leandro AC, Anderson ST, et al. Association between Gc genotype and susceptibility to TB is dependent on vitamin D status[J]. Eur Respir J 2010;35:1106-12.
[38]Leandro AC, Rocha MA, Cardoso CS, Bonecini-Almeida MG Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-gamma genes and its association with susceptibility to tuberculosis[J]. Braz J Med Biol Res 2009;42:312-22.
[39]Li F, Jiang L, Willis-Owen SA, Zhang Y, Gao J. Vitamin D binding protein variants associate with asthma susceptibility in the Chinese Han population[J]. BMC Med Genet 2011;12:103.
[40]Gressner OA, Gao C, Siluschek M, Kim P, Gressner AM. Inverse association between serum concentrations of actin-free vitamin D-binding protein and the histopathological extent of fibrogenic liver disease or hepatocellular carcinoma[J]. Eur J Gastroenterol Hepatol 2009;21:990-5.
[41]Weinstein SJ, Stolzenberg-Solomon RZ, Kopp W, Rager H, Virtamo J, Albanes D. Impact of circulating vitamin D binding protein levels on the association between 25-hydroxyvitamin D and pancreatic cancer risk:a nested case-control study [J]. Cancer Res 2012;72:1190-8.
[42]Poynter JN, Jacobs ET, Figueiredo JC, et al. Genetic variation in the vitamin D receptor (VDR) and the vitamin D-binding protein (GC) and risk for colorectal cancer: results from the Colon Cancer Family Registry [J]. Cancer Epidemiol Biomarkers Prev 2010;19:525-36.
[43]Blanton D, Han Z, Bierschenk L, et al. Reduced serum vitamin D-binding protein levels are associated with type 1 diabetes[J]. Diabetes 2011;60:2566-70.
[44]Orton SM, Ramagopalan SV, Para AE, et al. Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians[J]. J Neurol Sci 2011;305:116-20.
[45]Eloranta JJ, Wenger C, Mwinyi J, et al. Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease [J]. Pharmacogenet Genomics 2011;21:559-64.
[46]Jiang H, Xiong DH, Guo YF, et al. Association analysis of vitamin D-binding protein gene polymorphisms with variations of obesity-related traits in Caucasian nuclear families[J]. Int J Obes (Lond) 2007;31:1319-24.