Abstract
Peak bone mass is considered to be under strong genetic control. We studied the association among anthropometry, bone density and vitamin D receptor (VDR) genotype in an ethnically homogeneous group of 148 Caucasian children and young adults. Bone density was measured by dual energy X-ray absorptiometry (DXA) and VDR genotype was determined by a direct haplotyping procedure of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms. A second DXA measurement was made after approximately 4 years. Results are expressed as age- and sex-adjusted standard deviation scores (SDS). Previously, the collagen IA1 Sp1 polymorphism was studied in this population. We found VDR genotype to be associated with a 0.4 SDS increased height per allele copy of haplotype ‘3’ (P = 0.04) and a 0.4 SDS increased width of the lumbar vertebral body in the haplotype ‘3’ allele carriers (P = 0.05). We observed a trend towards a 0.3 SDS decreased bone mineral apparent density of lumbar spine (BMAD) per copy of haplotype ‘3’ allele (P = 0.10). In contrast, no association with areal bone mineral density (BMD) was observed. In the follow-up analyses, no differences in height or bone gain among the VDR genotypes were demonstrated. By combining the risk alleles of VDR and collagen IA1 Sp1 genotype, an additive genotype effect on height (P = 0.006) and vertebral body width (P = 0.001) was found. In this exploratory study we found VDR genotype to be associated with frame size and BMAD. The VDR genotype effects on stature and bone size seem to neutralize the effect on areal BMD.
Similar content being viewed by others
References
PJ Kelly M Harris (1995) ArticleTitleReview: genetic regulation of peak bone mass. Acta Paediatr 411 24–29 Occurrence Handle1:STN:280:BymC2MjhvVY%3D
NA Pocock JA Eisman JL Hopper MG Yeates PN Sambrook S Eberl (1987) ArticleTitleGenetic determinants of bone mass in adults: a twin study. J Clin Invest 80 706–710 Occurrence Handle1:STN:280:BiiA3cfotVM%3D Occurrence Handle3624485
DM Smith WE Nance KW Kang JC Christian CC Johnston (1973) ArticleTitleGenetic factors in determining bone mass. J Clin Invest 52 2800–2808 Occurrence Handle1:STN:280:CSuD387msVA%3D Occurrence Handle4795916
AM Boot MAJ de Ridder HAP Pols EP Krenning SMPF de Muinck Keizer-Schrama (1997) ArticleTitleBone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity. J Clin Endocrinol Metab 82 57–62 Occurrence Handle1:CAS:528:DyaK2sXkt1SnsA%3D%3D Occurrence Handle8989233
LA Rubin GA Hawker VD Peltekova LJ Fielding R Ridout DE Cole (1999) ArticleTitleDeterminants of peak bone mass: clinical and genetic analyses in a young female Canadian cohort. J Bone Miner Res 14 633–643 Occurrence Handle1:STN:280:DyaK1M3ltVyntw%3D%3D Occurrence Handle10234586
LA Soyka WP Fairfield A Klibanski (2000) ArticleTitleHormonal determinants and disorders of peak bone mass in children. J Clin Endocrinol Metab 85 3951–3963 Occurrence Handle1:CAS:528:DC%2BD3cXotlWnt74%3D Occurrence Handle11095413
DC Welten HCG Kemper GB Post W Van Mechelen J Twisk P Lips GJ Teule (1994) ArticleTitleWeight-bearing activity during youth is a more important factor for peak bone mass than calcium intake. J Bone Miner Res 9 1089–1096 Occurrence Handle1:STN:280:ByqD38fmt1I%3D Occurrence Handle7942156
AG Uitterlinden HA Pols H Burger Q Huang PL Van Daele CM Van Duijn A Hofman JC Birkenhager JP Van Leeuwen (1996) ArticleTitleA large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density. J Bone Miner Res 11 1241–1248 Occurrence Handle1:CAS:528:DyaK28Xls1ChtLw%3D Occurrence Handle8864898
LD Spotila J Caminis R Johnston KS Shimoya MP O’Conner DJ Prockop A Tenenhouse HS Tenenhouse (1996) ArticleTitleVitamin D receptor genotype is not associated with bone mineral density in three ethnic/regional groups. Calcif Tissue Int 59 235–237 Occurrence Handle10.1007/s002239900114 Occurrence Handle1:CAS:528:DyaK28XlvFCntbg%3D Occurrence Handle8781043
NA Morrison J Cheng Qi A Tokita PJ Kelly L Crofts TV Nguyen PN Sambrook JA Eisman (1994) ArticleTitlePrediction of bone density from vitamin D receptor alleles. Nature 367 284–287 Occurrence Handle1:CAS:528:DyaK2cXhsFGjur8%3D Occurrence Handle8161378
MA Hansen K Overgaard BJ Riis C Christiansen (1991) ArticleTitleRole of bone mass and bone loss in postmenopausal osteoporosis: 12 year study. BMJ 303 961–964 Occurrence Handle1:STN:280:By2D28zisVU%3D Occurrence Handle1954420
J Sainz JM Van Tornhout ML Loro J Sayre TF Roe V Gilsanz (1997) ArticleTitleVitamin D-receptorgene polymorphisms and bone density in prepubertal American girls of Mexican descent. N Engl J Med 337 77–82 Occurrence Handle1:CAS:528:DyaK2sXkvVCku7Y%3D Occurrence Handle9211676
M Gunnes JP Berg J Halse EH Lehman (1997) ArticleTitleLack of relationship between vitamin D receptor genotype and forearm bone gain in healthy children, adolescents, and young adults. J Clin Endocrinol Metab 82 851–855 Occurrence Handle1:CAS:528:DyaK2sXhsl2itbY%3D Occurrence Handle9062495
GI Baroncelli G Federico S Bertelloni C Ceccarelli D Cupelli G Saggese (1999) ArticleTitleVitamin-D receptor genotype does not predict bone mineral density, bone turnover, and growth in prepubertal children. Horm Res 51 150–156 Occurrence Handle10.1159/000023348 Occurrence Handle1:CAS:528:DyaK1MXlt1ahtLo%3D Occurrence Handle10461021
M Lorentzon R Lorentzon P Nordstrom (2000) ArticleTitleVitamin D receptor gene polymorphism is associated with birth height, growth to adolescence, and adult stature in healthy Caucasian men: a cross-sectional and longitudinal study. J Clin Endocrinol Metab 85 1666–1670 Occurrence Handle1:CAS:528:DC%2BD3cXisFyjs74%3D Occurrence Handle10770213
F Suarez F Zeghoud C Rossignol O Walrant M Garabédian (1997) ArticleTitleAssociation between vitamin D receptor gene polymorphism and sex-dependent growth during first two years of life. J Clin Endocrinol Metabol 82 2966–2970 Occurrence Handle1:CAS:528:DyaK2sXlvFemtrY%3D
JL Slack DJ Liska P Bornstein (1993) ArticleTitleRegulation of expression of the type I collagen genes. Am J Med Genet 45 140–151 Occurrence Handle1:STN:280:ByyB3cnptVI%3D Occurrence Handle8456796
D Pavlin A Bedalov MS Kronenberg BE Kream DW Rowe CL Smith JW Pike AC Lichtler (1994) ArticleTitleAnalysis of regulatory regions in the COL1A1 gene responsible for 1,25-dihydroxyvitamin D3-mediated transcriptional repression in osteoblastic cells. J Cell Biochem 56 490–501 Occurrence Handle1:CAS:528:DyaK2MXislSqtr0%3D Occurrence Handle7890807
IM Van der Sluis S de Muinck Keizer-Schrama HAP Pols MH Lequin EP Krenning AG Uitterlinden (2002) ArticleTitleCollagen IA1 polymorphism is associated with bone characteristics in Caucasian children and young adults. Calcif Tissue Int 71 393–399 Occurrence Handle10.1007/s00223-001-2093-8 Occurrence Handle1:CAS:528:DC%2BD38XovF2js7c%3D Occurrence Handle12232678
AM Boot J Bouquet MAJ de Ridder EP Krenning SMPF de Muinck Keizer-Schrama (1997) ArticleTitleDeterminants of body composition, measured by dual x-ray absorptiometry, in Dutch children and adolescents. Am J Clin Nutr 66 232–238 Occurrence Handle1:CAS:528:DyaK2sXltVagurY%3D Occurrence Handle9250099
AM Fredriks S van Buuren RJ Burgmeijer JF Meulmeester RJ Beuker E Brugman MJ Roede SP Verloove-Vanhorick JM Wit (2000) ArticleTitleContinuing positive secular growth change in The Netherlands 1955–1997. Pediatr Res 47 316–323 Occurrence Handle1:STN:280:DC%2BD3c7nt12lsQ%3D%3D Occurrence Handle10709729
MJ Roede JC van Wieringen (1985) ArticleTitleGrowth diagrams 1980, Netherlands. Third nation-wide survey. Tijdschrift voor Sociale Gezondheidszorg 63 suppl 1–34
PM Duke IF Litt RT Gross (1980) ArticleTitleAdolescents’ self-assessment of sexual maturation. Pediatrics 66 918–920 Occurrence Handle1:STN:280:Bi6C3c%2FjsVU%3D Occurrence Handle7454482
JM Tanner RH White house (1976) ArticleTitleClinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 51 170–179 Occurrence Handle1:STN:280:CSmB2M7mslI%3D Occurrence Handle952550
HPJ Kröger P Vainio J Nieminen A Kotaniemi (1995) ArticleTitleComparison of different models for interpreting bone mineral density measurements using DXA and MRI technology. Bone 17 157–159 Occurrence Handle8554924
IM van der Sluis MAJ de Ridder AM Boot EP Krenning SMPF de Muinck Keizer-Schrama (2002) ArticleTitleReference data for bone density and body composition measured with dual energy X ray absorptiometry in white children and young adults. Arch Dis Child 87 341–347
C Tao T Yu S Garnett J Briody J Knight H Woodhead CT Cowell (1998) ArticleTitleVitamin D receptor alleles predict growth and bone density in girls. Arch Dis Child 79 488–493 Occurrence Handle1:STN:280:DyaK1M3islCgug%3D%3D Occurrence Handle10210992
Y Kato A Shimazu M Iwamoto K Nakashima T Koike F Suzuki Y Nishii K Sato (1990) ArticleTitleRole of 1,25-dihydroxycholecalciferol in growth-plate cartilage: inhibition of terminal differentiation of chondrocytes in vitro and in vivo. Proc Natl Acad Sci U S A 87 6522–6526
LC Gerstenfeld FD Shapiro (1996) ArticleTitleExpression of bone-specific genes by hypertrophic chondrocytes: implication of the complex functions of the hypertrophic chondrocyte during endochondral bone development. J Cell Biochem 62 1–9 Occurrence Handle10.1002/(SICI)1097-4644(199607)62:1<1::AID-JCB1>3.3.CO;2-O Occurrence Handle1:CAS:528:DyaK28XkvVWgs7o%3D Occurrence Handle8836870
G Klaus J Merke H Eing U Hugel P Milde H Reichel E Ritz O Mehls (1991) ArticleTitle1,25(OH)2D3 receptor regulation and 1,25(OH)2D3 effects in primary cultures of growth cartilage cells of the rat. Calcif Tissue Int 49 340–348 Occurrence Handle1:CAS:528:DyaK38XnslSruw%3D%3D Occurrence Handle1664276
Z Schwartz DL Schlader V Ramirez MB Kennedy BD Boyan (1989) ArticleTitleEffects of vitamin D metabolites on collagen production and cell proliferation of growth zone and resting zone cartilage cells in vitro. J Bone Miner Res 4 199–207 Occurrence Handle1:CAS:528:DyaL1MXktlOjurY%3D Occurrence Handle2786322
H Narchi M El Jamil N Kulaylat (2001) ArticleTitleSymptomatic rickets in adolescence. Arch Dis Child 84 501–503 Occurrence Handle10.1136/adc.84.6.501 Occurrence Handle1:STN:280:DC%2BD3M3ns1Gruw%3D%3D Occurrence Handle11369569
JT Wang CJ Lin SM Burridge GK Fu M Labuda AA Portale WL Miller (1998) ArticleTitleGenetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. Am J Hum Genet 63 1694–1702 Occurrence Handle10.1086/302156 Occurrence Handle1:CAS:528:DyaK1MXlt1Sjsg%3D%3D Occurrence Handle9837822
O Dardenne J Prud’homme A Arabian FH Glorieux R St-Arnaud (2001) ArticleTitleTargeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets. Endocrinology 142 3135–3141
DK Panda D Miao ML Tremblay J Sirois R Farookhi GN Hendy D Goltzman (2001) ArticleTitleTargeted ablation of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc Natl Acad Sci USA 98 7498–7503 Occurrence Handle10.1073/pnas.131029498 Occurrence Handle1:CAS:528:DC%2BD3MXkslWlsrY%3D Occurrence Handle11416220
YC Li AE Pirro M Amling G Delling R Baron R Bronson MB Demay (1997) ArticleTitleTargeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA 94 9831–9835 Occurrence Handle10.1073/pnas.94.18.9831 Occurrence Handle1:CAS:528:DyaK2sXlvVWls7Y%3D Occurrence Handle9275211
T Yoshizawa Y Handa Y Uematsu et al. (1997) ArticleTitleMice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16 391–396 Occurrence Handle1:CAS:528:DyaK2sXkvFCht74%3D Occurrence Handle9241280
AM Viitanen M Kärkkäinen K Laitinen C Lamberg-Allardt K Kainulainen L Räsänen J Viikari MJ Välimäki K Kontula (1996) ArticleTitleCommon polymorphism of the vitamin D receptor gene is associated with variation of peak bone mass in young Finns. Calcif Tissue Int 59 231–234 Occurrence Handle10.1007/s002239900113 Occurrence Handle1:CAS:528:DyaK28XlvFCntbs%3D Occurrence Handle8781042
S Ferrari R Rizzoli D Manen D Slosman JP Bonjour (1998) ArticleTitleVitamin D receptor gene starts codon polymorphisms (Fokl) and bone mineral density: interaction with age, dietary calcium, and 3′-end region polymorphisms. J Bone Miner Res 13 925–930 Occurrence Handle1:CAS:528:DyaK1cXjvFelsbk%3D Occurrence Handle9626623
AG Uitterlinden AE Weel H Burger Y Fang CM van Duijn A Hofman JP van Leeuwen HA Pols (2001) ArticleTitleInteraction between the vitamin D receptor gene and collagen type I alpha 1 gene in susceptibility for fracture. J Bone Miner Res 16 379–385 Occurrence Handle1:CAS:528:DC%2BD3MXptlyjsA%3D%3D Occurrence Handle11204438
Acknowledgements
We gratefully thank Pascal Arp for his assistance in DNA analysis.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
van der Sluis, I., de Muinck Keizer-Schrama, S., Krenning, E. et al. Vitamin D Receptor Gene Polymorphism Predicts Height and Bone Size, Rather Than Bone Density in Children and Young Adults . Calcif Tissue Int 73, 332–338 (2003). https://doi.org/10.1007/s00223-002-2130-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-002-2130-2