This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gunnes, M. Articles by Lehmann, E. H. Search for Related Content PubMed PubMed Citation Articles by Gunnes, M. Articles by Lehmann, E. H. Pubmed/NCBI databases OMIM Medline Plus Health Information Child Development Seniors' Health

Lack of Relationship between Vitamin D Receptor Genotype and Forearm Bone Gain in Healthy Children, Adolescents, and Young Adults¹

Center for Clinical Osteoporosis Research (M.G., E.H.L.), Haugesund; and Hormone Laboratory, Aker University Hospital (J.P.B., J.H.), and The Osteoporosis Clinic (J.H.), Oslo, Norway

Address all correspondence and requests for reprints to: Jens P. Berg, M.D., Ph.D., Hormone Laboratory, Aker University Hospital, Trondheimsveien 235, N-0514 Oslo, Norway.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Recent studies have suggested that genetic effects on bone mineral density (BMD) are related to allelic variation in the vitamin D receptor (VDR) gene. We examined 1) allelic influences of the VDR gene on BMD of the forearm, spine, hip, and whole body; and 2) allelic influences of the VDR gene on forearm BMD gain. Two hundred and seventy-three healthy boys and girls, aged 8.2–16.5 yr, at baseline were eligible. Forearm BMD was assessed with single photon absorptiometry at baseline. BMD gain was calculated as the annual percent change in BMD measured by single photon absorptiometry from the baseline and after 3.8 ± 0.1 (±SD) yr. Calcium intake and physical activity were assessed by a detailed questionnaire at baseline and after 1 yr. VDR alleles were determined by BsaMI endonuclease restriction fragment analysis after PCR amplification. No significant differences in forearm BMD gain or in BMD assessed at the forearm, spine, hip, and whole body were observed among the three VDR genotypes. These findings did not change after adjusting for environmental factors such as calcium intake and physical activity or age, weight, height, and changes in weight and height during the observation period. In conclusion, our data do not support the idea that VDR genotypes are related to BMD gain or to BMD at the forearm, hip, spine, and whole body in healthy boys and girls, aged 8–21 yr. VDR genotyping is probably of little use for the detection of individuals who would benefit from increased calcium and physical activity to increase their peak bone densities.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A LOW PEAK bone mass achieved during growth and bone consolidation is a major risk factor for osteoporotic fractures later in life. Peak bone mass is strongly inherited (1, 2, 3). Morrison et al. (4) recently suggested that a polymorphism at the vitamin D receptor (VDR) gene could be responsible for up to 75% of the total genetic effect on peak bone mass. Although the results by Morrison et al. (4) have been confirmed in some studies (5, 6, 7, 8, 9), other studies found no relationship between bone mass and VDR alleles (10, 11, 12, 13, 14, 15, 16).

Furthermore, it has been suggested that VDR gene polymorphisms may predict postmenopausal bone loss (8, 9, 17). In addition, there may be an interaction between VDR alleles and intestinal calcium absorption such that an effect is greater in subjects with a low calcium intake (17, 18). These findings have not been corroborated in other studies that reported no effect on bone loss (14, 19, 20, 21), nor has a previously reported relationship between VDR polymorphisms and bone turnover (22) been confirmed (6, 11, 14, 20, 23, 24).

Given an influence of VDR polymorphisms on bone mineral density (BMD), it is unclear whether the effect is on bone gain, bone loss, or both. Theoretically, bone gain would be a stronger candidate for such an effect because bone loss has a very low heritability (25). In children, cross-sectional data (26, 27) have indicated an association between VDR polymorphisms and BMD, whereas Garnero et al. (12) failed to show an effect on peak bone mass in adult premenopausal women. Two preliminary reports on bone gain in relation to VDR polymorphisms have been conflicting (26, 28). Although there appeared to be an effect in 8-yr-old girls in one of these studies (26), no effect could be seen in infants 3–12 months of age (28).

Thus, results are conflicting, with no consistent pattern emerging across studies indicating how the VDR alleles might be involved. Furthermore, genetic and environmental factors may interact, and all influences may be different according to developmental stage and may be site dependent according to bone composition and physical loading.

At present no studies have examined the potential effects of these polymorphisms on bone gain during adolescence, a period that corresponds to the most crucial years of peak bone mass attainment (29, 30).

In the present study, comprising 273 children, adolescents, and young adults, aged 8.2–16.5 yr at baseline, we examined over a 3.8 ± 0.1-yr (±SD) period relationships between VDR genotypes and forearm trabecular and cortical BMD accretion rates and relationships between VDR genotypes and BMD in the forearm, hip, spine, and whole body.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The cohort of this study comprises 494 healthy boys and girls who had been enrolled in a prospective study on determinants of bone mass in 1992. Cross-sectional results (30, 31) as well as 1-yr follow-up data (32) have previously been presented.

In 1996, 3.8 ± 0.1 (±SD) yr after the baseline examination, 273 subjects from the original cohort agreed to a second follow-up, including assessment of forearm BMD gain; measurement of bone mass with dual x-ray absorptiometry (DXA) at the forearm, spine, hip, and whole body; and blood test for analysis of vitamin D receptor genotype. The age ranges of the study population were 8.2–16.5 yr at the baseline and 12.2–20.3 yr at the second follow-up examination.

At each examination, health condition, calcium intake (24-h recall), level of physical activity, and daylight exposure were assessed by a detailed questionnaire as described previously (30, 31). Measurements of calcium intake and weight-bearing physical activity assessed at baseline and at the 1-yr follow-up were used in the analyses.

The protocol was approved by the regional ethical committee, and parental written informed consent was obtained.

Bone mass measurements

BMD was assessed at baseline (1992), in 1993, and in 1996 at the nondominant distal and ultradistal forearm by single photon absorptiometry (SPA) using an Osteometer DT 100 as previously described (30). Briefly, the distal and ultradistal sites consist of approximately 65% cortical and 65% trabecular bone, respectively, according to measurements of bone composition along the radius (33). The in vivo short term precisions were 0.7% and 0.8%, and the in vivo long term precisions were 1.7% and 1.3% for trabecular and cortical measurements, respectively.

At the second follow-up, in 1996, BMD was additionally measured at the anterioposterior spine (L1–L4); the proximal femur (neck, trochanter, Ward’s triangle, and total hip); the one third, mid-, ultradistal, and total radius; and the whole body by DXA on a QDR 4500 device (Hologic, Waltham, MA). The DXA short time precisions, assessed in 15 subjects (age range, 12.2–20.3 yr), including reposition were 0.7%, 0.6%, 0.5%, and 0.6% for total radius, spine, total hip, and whole body, respectively. Body composition was measured by DXA and analyzed using available QDR software (Hologic version 4.40). Pearson’s correlation coefficients between SPA and DXA were 0.720 (P < 0.001) for ultradistal measurements and 0.935 (P < 0.001) between forearm measurements performed by SPA and measurements at the anatomically corresponding site (midforearm) performed by DXA.

VDR genotyping

Blood samples for VDR genotyping were drawn at the second follow-up in 1996 and analyzed as previously reported (21). Briefly, DNA was extracted from peripheral leukocytes, and a fragment of the vitamin D gene containing the BsaMI polymorphism was amplified using PCR and primers, as described by Morrison et al. (4). The PCR product was treated with the restriction enzyme BsaMI. The absence or presence of the BsaMI restriction site is indicated by B or b, respectively.

Statistics

BMD accretion rates, calculated from SPA measurements at baseline and after 3.8 ± 0.1 yr (±SD), were assessed as the annualized percent change from the baseline BMD. Associations between variables were analyzed by simple linear regression. Comparisons of variables between genotypes were assessed by ANOVA.

Similar comparisons were made after adjusting the mean values of BMD and BMD accretion rates for potential confounding factors, such as BMD, age, height, and weight at baseline; body fat and lean mass assessed by DXA in 1996; height and weight gain during the 3.8 ± 0.1-yr (±SD) observation period; and mean calcium intake and physical activity from baseline and 1-yr follow-up examinations.

All statistical analyses were performed using Systat program version 5 (Systat, Evanston, IL). Data are given as the mean ± 1 SD. P < 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 shows clinical characteristics, calcium intake, and weight-bearing physical activity of the population. Age, height, and weight at baseline; mean calcium intake and weight-bearing physical activity at baseline and after 1 yr; and weight gain from baseline to 3.8 ± 0.1 yr (±SD) follow-up were similar among the three VDR genotypes. In the pooled group, height gain and lean mass were significantly lower, and body fat was significantly higher in bb subjects than in Bb subjects, but this association disappeared when the group was split by sex.

Thus, no significant differences in any of the bone mass variables shown in Tables 2 and 3 were observed among the three VDR genotypes.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this study we found no association between forearm bone gain and the three VDR genotypes defined by the restriction enzyme BsaMI. In addition, there was no difference among the genotypes concerning BMD measured at the radius, spine, hip, or whole body. These results indicate that VDR gene polymorphisms do not contribute to peak bone mass attainment in this healthy population of young, growing subjects.

Recruitment bias was avoided by randomly selecting the subjects from various schools in the area and by excluding those with diseases known to affect bone metabolism or those taking drugs (30, 31, 32). Genotype frequencies were similar to those previously reported for other Caucasian populations (4, 10, 11). Our findings are not likely to be due to confounding factors, and girls as well as boys in the three genotypes were well matched for relevant anthropometric variables, calcium intake, and weight-bearing physical activity. Adjusting for these variables did not change our findings. Our study comprises a greater sample size than what has been recommended for reasonable power to reveal an effect of the VDR gene allele on BMD (34). Furthermore, bone density was measured at multiple sites, and forearm BMD values measured by SPA were verified by highly correlating DXA values at trabecular and cortical measuring sites.

Our study is the first to show that these polymorphisms are not predictive of forearm BMD gain in subjects observed during a time period corresponding to the most critical years of bone mass accumulation. As 30–40% of the peak bone mass is attained between 11–16 yr of age (29, 30), the possibility of an influence of VDR polymorphisms on peak bone mass is strongly weakened by our results. This is in accordance with the lack of relationship between VDR polymorphisms and peak bone mass reported by Garnero et al. (12), but conflicts with findings by Ferrari et al. (26), who reported a trend toward a higher rate of BMD increase in bb girls compared with BB girls. In the latter study (26), however, sample size as well as observation period were only about one third of ours, and the BMD response to calcium supplementation according to VDR genotype, rather than the effect of VDR genotype on BMD gain, was addressed.

It has previously been reported that these polymorphisms may be predictive of the response of bone mass to calcium intake (8, 17, 18, 26). In the current study we tested for this possibility by adjusting mean bone variables for calcium intake and other possible confounders. Interactions between calcium intake and VDR polymorphisms were also tested by analysis of covariance. No effect of VDR polymorphisms on BMD or BMD gain was found according to calcium intake, nor did similar analyses undertaken for physical activity or for calcium intake-physical activity interactions change our findings. A calcium-dependent effect of VDR genotypes would be difficult to show as overall calcium intake was relatively high in this population.

Based on one-way ANOVA at 5% significance, our study could detect a difference in BMD gain of about 0.7 SD with a power of 95% and of about 0.5 SD with a power of 80%. We, therefore, cannot rule out a small effect of VDR gene alleles on bone gain and peak bone mass attainment. Our data indicate that such an effect would be much smaller than the effect reported by Morrison et al. (35), who found a 1 SD greater mean lumbar spine BMD in the bb genotype compared with the BB genotype in the general population. The reason for this discrepancy is unclear. One possible explanation is that VDR genotypes are related to postmenopausal bone loss or to maintenance of the peak bone mass during adult premenopausal life rather than to bone gain and attainment of peak bone mass during ages of bone growth and bone consolidation. However, in a recent study, VDR genotypes were not associated with premenopausal or postmenopausal bone loss (21). In a large study by Uitterlinden et al. (36) in an elderly population, a VDR haplotype was weakly associated with low BMD, whereas no association was demonstrated between the individual polymorphisms studied at the VDR gene locus and low BMD.

Measures of bone gain were limited to the forearm, and questions of whether VDR genotype influences bone gain at other important sites, such as the spine and hip, remain unanswered. However, the lack of a relationship between bone gain at these sites and VDR polymorphisms would be expected from our data, as forearm BMD, assessed by SPA, correlated strongly with spine BMD (r = 0.739; P < 0.001) as well as with hip BMD (r = 0.724; P < 0.001).

In conclusion, our results do not support the idea that VDR genotypes are related to forearm BMD gain or to BMD measured at various sites including the forearm, hip, spine, and whole body in healthy individuals, aged 8–21 yr. Moreover, our results indicate that peak bone mass may not be influenced by VDR genotype. VDR genotyping is probably of little use for the detection of individuals who would benefit from increased amounts of calcium and physical activity to increase their peak bone densities.

	Acknowledgments

 
The authors thank A. M. Aasbu, A. L. Robins, A. Naerby, and N. Gjerlaugsen for excellent technical assistance.

	Footnotes

 
¹ This work was supported by the Norwegian Research Council.

² Deceased.

Received August 23, 1996.

Revised October 31, 1996.

Accepted November 11, 1996.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Pocock NA, Eisman JA, Hopper JL, Yeates PN, Sambrook PN, Ebert S. 1987 Genetic determinants of bone mass in adults: a twin study. J Clin Invest. 80:706–710.
2. Slemenda CW, Christian JC, Williams CJ, Norton JA, Johnston Jr CC. 1991 Genetic determinants of bone mass in adult women: a reevaluation of the twin model and potential importance of gene interaction on heritability estimates. J Bone Miner Res. 6:561–567.[Medline]
3. Dequecker J, Nijs J, Vestraeten A, Geusens P, Gevers G. 1987 Genetic determinants of bone mineral content at the spine and radius: a twin study. Bone. 8:207–209.[Medline]
4. Morrison NA, Qi JC, Tokita A, et al. 1994 Prediction of bone density from vitamin D receptor alleles. Nature. 367:284–287.[CrossRef][Medline]
5. Spector TD, Keen RW, Arden NK, et al. 1995 Influence of vitamin D receptor genotype on bone mineral density in postmenopausal women: a twin study in Britain. Br Med J. 310:1357–60.[Abstract/Free Full Text]
6. Fleet JM, Harris SS, Wood RJ, Dawson-Hughes B. 1995 The BsmI vitamin D receptor restriction fragment length polymorphism (BB) predicts low bone density in premenopausal black and white women. J Bone Miner Res. 10:985–990.[Medline]
7. Riggs BL, Ngyen TV, Melton III LJ, et al. 1995 The contribution of vitamin D receptor gene alleles to the determination of bone mineral density in normal and osteoporotic women. J Bone Miner Res. 10:991–996.[Medline]
8. Ferrari S, Rizzoli R, Chevalley T, Slosman D, Eisman JA, Bonjour J-P. 1995 Vitamin-D-receptor-gene polymorphisms and change in lumbar spine bone mineral density. Lancet. 345:423–424.[CrossRef][Medline]
9. Yamagata Z, Miyamura T, Iijima S, et al. 1994 Vitamin D receptor gene polymorphism and bone mineral density in healthy Japanese women. Lancet. 344:1027.[Medline]
10. Hustmyer FG, Peacock M, Hui S, Johnston CC, Christian J. 1994 Bone mineral density in relation to polymorphism at the vitamin D receptor gene locus. J Clin Invest. 94:2130–2134.
11. Melhus H, Kindmark A, Amér S, Wilén B, Lindh E, Ljunghall S. 1994 Vitamin D receptor genotypes in osteoporosis. Lancet. 344:949–950.
12. Garnero P, Borel O, Sornay-Rendu E, Delmas PD. 1995 Vitamin D receptor gene polymorphisms do not predict bone turnover and bone mass in healthy premenopausal women. J Bone Miner Res. 10:1283–1288.[Medline]
13. Looney JE, Yoon HK, Fischer M, et al. 1995 Lack of a high prevalence of the BB vitamin D receptor genotype in severely osteoporotic women. J Clin Endocrinol Metab. 80:2158–2162.[Abstract]
14. Garnero P, Borel O, Sornay-Rendu E, Arlo M, Delmas PD. 1996 Vitamin D receptor gene polymorphisms are not related to bone turnover, rate of bone loss, and bone mass in postmenopausal women: the OFELY study. J Bone Miner Res. 11:827–834.[Medline]
15. Garnero P, Arden NK, Griffiths G, Delmas PD, Spector TD. 1996 Genetic influence on bone turnover in postmenopausal twins. J Clin Endocrinol Metab. 81:140–146.[Abstract]
16. Gallagher JC, Goldgar D, Kinyamu H, Fannon P. 1994 Vitamin D receptor genotypes in type I osteoporosis. J Bone Miner Res 9:S143.
17. Krall EA, Parry P, Lichter JB, Dawson-Hughes B. 1995 Vitamin D receptor alleles and rates of bone loss: influences of years since menopause and calcium intake. J Bone Miner Res. 10:978–984.[Medline]
18. Dawson-Hughes B, Harris SS, Finneran S. 1995 Calcium absorption on high and low calcium intakes in relation to vitamin D receptor genotype. J Clin Endocrinol Metab. 80:3657–3661.[Abstract]
19. Keen RW, Major PJ, Lanchbury JS, Spector TD. 1995 Vitamin-D-receptor gene polymorphism and bone loss. Lancet. 345:990.[CrossRef][Medline]
20. Kröger H, Mahonen A, Ryhänen S, Turunen A-M, Alhava E, Mäenpää P. 1995 Vitamin D receptor genotypes and bone mineral density. Lancet. 345:1238.[CrossRef]
21. Berg JP, Falch JA, Haug E. 1996 Fracture rate, pre- and postmenopausal bone mass and early and late postmenopausal bone loss are not associated with vitamin D receptor genotype in a high-endemic area of osteoporosis. Eur J Endocrinol. 135:96–100.[Abstract]
22. Morrison NA, Yeoman R, Kelly PJ, Eisman JA. 1992 Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci USA. 89:6665–6669.[Abstract/Free Full Text]
23. Shiraki M, Eguchi H, Aoki C, Shiraki Y. 1995 Can allelic variation in vitamin D receptor gene predict bone densities and serum osteocalcin level in Japanese women? Bone. 16:84S.
24. Peacock M, Hustmyer FG, Johnston CC, Christian J. Heritability of bone mass, bone turnover, calcium regulation and calcium absorption in relation to RFLPs at the vitamin D and PTH receptor genes. Bone. 16:83S.
25. Slemenda CW, Christian CJ, Reed TK, Williams CJ, Johnston Jr CC. 1992 Long-term bone loss in men: effects of genetic and environmental factors. Ann Intern Med. 117:286–291.
26. Ferrari SL, Rizzoli R, Theintz G, Slosman DO, Bonjour JP. 1995 Vitamin D-receptor (VDR) gene polymorphisms and the effect of calcium supplementation on bone mass accumulation in prepubertal girls. J Bone Miner Res 10:S187.
27. Klisovic D, Young AP, Ilich M, Skugor M, Badenhop N, Matkovic V. 1995 Vitamin D receptor polymorphism (VDR) and bone mineral density (BMD) in prepubertal females. J Bone Miner Res 10:S189.
28. Specker BL, Williams LA, Kalkwarf H, et al. 1995 Vitamin D receptor genotype and its relation to bone growth and bone mineralization in infants 3 to 12 months of age. J Bone Miner Res 10:S188.
29. Theintz G, Bucks B, Rizzoli R, et al. 1992 Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the level of lumbar spine and femoral neck in female subjects. J Clin Endocrinol Metab. 75:1060–1065.[Abstract]
30. Gunnes M. 1994 Bone mineral density in the cortical and trabecular distal forearm in healthy children and adolescents. Acta Paediatr. 83:463–467.[Medline]
31. Gunnes M, Lehmann EH. 1995 Dietary calcium, saturated fat, fiber and vitamin C as predictors of forearm cortical and trabecular bone mineral density in healthy children and adolescents. Acta Paediatr. 84:388–392.[Medline]
32. Gunnes M, Lehmann EH. 1996 Physical activity and dietary constituents as predictors of forearm cortical and trabecular bone gain in healthy children and adolescents: a prospective study. Acta Paediatr. 85:19–25.[Medline]
33. Schlenker RA, von Seggen WW. 1976 The distribution of cortical and trabecular bone mass along the lengths of the radius and ulna and the implications for the in vivo bone mass measurements. Calcif Tissue Res. 20:41–52.[Medline]
34. Ngyen TV, Kelly PJ, Morrison NA, Sambrook PN, Eisman JA. 1994 Vitamin D receptor genotypes in osteoporosis. Lancet. 344:1580–1581.[Medline]
35. Morrison NA, Jiang Q, Tokita A, Sambrook P, Kelly P, Eisman J. 1995 Genetic susceptibility and resistance to osteoporosis and vitamin D receptor gene. Bone. 16:83S.
36. Uitterlinden AG, Pols HAP, Burger H, et al. 1996 A 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.[Medline]

This article has been cited by other articles:

				F. F. Bezerra, G. M. K. Cabello, L. M. C. Mendonca, and C. M. Donangelo Bone Mass and Breast Milk Calcium Concentration Are Associated with Vitamin D Receptor Gene Polymorphisms in Adolescent Mothers J. Nutr., February 1, 2008; 138(2): 277 - 281. [Abstract] [Full Text] [PDF]

				A. d'Alesio, M. Garabedian, J. P. Sabatier, G. Guaydier-Souquieres, C. Marcelli, A. Lemacon, O. Walrant-Debray, and F. Jehan Two single-nucleotide polymorphisms in the human vitamin D receptor promoter change protein-DNA complex formation and are associated with height and vitamin D status in adolescent girls Hum. Mol. Genet., November 15, 2005; 14(22): 3539 - 3548. [Abstract] [Full Text] [PDF]

				J. A. Eisman Pharmacogenetics of the Vitamin D Receptor and Osteoporosis Drug Metab. Dispos., April 1, 2001; 29(4): 505 - 512. [Abstract] [Full Text]

				D A Nelson, P J Vande Vord, and P H Wooley Polymorphism in the vitamin D receptor gene and bone mass in African-American and white mothers and children: a preliminary report Ann Rheum Dis, August 1, 2000; 59(8): 626 - 630. [Abstract] [Full Text]

				M. Lorentzon, R. Lorentzon, and P. Nordström Vitamin 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., April 1, 2000; 85(4): 1666 - 1671. [Abstract] [Full Text]

				J. A. Eisman Genetics of Osteoporosis Endocr. Rev., December 1, 1999; 20(6): 788 - 804. [Abstract] [Full Text]

				S. Ferrari, D. Manen, J.-P. Bonjour, D. Slosman, and R. Rizzoli Bone Mineral Mass and Calcium and Phosphate Metabolism in Young Men: Relationships with Vitamin D Receptor Allelic Polymorphisms J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2043 - 2048. [Abstract] [Full Text]

				C. Tao, T. Yu, S. Garnett, J. Briody, J. Knight, H. Woodhead, C. T Cowell;, and Z. MUGHAL Vitamin D receptor alleles predict growth and bone density in girls • Commentary Arch. Dis. Child., December 1, 1998; 79(6): 488 - 494. [Abstract] [Full Text]

				F. Suarez, C. Rossignol, and M. Garabédian Interactive Effect of Estradiol and Vitamin D Receptor Gene Polymorphisms as a Possible Determinant of Growth in Male and Female Infants J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3563 - 3568. [Abstract] [Full Text]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gunnes, M. Articles by Lehmann, E. H. Search for Related Content PubMed PubMed Citation Articles by Gunnes, M. Articles by Lehmann, E. H. Pubmed/NCBI databases OMIM Medline Plus Health Information Child Development Seniors' Health