Q J Med 2002; 95: 331-332
© 2002 Association of Physicians
Correspondence |
Determinants of size at birth
Department of Diabetes & Metabolism, Royal London Hospital, London
Sir,
The contribution of the degree to which adult vitamin D activation relates to birth weight, and inversely to intestinal calcium absorption in the adult, is an observation whose explanation must contribute to the risk of osteoporosis and fracture in later life.1 Since reduction in birth weight also marks increased risks for type 2 diabetes and ischaemic heart disease2 it is, as the authors suggest, important to identify mechanisms by which intra-uterine environment could contribute to the determination of later vitamin D activation, and to distinguish such factors from relevant genetic factors. There are several genetic factors that are of immediate relevance and it would be of interest to know whether the authors have examined their findings for variation with the following factors.
(i) The effects of vitamin D receptor genotype [VDRg], since variations in function are reported with non-expressed polymorphisms, for example for insulin secretion, itself relevant to fetal growth,3 might be affecting responsiveness to calcitriol, especially since there are conflicting reports on variation in size and weight at birth with VDRg.4,5
(ii) The gene for the enzyme activating circulating 25(OH)vitamin D, the 25(OH)2vitD 1-alphahydroxylase, is of interest but since only renal expression is normally relevant,6 might 1,25-dihydroxyvitamin D levels or 1,25-dihydroxy/25hydroxyvitamin D ratios provide a surrogate for examination of its’ activity with VDRg or with other relevant gene polymorphisms?
(iii) Since circulating vitamin D binding proteins contribute to the presentation of 25(OH)vitamin D to the kidney for re-absorption on the endocytic receptor megalin,7 is there any variation of the vitamin D metabolites studied or of calcium absorption or metabolite levels with Gc protein genotypes (easily assessed on stored serum samples) or with megalin polymorphisms?
References
1.
Arden NK, Major P, Poole JR, Keen RW, Vaja S, Swaminathan R, Cooper C, Spector TD. Size at birth, adult intestinal calcium absorption and 1,25(OH)2 vitamin D. Q J Med2002; 95:15–21.
2. Barker DJP, Hales CN, Osmond C, Phipps K, Clark PMS. Type 2 (non-insulin dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia1993; 306:422–6.
3. Hitman GA, Mannan N, McDermott MF, Aganna E, Ogunkolade WB, Hales CN, Boucher BJ. Vitamin D receptor polymorphisms influence insulin secretion in Bangladeshi Asians. Diabetes1998; 47:688–90.[ISI][Medline]
4. Dennison EM, Arden NK, Keen RW, Syddall HM, Day IN, Spector TD, Cooper C. Birthweight, vitamin D receptor genotype and the programming of osteoporosis. Paediatr Perinat Epidemiol2001; 15:211–19.[ISI][Medline]
5.
Suarez F, Zeghoud F, Rossignol C, Walrant O, Garabedian M. Association between vitamin D receptor polymorphism and sex-dependent growth during the first two years of life. J Clin Endocrinol Metab1997; 82:2966–70.
6. Breslau NA. Normal and abnormal regulation of 1,25-(OH)2D synthesis. Am J Med Sci1988; 296:417–25.[ISI][Medline]
7. Nyjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Hertz J, Melsen F, Christensen EI, Willnow TE. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell1999; 96:507–15.[ISI][Medline]
Sir,
Dr Boucher raises some very important issues. We agree that there are important genetic factors acting on adult bone mass, and probably on intestinal calcium absorption1,2 and serum vitamin D concentrations,3 and that these should be further studied. It is however, unlikely that genetic and environmental factors act in isolation,3 and it is essential that interactions between the environment and genome are sought. The effects of vitamin D receptor genotype on the calcium/vitamin D axis (including the vitamin D binding protein) and their interaction with environmental factors, including birthweight and early growth, are currently under investigation by the authors.
We agree that the recent publications on the endocytic receptor megalin highlight it as an important areas for future research: unfortunately, we have no information on this receptor at present.
References
1. Arden NK, Baker J, Hogg C, Baan K, Spector TD. The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J Bone Miner Res1996; 11:530–4.[ISI][Medline]
2. Dawson-Hughes B, Harris SS, Finneran S. Calcium absorption on high and low calcium intakes in relation to vitamin D receptor genotype. J Clin Endocrinol Metab1995; 80:3657–61.[Abstract]
3. Hunter D, De Lange M, Snieder H, MacGregor AJ, Swaminathan R, Thakker RV, Spector TD. Genetic contribution to bone metabolism, calcium excretion and vitamin D and parathyroid hormone regulation. J Bone Miner Res2001; 16:371–8.[ISI][Medline]
4. Dennison EM, Arden NK, Keen RW, Syddall H, Day IN, Spector TD, Cooper C. Birthweight, vitamin D receptor genotype and the programming of osteoporosis. Paediatr Perin Epidemio2001; 15:211–19.
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