Clinical Investigations Common Polymorphism of the Vitamin D Receptor Gene is Associated with Variation of Peak Bone Mass in Young Finns A.-M. Viitanen, 1 M. Ka ¨rkka ¨inen, 4 K. Laitinen, 2 C. Lamberg-Allardt, 4 K. Kainulainen, 1 L. Ra ¨sa ¨nen, 3 J. Viikari, 5 M. J. Va ¨lima ¨ki, 1 K. Kontula 1 1 Department of Medicine, University of Helsinki, Central Hospital, FIN-00290 Helsinki, Finland 2 Research Unit of Alcohol Diseases, University of Helsinki, Central Hospital, FIN-00290 Helsinki, Finland 3 Department of Applied Chemistry and Microbiology, Division of Nutrition, University of Helsinki, Helsinki, Finland 4 Minerva Foundation Institute for Medical Research, Helsinki, Finland 5 Department of Medicine, University of Turku, Turku, Finland Received: 3 July 1995 / Accepted: 13 February 1996 Abstract. Previous studies suggested a relation between polymorphism of the vitamin D receptor (VDR) gene and bone mineral density (BMD) at perimenopausal age. To enlighten the possible association of the VDR gene poly- morphism and BMD, we studied young (20–29 years) adults whose BMD provides a measure of their maximal bone mass. After sequencing the DNA regions flanking the polymorphic BsmI site, we set up a specific solid-phase minisequencing technique to assay this allelic variation. BMD values were adjusted for age, sex, weight, physical activity, smoking, and calcium intake. Young subjects ho- mozygous for the b allele (BsmI site present) had a signifi- cantly higher BMD in lumbar spine and femoral neck than those homozygous for the B allele (BsmI site absent). This data shows that the BsmI polymorphism of the VDR gene is associated with peak bone mass. The implication of this result regarding the prevention of osteoporosis deserves fur- ther attention. Key words: Vitamin D receptor — Peak bone mass — Osteoporosis — Solid-phase minisequencing. Although many acquired or environmental factors are known to affect the adult bone mineral density (BMD) [1], genetic factors play a major role as determinants of varia- tion in BMD. This has been widely shown by twin [2] as well as family studies [3]. It has been estimated that up to 80% of BMD could be genetically controlled, and it is the rate of bone formation in particular that is influenced by genes [4]. Association between genetic polymorphism of the vita- min D receptor (VDR) and BMD was recently reported [5]. According to this study conducted in twins and perimeno- pausal women, about 75% of the total genetic variance of BMD was predicted by a biallelic single nucleotide poly- morphism in the VDR gene. The allele with the polymor- phic BsmI site (allele b) was associated with a significantly higher BMD than the allele lacking this site (allele B). Sub- sequent studies have yielded apparently contradictory re- sults on the association of the VDR polymorphism and BMD. In support of the data of Morrison et al. [5], the b allele was associated with a higher BMD in healthy Japa- nese women [6]. Furthermore, Ferrari et al. [7] showed an association between the rate of lumbar spine bone loss and the VDR genotypes in a group of 72 elderly subjects. In contrast, a study of 86 North American monozygotic and 39 dizygotic adult female white twins revealed no relationship between polymorphism of the VDR gene and BMD [8]. Moreover, no statistically significant relation between BMD and VDR genotype was detected in 70 Swedish postmeno- pausal women with osteoporosis and 76 controls [9]. Both racial differences and technical problems related to BMD measurements and assays of VDR polymorphism could underlie the discrepant data. We chose two new strat- egies to enlighten the association of VDR gene polymor- phism and BMD. First, instead of studying postmenopausal or elderly people, we selected an age group displaying a bone mass at its maximum. Detailed long-lasting informa- tion on the environmental factors affecting BMD in this cohort provided an additional unique advantage. Second, genotyping of VDR was accomplished by a solid-phase minisequencing technique based on an initial DNA se- quencing of the polymorphic area of the gene. Materials and Methods Subjects Originally, the subjects were participants in the Cardiovascular Risk in Young Finns Study which was aimed to study risk factors of coronary artery disease and their determinants in Finnish chil- dren and young adults [10]. On a later occasion they participated in a study investigating the relation of BMD to exercise, smoking, Correspondence to: A.-M. Viitanen Calcif Tissue Int (1996) 59:231–234 © 1996 Springer-Verlag New York Inc.