Genetic control of bone density and turnover: Role of the collagen 1 alpha1, estrogen receptor, and vitamin D receptor genes

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural g enes has been proposed to be involved including collagen 1 alpha1 (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actu al genes involved are uncertain. We therefore studied the role of the COL1A 1 and VDR loci in control of bone density by linkage in 45 dizygotic twin p airs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by associ ation both cross-sectionally and Longitudinally in 193 elderly postmenopaus al women (average age, 69 years) over a mean follow-up time of 6.3 years. W eak linkage of the COL1A1 locus with bone density was observed in both twin s and families (p = 0.02 in both data sets), confirming previous observatio ns of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed wit h significant gene-environment interaction related to dietary calcium intak e (p = 0,0006), In the lowest tertile of dietary calcium intake, carriers o f "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003), As sociation also was observed between rate of bone loss at both the femoral n eck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03), This ass ociation was strongest in those in the lowest tertile of calcium intake, al so suggesting the presence of gene-environment interaction involving dietar y calcium and VDR, influencing bone turnover. No significant association wa s observed between the P nu uII ER polymorphism alone or in combination wit h VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone densi ty and the interaction of both COL1A1 and VDR with calcium intake in regula tion of change of bone density over time.