A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality.

Osteoporosis is a common disease with a strong genetic component. We previously described a polymorphic Sp1 binding site in the COL1A1 gene that has been associated with osteoporosis in several populations. Here we explore the molecular mechanisms underlying this association. A meta-analysis showed significant associations between COL1A1 "s" alleles and bone mineral density (BMD), body mass index (BMI), and osteoporotic fractures. The association with fracture was stronger than expected on the basis of the observed differences in BMD and BMI, suggesting an additional effect on bone strength. Gel shift assays showed increased binding affinity of the "s" allele for Sp1 protein, and primary RNA transcripts derived from the "s" allele were approximately three times more abundant than "S" allele--derived transcripts in "Ss" heterozygotes. Collagen produced from osteoblasts cultured from "Ss" heterozygotes had an increased ratio of alpha 1(I) protein relative to alpha 2(I), and this was accompanied by an increased ratio of COL1A1 mRNA relative to COL1A2. Finally, the yield strength of bone derived from "Ss" individuals was reduced when compared with bone derived from "SS" subjects. We conclude that the COL1A1 Sp1 polymorphism is a functional genetic variant that predisposes to osteoporosis by complex mechanisms involving changes in bone mass and bone quality.

Protrusio acetabuli in Marfan's syndrome.

Marfan's syndrome is an autosomal dominant disorder of connective tissue, commonly involving the cardiovascular, ocular, and skeletal systems. Revised criteria for the clinical diagnosis of Marfan's syndrome regard skeletal involvement as a major criterion if at least four of eight typical skeletal manifestations are present, one of which is protrusio acetabuli. Using Kulman's method to determine the presence of protrusio, we analysed the pelvic X-rays of 15 patients with Marfan's syndrome and 15 controls. Protrusio was present in 47% (7/15) of Marfan patients, compared with 7% (1/15) of controls (P = 0.035). Using the revised criteria, the presence of protrusio would have affected the final diagnosis of Marfan's syndrome in only one patient out of 15. Therefore, we recommend that a pelvic X-ray is reserved for those cases in which the presence of protrusio will alter the final diagnosis. With regard to the radiological assessment of protrusio, in our opinion this can be performed simply and reliably using the position of the acetabular line alone.