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Variant of a collagen gene affects bone strength, correlates to fracture risk
By Roberta Friedman

British scientists have determined that a variant of a collagen gene results in a bone-weakening imbalance of bone proteins. Two copies of the variant of the COL1A1 gene were associated with a nearly two-fold increased risk for fracture in osteoporosis, according to a statistical meta-analysis of data.

The researchers reviewed published data on function of the Sp1 transcription site in the COL1A1 gene and backed their statistical analysis with experiments on bone samples and cultured bone cells culled from individuals with different forms of the gene. Studies of the material properties of bone, as well as studies of how the genes are transcribed into protein, "showed clear evidence of functional differences between COL1A1 Sp1 alleles," the researchers write in The Journal of Clinical Investigation.

The scientists examined polymorphisms in the Sp1 transcription factor-binding site on the gene. A change of chemical bases from G to T increases the binding of the Sp1 protein to the gene, which codes for the alpha1(I) protein chain of type I collagen, the major protein in bone.

"This increased affinity for Sp1 causes the transcription of COL1A1 to increase and causes the production of too much COL1A1 relative to COL1A2," says Stuart Ralston, professor of medicine and therapeutics at the University of Aberdeen, in the United Kingdom. The normal ratio is 2:1; the polymorphism results in approximately 2.4 molecules of COL1A1 to 1 molecule of COL1A2.

"It is known that COL1A1 trimers weaken the bone, and we also found that...patients with the 's' [allele] had weaker bones than normal," Ralston says. Collagen is made of three chains, a trimer that usually consists of two alpha1 chains and one alpha2 chain.

By their meta-analysis, the researchers demonstrated that carrying the 'ss' variant is associated with a nearly twofold greater risk of fractures of the vertebral bones of the spine compared to the 'SS' variant. Individuals with one of each type of the gene variant have an intermediate risk of fracture.

Collagen made by cultured bone cells from the 'Ss' heterozygous individuals had increased amounts of collagen alpha1(I) protein compared to alpha2(I). Bone tissue was obtained during routine orthopedic procedures and during surgery to repair hip fractures or treat osteoarthritis.

About three times more transcripts deriving from the 's' allele appeared in bone extracts from 'Ss' individuals. This may be due to either a more efficient transcription of the gene or may occur because the transcripts of the 's' allele are spliced or processed differently, the researchers say.

"These data support previous work which has shown COL1A1 genotype predicts osteoporotic fractures," the researchers write, "and raises the possibility that COL1A1 alleles act as a marker for reduced bone quality."

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Mann, V. et al. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 107, 899-907 (April 2001).

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