Gene variant linked to postmenopausal fracture risk

Jun 1 2012

By Laura Cowen

Women who carry a variation in a gene involved in blocking bone morphogenic proteins (BMPs) are more likely to have fragility fractures than women without the variant, Greek research shows.

Postmenopausal women who carried the minor allele of the c.507+506G>T single nucleotide polymorphism (SNP) in the CER1 gene (encoding the human Cerberus 1) were seven times more likely to have had a hip fracture and five times more likely to have had any fragility fracture than women homozygous for the major allele, report Theodora Koromila (University of Athens) and colleagues.

These findings "might be helpful in clinical practice to identify patients with increased fracture risk," they write in Calcified Tissue International.

The researchers investigated the possible association of two novel osteoporosis candidate genes, CER1 and TOB1 (encoding transducer of ERBB2, 1), with bone mineral density (BMD) and fragility fracture risk in 300 postmenopausal Greek women.

They explain that CER1 belongs to a cystine knot superfamily and acts as an inhibitor of the bone morphogenic proteins (BMPs), which play a significant role in bone remodeling. TOB1 also inhibits BMP activity by acting as a negative regulator of the BMP signaling pathway.

When the researchers amplified and sequenced the CER1 and TOB1 genes they identified 22 SNPs in CER1 and four SNPs in TOB1. Further analysis revealed that none of the SNPs were significantly associated with osteoporosis in these women.

However, the minor alleles of five SNPs in CER1, namely c.194C>G, c.507+506G>T, c.508−182A>G, c.531A>G, and c.*121T>C, were significantly more common among women with osteoporosis (n=200) than among those without (n=100).

Furthermore, each of the five SNPs was significantly associated with T score in an analysis of the whole cohort. Specifically, major alleles of each SNP were associated with a mean T score ≥-1.3, while minor alleles of each of the SNPs (in either heterozygosity or homozygosity) were correlated with a mean T score ≤-2.2.

After adjustment for age, gender, smoking, body mass index, years since menopause, and calcium intake, only the c.507+506G>T SNP was independently associated with hip fractures or the presence of any fracture.

"These results suggest that CER1 gene variations play a significant role in determining BMD and vertebral or hip fractures," Koromila and co-authors conclude.

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