Gene Linked to OA, Nonvertebral Fractures

A genetic variant known to affect height and osteoarthritis risk has now been shown to increase the risk of nonvertebral fracture in older women, possibly because of the increased hip axis length seen in those with two copies of the gene.

“Our results suggest that the GDF5 variants target the long bones, since we find an association with hip axis length,” lead investigator Dr. Joyce van Meurs said in an interview. “This difference in hip axis length could cause a difference in fracture risk.”

Findings from the Rotterdam Study, a prospective population-based cohort of 6,114 individuals aged 55 years and over, showed that women who carried two copies of the gene were 32% more likely to experience nonvertebral fracture during the follow-up period than were noncarriers. Women with one copy of the gene had no increased risk; nor did men, regardless of their genotype, wrote Dr. van Meurs of the Erasmus Medical Centre, Rotterdam, the Netherlands, and her colleagues (Ann. Rheum. Dis. 2008 Nov. 24 [doi:10.1136/ard.2008.099655]).

The Rotterdam Study is an ongoing prospective cohort study that is examining the risks for cardiovascular, neurologic, ophthalmologic, and endocrine diseases in 15,000 subjects aged 45 years and older.

All of those in the genetic study were genotyped for rs143383. The polymorphism lies near the GDF5 gene. Mutations in this area have been linked with skeletal dysplasias, including shortening of the digits, and chondrodysplasias involving joint ankylosis.

In addition to genotyping, the subjects in the Rotterdam study underwent bone mineral density testing and radiologic assessment for osteoarthritis, and were measured for hip axis length and C-telopeptide levels. Fractures were assessed over a 10-year period.

Sixteen percent of the women and 14% of the men were homozygous carriers of rs143383; 48% of both sexes were heterozygous for the variant.

In the men there were no associations between the genotype and osteoarthritis at the hip, knee, or hand; fracture risk; or C-telopeptide levels. However, there were some significant associations among women.

Heterozygous women were 32% less likely to have osteoarthritis of the knee and hand than were noncarriers. Homozygous women were 34% less likely to have knee osteroarthritis and 48% less likely to have hand osteoarthritis than were noncarriers. Women with two copies of the gene also had significantly lower C-telopeptide levels than did noncarriers.

Among women, each copy of the gene was associated with a height increase of 0.55 cm; there was a similar, but nonsignificant, trend in men. The gene was not associated with weight or body mass index in either gender.

Nonvertebral fracture risk also was associated with rs143383 in women, but not in men. Women with two copies of the gene were 32% more likely than were noncarriers to experience a nonvertebral fracture over the follow-up period—a significant difference.

“Neither adjustment nor stratification for height and presence of osteoarthritis had an effect on the association with fracture risk,” the authors noted. “This implies that the association is not driven by any of the other observed associations, and genetic variation in the GDF5 gene seems to contribute independently to an increased fracture risk.”

The hip axis length in female homozygotes was significantly larger than that of either heterozygotes or noncarriers.

The Rotterdam Study is being funded by the European Union and national grants from the Netherlands. None of the authors declared a financial conflict with regard to the study.

A genetic variant known to affect height and osteoarthritis risk has now been shown to increase the risk of nonvertebral fracture in older women, possibly because of the increased hip axis length seen in those with two copies of the gene.

“Our results suggest that the GDF5 variants target the long bones, since we find an association with hip axis length,” lead investigator Dr. Joyce van Meurs said in an interview. “This difference in hip axis length could cause a difference in fracture risk.”

Findings from the Rotterdam Study, a prospective population-based cohort of 6,114 individuals aged 55 years and over, showed that women who carried two copies of the gene were 32% more likely to experience nonvertebral fracture during the follow-up period than were noncarriers. Women with one copy of the gene had no increased risk; nor did men, regardless of their genotype, wrote Dr. van Meurs of the Erasmus Medical Centre, Rotterdam, the Netherlands, and her colleagues (Ann. Rheum. Dis. 2008 Nov. 24 [doi:10.1136/ard.2008.099655]).

The Rotterdam Study is an ongoing prospective cohort study that is examining the risks for cardiovascular, neurologic, ophthalmologic, and endocrine diseases in 15,000 subjects aged 45 years and older.

All of those in the genetic study were genotyped for rs143383. The polymorphism lies near the GDF5 gene. Mutations in this area have been linked with skeletal dysplasias, including shortening of the digits, and chondrodysplasias involving joint ankylosis.

In addition to genotyping, the subjects in the Rotterdam study underwent bone mineral density testing and radiologic assessment for osteoarthritis, and were measured for hip axis length and C-telopeptide levels. Fractures were assessed over a 10-year period.

Sixteen percent of the women and 14% of the men were homozygous carriers of rs143383; 48% of both sexes were heterozygous for the variant.

In the men there were no associations between the genotype and osteoarthritis at the hip, knee, or hand; fracture risk; or C-telopeptide levels. However, there were some significant associations among women.

Heterozygous women were 32% less likely to have osteoarthritis of the knee and hand than were noncarriers. Homozygous women were 34% less likely to have knee osteroarthritis and 48% less likely to have hand osteoarthritis than were noncarriers. Women with two copies of the gene also had significantly lower C-telopeptide levels than did noncarriers.

Among women, each copy of the gene was associated with a height increase of 0.55 cm; there was a similar, but nonsignificant, trend in men. The gene was not associated with weight or body mass index in either gender.

Nonvertebral fracture risk also was associated with rs143383 in women, but not in men. Women with two copies of the gene were 32% more likely than were noncarriers to experience a nonvertebral fracture over the follow-up period—a significant difference.

“Neither adjustment nor stratification for height and presence of osteoarthritis had an effect on the association with fracture risk,” the authors noted. “This implies that the association is not driven by any of the other observed associations, and genetic variation in the GDF5 gene seems to contribute independently to an increased fracture risk.”

The hip axis length in female homozygotes was significantly larger than that of either heterozygotes or noncarriers.

The Rotterdam Study is being funded by the European Union and national grants from the Netherlands. None of the authors declared a financial conflict with regard to the study.

A genetic variant known to affect height and osteoarthritis risk has now been shown to increase the risk of nonvertebral fracture in older women, possibly because of the increased hip axis length seen in those with two copies of the gene.

“Our results suggest that the GDF5 variants target the long bones, since we find an association with hip axis length,” lead investigator Dr. Joyce van Meurs said in an interview. “This difference in hip axis length could cause a difference in fracture risk.”

Findings from the Rotterdam Study, a prospective population-based cohort of 6,114 individuals aged 55 years and over, showed that women who carried two copies of the gene were 32% more likely to experience nonvertebral fracture during the follow-up period than were noncarriers. Women with one copy of the gene had no increased risk; nor did men, regardless of their genotype, wrote Dr. van Meurs of the Erasmus Medical Centre, Rotterdam, the Netherlands, and her colleagues (Ann. Rheum. Dis. 2008 Nov. 24 [doi:10.1136/ard.2008.099655]).

The Rotterdam Study is an ongoing prospective cohort study that is examining the risks for cardiovascular, neurologic, ophthalmologic, and endocrine diseases in 15,000 subjects aged 45 years and older.

All of those in the genetic study were genotyped for rs143383. The polymorphism lies near the GDF5 gene. Mutations in this area have been linked with skeletal dysplasias, including shortening of the digits, and chondrodysplasias involving joint ankylosis.

In addition to genotyping, the subjects in the Rotterdam study underwent bone mineral density testing and radiologic assessment for osteoarthritis, and were measured for hip axis length and C-telopeptide levels. Fractures were assessed over a 10-year period.

Sixteen percent of the women and 14% of the men were homozygous carriers of rs143383; 48% of both sexes were heterozygous for the variant.

In the men there were no associations between the genotype and osteoarthritis at the hip, knee, or hand; fracture risk; or C-telopeptide levels. However, there were some significant associations among women.

Heterozygous women were 32% less likely to have osteoarthritis of the knee and hand than were noncarriers. Homozygous women were 34% less likely to have knee osteroarthritis and 48% less likely to have hand osteoarthritis than were noncarriers. Women with two copies of the gene also had significantly lower C-telopeptide levels than did noncarriers.

Among women, each copy of the gene was associated with a height increase of 0.55 cm; there was a similar, but nonsignificant, trend in men. The gene was not associated with weight or body mass index in either gender.

Nonvertebral fracture risk also was associated with rs143383 in women, but not in men. Women with two copies of the gene were 32% more likely than were noncarriers to experience a nonvertebral fracture over the follow-up period—a significant difference.

“Neither adjustment nor stratification for height and presence of osteoarthritis had an effect on the association with fracture risk,” the authors noted. “This implies that the association is not driven by any of the other observed associations, and genetic variation in the GDF5 gene seems to contribute independently to an increased fracture risk.”

The hip axis length in female homozygotes was significantly larger than that of either heterozygotes or noncarriers.

The Rotterdam Study is being funded by the European Union and national grants from the Netherlands. None of the authors declared a financial conflict with regard to the study.