Elsevier

Bone

Volume 23, Issue 4, October 1998, Pages 367-371
Bone

Original Articles
Allelic variation at the interleukin-1 receptor antagonist gene is associated with early postmenopausal bone loss at the spine

https://doi.org/10.1016/S8756-3282(98)00109-4Get rights and content

Abstract

Genetic factors play an important role in determining bone mineral density (BMD) in later life, with the genetic influence mediated through effects on both peak mass and on age- and menopause-related bone loss. At menopause there is an increase in the production and activity of various cytokines and growth factors within the bone microenvironment. The activity of interleukin-1 (IL-1), a powerful stimulant of osteoclastic bone resorption, is increased in estrogen-deficient states with increased production of IL-1 and inhibition of the IL-1 receptor antagonist (IL-1ra). Treatment with IL-1ra blocks the bone loss associated with ovariectomy in animals and the IL-1 receptor antagonist gene (IL-1RN) is therefore a potential candidate gene for the regulation of postmenopausal bone loss. We examined the relationship between annual rates of change in BMD over 5 years and an 86 bp variable number tandem-repeat polymorphism of the IL-1RN gene in 108 early postmenopausal women. All women were within 5 years of a natural menopause at the study’s onset, healthy, and not on hormone replacement therapy or other medication known to affect bone metabolism. BMD was measured annually over the 5 year study period at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Three alleles were identified (A1 = 4 repeats, A2 = 2 repeats, A3 = 5 repeats), with five genotypes observed: A1A1 (41.7%), A1A2 (45.4%), A2A2 (6.5%), A1A3 (2.8%), and A2A3 (3.7%). For analysis, alleles were collapsed into a biallelic system grouping the A1 and A3 alleles. There was no significant relationship between the IL-1RN genotypes and baseline bone mass at either the spine or hip. IL-1RN genotype was significantly associated with annual rates of change in spinal bone mass (p < 0.05), and this finding remained significant after adjustment for age, weight, and baseline BMD. Carriage of at least one copy of the A2 allele was associated with reduced bone loss at the spine (mean change in BMD ± SD: −0.81 ± 1.46%/year) when compared with noncarriage of the A2 allele (mean change −1.38 ± 1.48%/year), p = 0.05. We therefore conclude that allelic variation at the IL-1RN locus is associated with differential rates of early postmenopausal bone loss at the spine. Further research will be required to clarify the mechanisms underlying these findings and to determine whether this association translates into a significant long-term effect on BMD and fracture in later life.

Introduction

Bone mineral density (BMD) in later life is a strong predictor of subsequent osteoporotic fracture6 and is determined by both the peak value achieved during skeletal growth and by age- and menopause-related bone loss. Family and twin studies suggest a strong genetic component in the determination of peak bone mass, with 50%–85% of the population variance in BMD being attributable to genetic factors.22, 24 Twin studies in postmenopausal and elderly women also support a persistent and significant genetic influence on bone mass in later life.1, 8 This may represent either a strong residual effect from the genetic contribution to peak bone mass or an independent genetic effect on the regulation of bone loss. Indirect assessment of bone turnover through biochemical markers suggests a genetic regulation of bone metabolism that may translate into differing effects on bone loss,9, 15, 29 although to date only two twin studies have directly attempted to explore the genetic contribution to age- and menopause-related bone loss, with conflicting and uncertain results.4, 16

Osteoporosis is a complex disease that is likely to have a polygenic etiology,11 and candidate gene analysis has demonstrated that polymorphisms of the vitamin D receptor (VDR) locus,26 the estrogen receptor (ER) locus,18 and the collagen type I α1 (COL1-A1) locus10 are all potential genetic markers for bone mass and perhaps bone loss. Estrogen deficiency is associated with an increase in local production of various cytokines and growth factors within the bone marrow and bone cells, and these inflammatory factors appear to play an important role in the development of postmenopausal osteoporosis.23 Interleukin-1 (IL-1) is a powerful stimulant of bone resorption and a well-recognized inhibitor of bone formation.7 The observed postmenopausal increase in IL-1 activity results from an effect of estrogen on the production of both IL-1 and the IL-1 inhibitor, IL-1 receptor antagonist (IL-1ra). These data, therefore, raise the possibility that the IL-1 receptor antagonist gene (IL-1RN) may be a potential candidate for genetic regulation of early postmenopausal bone loss. In this study we have therefore examined the relationship between bone mass, early postmenopausal bone loss, and a variable number tandem repeat (VNTR) in the IL-1RN gene.

Section snippets

Patients and methods

Subjects were selected from a large general population cohort of 1003 white women, with a mean (±SD) age for the total cohort of 54.2 ± 6.0 years.12 Women in the age range 45–64 years had been selected from a large, single general practice in Chingford in northeast London (total 11,000 registered patients) to participate in a longitudinal epidemiological study of rheumatic diseases. A total of 1353 women were found to be in the age range specified and, of these, 78% (1003) agreed to

Results

Characteristics of the 125 women entered into the study are shown in Table 1. Full clinical and genotype results were available on 108 of these women. No significant differences were observed between subjects with genotype results and those in whom DNA was either unavailable or attempts at PCR unsuccessful.

Analysis of the genotypes in the 108 women showed evidence of three alleles, which corresponded both in size and frequency to those previously identified (Table 2). From the three alleles

Discussion

Family and twin studies demonstrate a strong genetic component to osteoporosis. We have studied the relationship between a VNTR in intron 2 of the IL-1RN gene and both bone mass and annual change in bone mass at the lumbar spine and femoral neck in early postmenopausal women. Our data demonstrate that the IL-1RN gene is a potential candidate for the development of postmenopausal osteoporosis, with allelic variation at the IL-1RN locus associated with differential rates of bone loss from the

Acknowledgements

The authors thank Dr. David Doyle and all the staff at the Silverthorn Osteoporosis Centre, the women participating in the Chingford study, Higham’s Park Medical Practice, and Gabriela Surdulescu for laboratory assistance. This work was supported in part by the Wellcome Trust, St. Thomas’ Hospital Special Trustees, and the Arthritis and Rheumatism Council. R.W.K was in receipt of an ARC Clinical Research Fellowship (K0504).

References (30)

  • L. Flicker et al.

    Bone density determinants in elderly womenA twin study

    J Bone Miner Res

    (1995)
  • P. Garnero et al.

    Genetic influence on bone turnover in postmenopausal twins

    J Clin Endocrinol Metab

    (1996)
  • S.F. Grant et al.

    Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene

    Nature Genet

    (1996)
  • R. Gueguen et al.

    Segregation analysis and variance components analysis of bone mineral density in healthy families

    J Bone Miner Res

    (1995)
  • D.J. Hart et al.

    The relationship of obesity, fat distribution and osteoarthritis in the general populationThe Chingford Study

    J Rheumatol

    (1993)
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