ASSOCIATION OF INTERLEUKIN-1β GENE POLYMORPHISM WITH POSTMENOPAUSAL OSTEOPOROSIS IN WOMEN IN THE RUSSIAN POPULATION

Interleukin-1β (IL-1β) is a potential stimulant of bone resorption. IL-1β receptor antagonist (IL-1RA) is a natural inhibitor of the biological effects of IL-1β.

Objective: to study the frequency distribution of polymorphisms in the IL-1β and IL-1RA genes and their association with bone mineral density (BMD) in women with primary osteoporosis (OP).

Subjects and methods. The distribution of genotype frequency of IL-1β (-511C/T) polymorphism and that of IL-1RA 511C/T polymorphism that is associated with the number of variable tandem repeats (VTR), were investigated in 254 women with OP and 214 healthy women.

Results and discussion. IL-1β (-511C/T) genotype carriers were encountered somewhat more frequently among the patients with OP (53.0%) than in the control group (43.4%); however, the differences were insignificant. In these carriers, the risk of OP was 1.5-fold higher than that in those of other genotypes (odds ratio, 1.49; confidence interval, 1.02–2.18; p = 0.041). The patients who were IL-1β T allele (CT- and TT-genotype) carriers had a significantly lower spine (LI–IV) BMD than those who had not this allele (CC-genotype; p = 0.011). The patients and the controls showed no differences in the frequency distribution of IL-1RA gene polymorphism associated with the number of VTR. In the OP group, the carriers of the rare genotype A1A3 in the IL-1RA gene (3.1%) had significantly higher femoral neck BMD (0.698±0.064 g/cm2) than those of the А1А1, А1А2 and А2А2 genotypes (0.613±0.078; 0.607±0.082. and 0.615±0.064 g/cm2; р = 0.003, р = 0.003, and р = 0.002, respectively).

Conclusion. IL-1β (-511C/T) polymorphism is associated with lower spine BMD and IL-1RA A1A3 genotype polymorphism is related to higher femoral neck BMD.

1. World Health Organization Study Group. Assessment of fracture risk and its application for screening, for postmenopausal osteoporosis. Geneva: WHO; 1994.

2. Rosen CJ, Beamer WG, Donahue LR, et al. Defining the genetics of osteoporosis: Using the mouse to understand man. Osteoporosis Int. 2001;12:803–10. doi: 10.1007/s001980170030

3. Untterlinden AG, van Meurs JB, Rivadeneira F, et al. Identifying genetic risk factors for osteoporosis. J Musculoskelet Neuronal Interact. 2006;6:16–26.

4. Ralston SH, de Crombrugghe B. Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev. 2006;20:2492–506. doi: 10.1101/gad.1449506

5. Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature. 1993;362:801–9. doi: 10.1038/362801a0

6. Romas E, Martin TJ. Cytokines in the pathogenesis of osteoporosis. Osteoporos Int. 1997;7:S47–3. doi: 10.1007/BF03194342

7. Kim JG, Ku SY, Lim KS, et al. Cytokine production by whole blood cells: Relationship to interleukin gene polymorphism and bone mass. J Korean Med Sci. 2005;20:1017–22. doi: 10.3346/jkms.2005.20.6.1017

8. Al Moundhri MS, Al Nabhani M, Al Bahrani B, et al. Interleukin-1beta gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms and gastric cancer risk in an Omani Arab population. Gastric Cancer. 2006;9:284–90. doi: 10.1007/s10120-006-0392-5

9. Tarlow JK, Blakemore AI, Lennard A, et al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet. 1993;91:403–4. doi: 10.1007/BF00217368

10. Bajnok E, Takacs I, Vargha P, et al. Lack of association between interleukin-1 receptor antagonist protein gene polymorphism and bone mineral density in Hungarian postmenopausal women. Bone. 2000;27:559–62. doi: 10.1016/S8756-3282(00)00360-4

11. Langdahl BL, Lokke E, Carsyens M, et al. Osteoporotic fractures are associated with an 86-base pair repeat polymorphism in the interleukin-1-receptor antagonist gene but not with polymorphism in the interleukin-1 gene. J Bone Miner Res. 2000;15: 402–14. doi: 10.1359/jbmr.2000.15.3.402

12. Chen HY, Chen WC, Wu MC, et al. Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphism in postmenopausal women: Correlation to bone mineral density and susceptibility to osteoporosis. Maturitas. 2003;44:49–54. doi: 10.1016/S0378-5122(02)00313-4

13. Nemetz A, Toth M, Garcia-Gonzalez MA, et al. Allelic variation at the interleukin 1beta gene is associated with decreased bone mass in patients with inflammatory bowel diseases. Gut. 2001;49:644–9. doi: 10.1136/gut.49.5.644

14. Miller SA, Dykes DD, Polesky HF A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res.1988;16:12–5. doi: 10.1093/nar/16.3.1215

15. Hustmyer FG, Wallker E, Yu XP, et al. Cytokine production and surface antigen expression by peripheral blood mononuclear cells in postmenopausal osteoporosis. J Bone Miner Res. 1993;8:51–9. doi: 10.1002/jbmr.5650080108

16. Ivanova JT, Boyanov MA, Tochev AK Polymorphisms of the human IL-1 receptor antagonist gene and forearm bone mineral density in postmenopausal women. Ind J Endocrinol Metab. 2012;16(4):580–6.