• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of gutGutCurrent TOCInstructions to authors
Gut. Nov 2001; 49(5): 644–649.
PMCID: PMC1728500

Allelic variation at the interleukin 1β gene is associated with decreased bone mass in patients with inflammatory bowel diseases

Abstract

BACKGROUND—Interleukin 1β (IL-1β) and its natural antagonist have been implicated in the pathogenesis of inflammatory bowel disease (IBD). Both cytokines influence bone formation. IL-1β stimulates osteoclast activity while interleukin 1 receptor antagonist (IL-1ra) enhances bone formation.
AIMS—To determine whether the decreased bone mass in IBD is related to gene polymorphisms coding for IL-1β and IL-1ra, and thus identify patients with an increased risk.
METHODS—Bone mineral densitometry was performed at the femoral neck, lumbar spine, and the distal third of the radius in 75 IBD patients (34 men/41 women; 40.3 (1.6) years) and in 58 healthy controls (HC; 28 men/30 women; 32.4 (1.2) years). Values were correlated with the TaqI and AvaI gene polymorphisms in the IL1B and the variable number of tandem repeats gene polymorphism in the IL1RN gene.
RESULTS—In IBD patients, but not in HC, carriers of allele 2 at the AvaI gene polymorphism (IL1B-511*2) had significantly lower Z scores at the lumbar spine (−0.82 (0.13) v −0.29 (0.21) p=0.03) and the femoral neck (−0.59 (0.14) v 0.15 (0.19); p=0.003) than non-carriers. These patients also had a higher risk for osteopenia or osteoporosis at the femoral neck (odds ratio 3.63 (95% confidence interval 0.95-13.93)). No association was found between bone mass and the other gene polymorphisms analysed in IBD patients or in HC.
CONCLUSIONS—Our results suggest that genetic variability may be a major determinant of bone loss in IBD. Carriers of IL1B-511*2, who are hypersecretors of IL-1β, have a higher risk of presenting with low bone mass in IBD. Screening for this allele may contribute to determination of the risk of bone loss at the time of disease onset.


Keywords: inflammatory bowel diseases; ulcerative colitis; Crohn's disease; osteoporosis; bone density; genetic polymorphisms; interleukin 1

Full Text

The Full Text of this article is available as a PDF (153K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Compston JE, Judd D, Crawley EO, Evans WD, Evans C, Church HA, Reid EM, Rhodes J. Osteoporosis in patients with inflammatory bowel disease. Gut. 1987 Apr;28(4):410–415. [PMC free article] [PubMed]
  • Pfeilschifter J, Chenu C, Bird A, Mundy GR, Roodman GD. Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro. J Bone Miner Res. 1989 Feb;4(1):113–118. [PubMed]
  • Smith DD, Gowen M, Mundy GR. Effects of interferon-gamma and other cytokines on collagen synthesis in fetal rat bone cultures. Endocrinology. 1987 Jun;120(6):2494–2499. [PubMed]
  • Kimble RB, Matayoshi AB, Vannice JL, Kung VT, Williams C, Pacifici R. Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period. Endocrinology. 1995 Jul;136(7):3054–3061. [PubMed]
  • Salamone LM, Whiteside T, Friberg D, Epstein RS, Kuller LH, Cauley JA. Cytokine production and bone mineral density at the lumbar spine and femoral neck in premenopausal women. Calcif Tissue Int. 1998 Dec;63(6):466–470. [PubMed]
  • Pacifici R, Rifas L, Teitelbaum S, Slatopolsky E, McCracken R, Bergfeld M, Lee W, Avioli LV, Peck WA. Spontaneous release of interleukin 1 from human blood monocytes reflects bone formation in idiopathic osteoporosis. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4616–4620. [PMC free article] [PubMed]
  • Nakamura M, Saito H, Kasanuki J, Tamura Y, Yoshida S. Cytokine production in patients with inflammatory bowel disease. Gut. 1992 Jul;33(7):933–937. [PMC free article] [PubMed]
  • Casini-Raggi V, Kam L, Chong YJ, Fiocchi C, Pizarro TT, Cominelli F. Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation. J Immunol. 1995 Mar 1;154(5):2434–2440. [PubMed]
  • Hyams JS, Fitzgerald JE, Wyzga N, Muller R, Treem WR, Justinich CJ, Kreutzer DL. Relationship of interleukin-1 receptor antagonist to mucosal inflammation in inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1995 Nov;21(4):419–425. [PubMed]
  • Reimund JM, Wittersheim C, Dumont S, Muller CD, Baumann R, Poindron P, Duclos B. Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn's disease. J Clin Immunol. 1996 May;16(3):144–150. [PubMed]
  • Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas M, Forgacs I, Moniz C. Reduced bone density in patients with inflammatory bowel disease. Gut. 1997 Feb;40(2):228–233. [PMC free article] [PubMed]
  • Evans RA, Marel GM, Lancaster EK, Kos S, Evans M, Wong SY. Bone mass is low in relatives of osteoporotic patients. Ann Intern Med. 1988 Dec 1;109(11):870–873. [PubMed]
  • Young D, Hopper JL, Nowson CA, Green RM, Sherwin AJ, Kaymakci B, Smid M, Guest CS, Larkins RG, Wark JD. Determinants of bone mass in 10- to 26-year-old females: a twin study. J Bone Miner Res. 1995 Apr;10(4):558–567. [PubMed]
  • Cummings SR, Cauley JA, Palermo L, Ross PD, Wasnich RD, Black D, Faulkner KG. Racial differences in hip axis lengths might explain racial differences in rates of hip fracture. Study of Osteoporotic Fractures Research Group. Osteoporos Int. 1994 Jul;4(4):226–229. [PubMed]
  • Kelly PJ, Hopper JL, Macaskill GT, Pocock NA, Sambrook PN, Eisman JA. Genetic factors in bone turnover. J Clin Endocrinol Metab. 1991 Apr;72(4):808–813. [PubMed]
  • Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA. Prediction of bone density from vitamin D receptor alleles. Nature. 1994 Jan 20;367(6460):284–287. [PubMed]
  • Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M, Orimo H. Association of bone mineral density with polymorphism of the estrogen receptor gene. J Bone Miner Res. 1996 Mar;11(3):306–311. [PubMed]
  • Langdahl BL, Knudsen JY, Jensen HK, Gregersen N, Eriksen EF. A sequence variation: 713-8delC in the transforming growth factor-beta 1 gene has higher prevalence in osteoporotic women than in normal women and is associated with very low bone mass in osteoporotic women and increased bone turnover in both osteoporotic and normal women. Bone. 1997 Mar;20(3):289–294. [PubMed]
  • Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet. 1996 Oct;14(2):203–205. [PubMed]
  • Cooper GS, Umbach DM. Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis. J Bone Miner Res. 1996 Dec;11(12):1841–1849. [PubMed]
  • Han KO, Moon IG, Kang YS, Chung HY, Min HK, Han IK. Nonassociation of estrogen receptor genotypes with bone mineral density and estrogen responsiveness to hormone replacement therapy in Korean postmenopausal women. J Clin Endocrinol Metab. 1997 Apr;82(4):991–995. [PubMed]
  • Keen RW, Woodford-Richens KL, Lanchbury JS, Spector TD. Allelic variation at the interleukin-1 receptor antagonist gene is associated with early postmenopausal bone loss at the spine. Bone. 1998 Oct;23(4):367–371. [PubMed]
  • Cox A, Camp NJ, Cannings C, di Giovine FS, Dale M, Worthington J, John S, Ollier WE, Silman AJ, Duff GW. Combined sib-TDT and TDT provide evidence for linkage of the interleukin-1 gene cluster to erosive rheumatoid arthritis. Hum Mol Genet. 1999 Sep;8(9):1707–1713. [PubMed]
  • Danis VA, Millington M, Hyland VJ, Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol. 1995 Feb;99(2):303–310. [PMC free article] [PubMed]
  • Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol. 1998 Mar;47(3):195–198. [PubMed]
  • Hurme M, Santtila S. IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunol. 1998 Aug;28(8):2598–2602. [PubMed]
  • Nemetz A, Nosti-Escanilla MP, Molnár T, Köpe A, Kovács A, Fehér J, Tulassay Z, Nagy F, García-González MA, Peña AS. IL1B gene polymorphisms influence the course and severity of inflammatory bowel disease. Immunogenetics. 1999 Jun;49(6):527–531. [PubMed]
  • Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:2–19. [PubMed]
  • Gasche C, Scholmerich J, Brynskov J, D'Haens G, Hanauer SB, Irvine EJ, Jewell DP, Rachmilewitz D, Sachar DB, Sandborn WJ, et al. A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis. 2000 Feb;6(1):8–15. [PubMed]
  • di Giovine FS, Takhsh E, Blakemore AI, Duff GW. Single base polymorphism at -511 in the human interleukin-1 beta gene (IL1 beta). Hum Mol Genet. 1992 Sep;1(6):450–450. [PubMed]
  • Pociot F, Mølvig J, Wogensen L, Worsaae H, Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest. 1992 Jun;22(6):396–402. [PubMed]
  • Bioque G, Crusius JB, Koutroubakis I, Bouma G, Kostense PJ, Meuwissen SG, Peña AS. Allelic polymorphism in IL-1 beta and IL-1 receptor antagonist (IL-1Ra) genes in inflammatory bowel disease. Clin Exp Immunol. 1995 Nov;102(2):379–383. [PMC free article] [PubMed]
  • Nemetz A, Köpe A, Molnár T, Kovács A, Fehér J, Tulassay Z, Nagy F, García-González MA, Peña AS. Significant differences in the interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in a Hungarian population with inflammatory bowel disease. Scand J Gastroenterol. 1999 Feb;34(2):175–179. [PubMed]
  • Silvennoinen JA, Karttunen TJ, Niemelä SE, Manelius JJ, Lehtola JK. A controlled study of bone mineral density in patients with inflammatory bowel disease. Gut. 1995 Jul;37(1):71–76. [PMC free article] [PubMed]
  • Jahnsen J, Falch JA, Aadland E, Mowinckel P. Bone mineral density is reduced in patients with Crohn's disease but not in patients with ulcerative colitis: a population based study. Gut. 1997 Mar;40(3):313–319. [PMC free article] [PubMed]
  • Pollak RD, Karmeli F, Eliakim R, Ackerman Z, Tabb K, Rachmilewitz D. Femoral neck osteopenia in patients with inflammatory bowel disease. Am J Gastroenterol. 1998 Sep;93(9):1483–1490. [PubMed]
  • Silvennoinen J, Risteli L, Karttunen T, Risteli J. Increased degradation of type I collagen in patients with inflammatory bowel disease. Gut. 1996 Feb;38(2):223–228. [PMC free article] [PubMed]
  • Tibble JA, Sigthorsson G, Bridger S, Fagerhol MK, Bjarnason I. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology. 2000 Jul;119(1):15–22. [PubMed]
  • Kornman KS, Crane A, Wang HY, di Giovine FS, Newman MG, Pirk FW, Wilson TG, Jr, Higginbottom FL, Duff GW. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol. 1997 Jan;24(1):72–77. [PubMed]
  • Gore EA, Sanders JJ, Pandey JP, Palesch Y, Galbraith GM. Interleukin-1beta+3953 allele 2: association with disease status in adult periodontitis. J Clin Periodontol. 1998 Oct;25(10):781–785. [PubMed]
  • Loughrey BV, Maxwell AP, Fogarty DG, Middleton D, Harron JC, Patterson CC, Darke C, Savage DA. An interluekin 1B allele, which correlates with a high secretor phenotype, is associated with diabetic nephropathy. Cytokine. 1998 Dec;10(12):984–988. [PubMed]
  • Katila H, Hänninen K, Hurme M. Polymorphisms of the interleukin-1 gene complex in schizophrenia. Mol Psychiatry. 1999 Mar;4(2):179–181. [PubMed]
  • El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000 Mar 23;404(6776):398–402. [PubMed]
  • Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. 1994 Oct 20;331(16):1056–1061. [PubMed]
  • Lorenzo JA, Naprta A, Rao Y, Alander C, Glaccum M, Widmer M, Gronowicz G, Kalinowski J, Pilbeam CC. Mice lacking the type I interleukin-1 receptor do not lose bone mass after ovariectomy. Endocrinology. 1998 Jun;139(6):3022–3025. [PubMed]
  • Sunyer T, Lewis J, Collin-Osdoby P, Osdoby P. Estrogen's bone-protective effects may involve differential IL-1 receptor regulation in human osteoclast-like cells. J Clin Invest. 1999 May 15;103(10):1409–1418. [PMC free article] [PubMed]
  • Ghosh S, Cowen S, Hannan WJ, Ferguson A. Low bone mineral density in Crohn's disease, but not in ulcerative colitis, at diagnosis. Gastroenterology. 1994 Oct;107(4):1031–1039. [PubMed]
  • Schulte CM, Dignass AU, Goebell H, Röher HD, Schulte KM. Genetic factors determine extent of bone loss in inflammatory bowel disease. Gastroenterology. 2000 Oct;119(4):909–920. [PubMed]

Articles from Gut are provided here courtesy of BMJ Group

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...