Skip to main content
PMC home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2004 May;63(5):544–548. doi: 10.1136/ard.2003.010751

Insulin-like growth factor I gene promoter polymorphism, collagen type II α1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam Study

G Zhai 1, F Rivadeneira 1, J Houwing-Duisterma 1, I Meulenbelt 1, C Bijkerk 1, A Hofman 1, J B J van Meurs 1, A Uitterlinden 1, H Pols 1, P Slagboom 1, C M van Duijn 1
PMCID: PMC1754973  PMID: 15082485

Abstract

Objective: To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene.

Methods: Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested.

Results: Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years.

Conclusions: Subjects with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested.

Full Text

The Full Text of this article is available as a PDF (314.2 KB).

Figure 1 .

Figure 1

Open in a new tab

Interaction between the IGF-I and COL2A1 genes in the occurrence of radiographic osteoarthritis (ROA). Risk estimates adjusted for age, sex, body mass index, and bone mineral density. *Total number by genotype and percentage of subjects with ROA. bp, base pair; CI, confidence interval; OA, osteoarthritis.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berg E. S., Olaisen B. Characterization of the COL2A1 VNTR polymorphism. Genomics. 1993 May;16(2):350–354. doi: 10.1006/geno.1993.1196. [DOI] [PubMed] [Google Scholar]
  2. Bijkerk C., Houwing-Duistermaat J. J., Valkenburg H. A., Meulenbelt I., Hofman A., Breedveld F. C., Pols H. A., van Duijn C. M., Slagboom P. E. Heritabilities of radiologic osteoarthritis in peripheral joints and of disc degeneration of the spine. Arthritis Rheum. 1999 Aug;42(8):1729–1735. doi: 10.1002/1529-0131(199908)42:8<1729::AID-ANR23>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  3. Burger H., van Daele P. L., Algra D., van den Ouweland F. A., Grobbee D. E., Hofman A., van Kuijk C., Schütte H. E., Birkenhäger J. C., Pols H. A. The association between age and bone mineral density in men and women aged 55 years and over: the Rotterdam Study. Bone Miner. 1994 Apr;25(1):1–13. doi: 10.1016/s0169-6009(08)80203-6. [DOI] [PubMed] [Google Scholar]
  4. Chapman K., Mustafa Z., Irven C., Carr A. J., Clipsham K., Smith A., Chitnavis J., Sinsheimer J. S., Bloomfield V. A., McCartney M. Osteoarthritis-susceptibility locus on chromosome 11q, detected by linkage. Am J Hum Genet. 1999 Jul;65(1):167–174. doi: 10.1086/302465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Corpas E., Harman S. M., Blackman M. R. Human growth hormone and human aging. Endocr Rev. 1993 Feb;14(1):20–39. doi: 10.1210/edrv-14-1-20. [DOI] [PubMed] [Google Scholar]
  6. Denko C. W., Boja B., Moskowitz R. W. Growth promoting peptides in osteoarthritis: insulin, insulin-like growth factor-1, growth hormone. J Rheumatol. 1990 Sep;17(9):1217–1221. [PubMed] [Google Scholar]
  7. Felson D. T., Couropmitree N. N., Chaisson C. E., Hannan M. T., Zhang Y., McAlindon T. E., LaValley M., Levy D., Myers R. H. Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis: the Framingham Study. Arthritis Rheum. 1998 Jun;41(6):1064–1071. doi: 10.1002/1529-0131(199806)41:6<1064::AID-ART13>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  8. Felson D. T., Lawrence R. C., Dieppe P. A., Hirsch R., Helmick C. G., Jordan J. M., Kington R. S., Lane N. E., Nevitt M. C., Zhang Y. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann Intern Med. 2000 Oct 17;133(8):635–646. doi: 10.7326/0003-4819-133-8-200010170-00016. [DOI] [PubMed] [Google Scholar]
  9. Hirsch R., Lethbridge-Cejku M., Hanson R., Scott W. W., Jr, Reichle R., Plato C. C., Tobin J. D., Hochberg M. C. Familial aggregation of osteoarthritis: data from the Baltimore Longitudinal Study on Aging. Arthritis Rheum. 1998 Jul;41(7):1227–1232. doi: 10.1002/1529-0131(199807)41:7<1227::AID-ART13>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  10. Hochberg M. C., Lethbridge-Cejku M., Scott W. W., Jr, Reichle R., Plato C. C., Tobin J. D. Serum levels of insulin-like growth factor in subjects with osteoarthritis of the knee. Data from the Baltimore Longitudinal Study of Aging. Arthritis Rheum. 1994 Aug;37(8):1177–1180. doi: 10.1002/art.1780370811. [DOI] [PubMed] [Google Scholar]
  11. Hofman A., Grobbee D. E., de Jong P. T., van den Ouweland F. A. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol. 1991 Jul;7(4):403–422. doi: 10.1007/BF00145007. [DOI] [PubMed] [Google Scholar]
  12. Hottenga J. J., Houwing-Duistermaat J. J., van Duijn C. M. Dwalingen in de methodologie. XXXVII. Onbedoelde populatieselectie in het genetische patiënt-controleonderzoek. Ned Tijdschr Geneeskd. 2002 Jan 5;146(1):17–22. [PubMed] [Google Scholar]
  13. Howell D. S. Pathogenesis of osteoarthritis. Am J Med. 1986 Apr 28;80(4B):24–28. doi: 10.1016/0002-9343(86)90075-6. [DOI] [PubMed] [Google Scholar]
  14. KELLGREN J. H., LAWRENCE J. S., BIER F. GENETIC FACTORS IN GENERALIZED OSTEO-ARTHROSIS. Ann Rheum Dis. 1963 Jul;22:237–255. doi: 10.1136/ard.22.4.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Knowler W. C., Williams R. C., Pettitt D. J., Steinberg A. G. Gm3;5,13,14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture. Am J Hum Genet. 1988 Oct;43(4):520–526. [PMC free article] [PubMed] [Google Scholar]
  16. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  17. Leppävuori J., Kujala U., Kinnunen J., Kaprio J., Nissilä M., Heliövaara M., Klinger N., Partanen J., Terwilliger J. D., Peltonen L. Genome scan for predisposing loci for distal interphalangeal joint osteoarthritis: evidence for a locus on 2q. Am J Hum Genet. 1999 Oct;65(4):1060–1067. doi: 10.1086/302569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lloyd M. E., Hart D. J., Nandra D., McAlindon T. E., Wheeler M., Doyle D. V., Spector T. D. Relation between insulin-like growth factor-I concentrations, osteoarthritis, bone density, and fractures in the general population: the Chingford study. Ann Rheum Dis. 1996 Dec;55(12):870–874. doi: 10.1136/ard.55.12.870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Loeser R. F., Shanker G., Carlson C. S., Gardin J. F., Shelton B. J., Sonntag W. E. Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis: studies in a non-human primate model of naturally occurring disease. Arthritis Rheum. 2000 Sep;43(9):2110–2120. doi: 10.1002/1529-0131(200009)43:9<2110::AID-ANR23>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  20. Loughlin J. Genetic epidemiology of primary osteoarthritis. Curr Opin Rheumatol. 2001 Mar;13(2):111–116. doi: 10.1097/00002281-200103000-00004. [DOI] [PubMed] [Google Scholar]
  21. Loughlin J., Irven C., Fergusson C., Sykes B. Sibling pair analysis shows no linkage of generalized osteoarthritis to the loci encoding type II collagen, cartilage link protein or cartilage matrix protein. Br J Rheumatol. 1994 Dec;33(12):1103–1106. doi: 10.1093/rheumatology/33.12.1103. [DOI] [PubMed] [Google Scholar]
  22. Loughlin J., Mustafa Z., Irven C., Smith A., Carr A. J., Sykes B., Chapman K. Stratification analysis of an osteoarthritis genome screen-suggestive linkage to chromosomes 4, 6, and 16. Am J Hum Genet. 1999 Dec;65(6):1795–1798. doi: 10.1086/302685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. MacGregor A. J., Antoniades L., Matson M., Andrew T., Spector T. D. The genetic contribution to radiographic hip osteoarthritis in women: results of a classic twin study. Arthritis Rheum. 2000 Nov;43(11):2410–2416. doi: 10.1002/1529-0131(200011)43:11<2410::AID-ANR6>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  24. McAlindon T. E., Teale J. D., Dieppe P. A. Levels of insulin related growth factor 1 in osteoarthritis of the knee. Ann Rheum Dis. 1993 Mar;52(3):229–231. doi: 10.1136/ard.52.3.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Meulenbelt I., Bijkerk C., Miedema H. S., Breedveld F. C., Hofman A., Valkenburg H. A., Pols H. A., Slagboom P. E., van Duijn C. M. A genetic association study of the IGF-1 gene and radiological osteoarthritis in a population-based cohort study (the Rotterdam Study). Ann Rheum Dis. 1998 Jun;57(6):371–374. doi: 10.1136/ard.57.6.371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Osborn K. D., Trippel S. B., Mankin H. J. Growth factor stimulation of adult articular cartilage. J Orthop Res. 1989;7(1):35–42. doi: 10.1002/jor.1100070106. [DOI] [PubMed] [Google Scholar]
  27. Schneiderman R., Rosenberg N., Hiss J., Lee P., Liu F., Hintz R. L., Maroudas A. Concentration and size distribution of insulin-like growth factor-I in human normal and osteoarthritic synovial fluid and cartilage. Arch Biochem Biophys. 1995 Dec 1;324(1):173–188. doi: 10.1006/abbi.1995.9913. [DOI] [PubMed] [Google Scholar]
  28. Spector T. D., Cicuttini F., Baker J., Loughlin J., Hart D. Genetic influences on osteoarthritis in women: a twin study. BMJ. 1996 Apr 13;312(7036):940–943. doi: 10.1136/bmj.312.7036.940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tyler J. A. Insulin-like growth factor 1 can decrease degradation and promote synthesis of proteoglycan in cartilage exposed to cytokines. Biochem J. 1989 Jun 1;260(2):543–548. doi: 10.1042/bj2600543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Uitterlinden A. G., Burger H., van Duijn C. M., Huang Q., Hofman A., Birkenhäger J. C., van Leeuwen J. P., Pols H. A. Adjacent genes, for COL2A1 and the vitamin D receptor, are associated with separate features of radiographic osteoarthritis of the knee. Arthritis Rheum. 2000 Jul;43(7):1456–1464. doi: 10.1002/1529-0131(200007)43:7<1456::AID-ANR7>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  31. Uitterlinden A. G., Huang Q., Pols H. A., van Leeuwen J. P. Population analysis of the collagen type IIalpha1 3' variable number of tandem repeat polymorphism by heteroduplex genotyping. Electrophoresis. 1998 May;19(5):661–666. doi: 10.1002/elps.1150190509. [DOI] [PubMed] [Google Scholar]
  32. Vaessen N., Heutink P., Janssen J. A., Witteman J. C., Testers L., Hofman A., Lamberts S. W., Oostra B. A., Pols H. A., van Duijn C. M. A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes. 2001 Mar;50(3):637–642. doi: 10.2337/diabetes.50.3.637. [DOI] [PubMed] [Google Scholar]
  33. Vikkula M., Nissilä M., Hirvensalo E., Nuotio P., Palotie A., Aho K., Peltonen L. Multiallelic polymorphism of the cartilage collagen gene: no association with osteoarthrosis. Ann Rheum Dis. 1993 Oct;52(10):762–764. doi: 10.1136/ard.52.10.762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Weber J. L., May P. E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet. 1989 Mar;44(3):388–396. [PMC free article] [PubMed] [Google Scholar]
  35. Willis D. H., Jr, Liberti J. P. Post-receptor actions of somatomedin on chondrocyte collagen biosynthesis. Biochim Biophys Acta. 1985 Jan 18;844(1):72–80. doi: 10.1016/0167-4889(85)90236-8. [DOI] [PubMed] [Google Scholar]
  36. Wright G. D., Hughes A. E., Regan M., Doherty M. Association of two loci on chromosome 2q with nodal osteoarthritis. Ann Rheum Dis. 1996 May;55(5):317–319. doi: 10.1136/ard.55.5.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. van Meurs J. B., Arp P. P., Fang Y., Slagboom P. E., Meulenbelt I., van Leeuwen J. P., Pols H. A., Uitterlinden A. G. Detection of sequence variability of the collagen type IIalpha 1 3' variable number of tandem repeat. Electrophoresis. 2000 Nov;21(17):3571–3577. doi: 10.1002/1522-2683(200011)21:17<3571::AID-ELPS3571>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  38. van Saase J. L., van Romunde L. K., Cats A., Vandenbroucke J. P., Valkenburg H. A. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis. 1989 Apr;48(4):271–280. doi: 10.1136/ard.48.4.271. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group

RESOURCES