Advertisement

International Orthopaedics

, Volume 39, Issue 4, pp 793–798 | Cite as

Association of TGFB1 29C/T and IL6 -572G/C polymorphisms with developmental hip dysplasia: a case–control study in adults with severe osteoarthritis

  • Tomislav ČengićEmail author
  • Vladimir Trkulja
  • Sandra Kraljević Pavelić
  • Ivana Ratkaj
  • Elitza Markova-Car
  • Michele Mikolaučić
  • Robert KolundžićEmail author
Original Paper

Abstract

Purpose

Developmental dysplasia of the hip (DDH) increases the risk of severe adult hip osteoarthritis (OA). Transforming growth factor-β1 (TGF-beta1) and interleukin-6 (IL-6) are included in pathogenesis of OA, as well as in development of the musculoskeletal system. We investigated the association of single nucleotide polymorphisms (SNPs) known to reflect on the circulating levels of the two cytokines, specifically, 29 T → C transition in the TGFB1 signal sequence (rs1800470) and -572G → C transversion in the IL6 promoter (rs1800796), with DDH.

Methods

We conducted a case–control study in consecutive unrelated adults with severe hip OA scheduled for total hip arthroplasty. Cases, patients with OA secondary to DDH (n = 68) and controls, patients with OA unrelated to DDH (n = 152) were genotyped at the two loci.

Results

With adjustment for age, sex and genotype at the concurrent locus, cases were more likely (OR = 2.42, 95%CI 1.08–5.43; p = 0.032) to be transition homozygous at TGFB1 locus 29, and also more likely (OR = 6.36, 95%CI 2.57–15.7; p < 0.001) to be transversion homozygous at IL6 locus −572 than controls. Cases were also more likely (OR = 11.3, 95%CI 4.25–29.8; p < 0.001) than controls to carry one of the three genotypes combining transition/transversion homozygosity at both loci, or transition/transversion homozygosity at one and heterozygosity at the concurrent locus.

Conclusions

Data suggest association between TGFB1 29 T → C transition (rs1800470) and IL6 -572G → C transversion (rs1800796) with DDH, and also a possibility of TGF-beta1 and IL-6 interaction in DDH pathogenesis.

Keywords

Developmental dysplasia of the hip Hip osteoarthritis TGFB1 IL6 Single nucleotide polymorphisms 

Notes

Acknowledgments

This work has been supported by the Ministry of Education, Science and Sports of Croatia grants 335-0000000-3532 and 098-0000000-3530. The authors are grateful to Krešimir Crnogaća, MD, for assistance in X-ray analysis.

Conflict of interest

The authors declare that they have no conflict of interest.

Authors’ contributions

RK, VT and SKP conceived the study; RK, TC, SKP and VT defined the study protocol; RK, TC and MM recruited the patients and collected blood samples; SKP, IR, EMC performed genotyping; VT analysed the data; TC, VT, SKP and RK drafted the manuscript. All authors edited and approved the final version of the manuscript. RK coordinated and overlooked the entire project.

Ethics

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All patients gave an informed consent and the study was approved by the Local Ethics Committee (EP 7426/14-16).

References

  1. 1.
    Dezateux C, Rosendahl K (2007) Developmental dysplasia of the hip. Lancet 369:1541–1552CrossRefPubMedGoogle Scholar
  2. 2.
    Harris-Hayes M, Royer NK (2011) Relationship of acetabular dysplasia and femoroacetabular impingement to hip osteoarthritis: a focused review. PM R 3:1055–1067CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Shi D, Dai J, Ikegawa S, Jiang Q (2012) Genetic study on developmental dysplasia of the hip (review). Eur J Clin Investig 42:1121–1125CrossRefGoogle Scholar
  4. 4.
    Sandell LJ (2012) Etiology of osteoarthritis: genetics and synovial joint development (review). Nat Rev Rheumatol 8:77–89CrossRefPubMedGoogle Scholar
  5. 5.
    Hochberg MC, Yerges-Armstrong L, Yau M, Mitchell BD (2013) Genetic epidemiology of osteoarthritis: recent developments and future directions. Curr Opin Rheumatol 25:192–197CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Malemud CJ (2010) Anticytokine therapy for osteoarthritis: evidence to date. Drugs Aging 27:95–115CrossRefPubMedGoogle Scholar
  7. 7.
    Roelen BA, Dijke P (2003) Controlling mesenchymal stem cell differentiation by TGFBeta family members. J Orthop Sci 8:740–748CrossRefPubMedGoogle Scholar
  8. 8.
    Lieskovska J, Guo D, Derman E (2002) IL-6-overexpression brings about growth impairment potentially through a GH receptor defect. Growth Hormon IGF Res 12:388–398CrossRefGoogle Scholar
  9. 9.
    Kolundžić R, Trkulja V, Mikolaučić M, Jovanić Kolundžić M, Kraljević Pavelić S et al (2011) Association of interleukin-6 and transforming growth factor-β1 gene polymorphisms with developmental hip dysplasia and severe adult hip osteoarthritis: a preliminary report. Cytokine 54:125–128CrossRefPubMedGoogle Scholar
  10. 10.
    Gaunt TR, Rodriguez S, Day INM (2007) Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool “CubeX”. BMC Informatics 8:428. doi: 10.1186/1471-2105-8-428 CrossRefGoogle Scholar
  11. 11.
    Loder RT, Skopelja EN (2011) The epidemiology and demographics of hip dysplasia. ISRN Orthop 1–46Google Scholar
  12. 12.
    Hinke V, Seck T, Clanget C, Scheidt-Nave C, Ziegler R, Pfeilschifter J (2001) Association of transforming growth factor-beta1 (TGFbeta1) T29 – > C gene polymorphism with bone mineral density (BMD), changes in BMD, and serum concentrations of TGF-beta1 in a population-based sample of postmenopausal German women. Calcif Tissue Int 69:315–320CrossRefPubMedGoogle Scholar
  13. 13.
    Tzakas P, Wong BYL, Logan AG, Rubin LA, Cole DEC (2005) Transforming growth factor beta-1 (TGFβ-1) and peak bone mass: association between intragenic polymorphisms and quantitative ultrasound of the heel. BMC Musculoskelet Disord 6:29CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Koludžić R, Orlić D, Trkulja V, Pavelić K, Gall-Trošelj K (2006) Single nucleotide polymorphisms in the interleukin-6 gene promoter, tumor necrosis factor-α promoter, and transforming growth factor β1 gene signal sequence as predictors of time to onset of aseptic loosening after total hip arthroplasty: preliminary study. J Orthop Sci 11:592–600CrossRefGoogle Scholar
  15. 15.
    Qiu LX, Yao L, Mao C, Chen B, Zhan P, Xue K et al (2010) TGFB1 L10P polymorphism is associated with breast cancer susceptibility: evidence from a meta-analysis involving 47817 subjects. Breast Cancer Res Treat 123:563–567CrossRefPubMedGoogle Scholar
  16. 16.
    Huang Y, Li B, Qian J, Xie J, Yu L (2010) TGF-beta 1 29 T/C polymorphism and breast cancer risk: a meta-analysis involving 25996 subjects. Breast Cancer Res Treat 123:863–868CrossRefPubMedGoogle Scholar
  17. 17.
    Morris DR, Moxon JV, Biros E, Krishna S, Golledge J (2012) Meta-analysis of the association between transforming growth factor-beta polymorphisms and complications of coronary heart disease. PLosONE 7(5):e37878. doi: 10.1371/journal.pone.0037878 CrossRefGoogle Scholar
  18. 18.
    Terry CF, Loukaci V, Green FR (2000) Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 275:18138–18144CrossRefPubMedGoogle Scholar
  19. 19.
    Drull DJ, Montgomery HE, Sanders J, Dhamrait S, Luong L, Rumley A et al (2001) Interleukin-6 gene –174 g > c and –572 g > c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol 21:1458–1463CrossRefGoogle Scholar
  20. 20.
    Yin YW, Sun QQ, Zhang BB, Hu AM, Wang Q, Heng YH et al (2013) Association between the interleukin-6 gene −572 C/G polymorphism and the risk of type 2 diabetes mellitus: a meta-analysis of 11681 subjects. Ann Hum Genet 77:106–114CrossRefPubMedGoogle Scholar
  21. 21.
    Balding DJ (2006) A tutorial on statistical methods for population association studies. Nat Rev Genet 7:781–791CrossRefPubMedGoogle Scholar
  22. 22.
    Nielsen DM, Ehm MG, Weir BS (1999) Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 63:1531–1540CrossRefGoogle Scholar
  23. 23.
    Ioannidis JP, Boffetta P, Little J, O’Brien TR, Uitterlinden AG, Vineis P et al (2008) Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol 37:120–132CrossRefPubMedGoogle Scholar

Copyright information

© SICOT aisbl 2015

Authors and Affiliations

  • Tomislav Čengić
    • 1
    Email author
  • Vladimir Trkulja
    • 2
  • Sandra Kraljević Pavelić
    • 3
  • Ivana Ratkaj
    • 3
  • Elitza Markova-Car
    • 3
  • Michele Mikolaučić
    • 4
  • Robert Kolundžić
    • 1
    • 3
    Email author
  1. 1.Department of TraumatologyUniversity Hospital Centre Sestre milosrdniceZagrebCroatia
  2. 2.Department of PharmacologyZagreb University School of MedicineZagrebCroatia
  3. 3.Department of BiotechnologyUniversity of RijekaRijekaCroatia
  4. 4.Department of OrthopaedicsGeneral Hospital DubrovnikDubrovnikCroatia

Personalised recommendations