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01-09-2015 | Original Article

Genetic susceptibility of lumbar degenerative disc disease in young Indian adults

Authors: S. Rajasekaran, Rishi Mugesh Kanna, Natesan Senthil, Muthuraja Raveendran, Veera Ranjani, Kenneth M. C. Cheung, Danny Chan, Patrick Y. P. Kao, Anita Yee, Ajoy Prasad Shetty

Published in: European Spine Journal | Issue 9/2015

Abstract

Purpose

Although the exact mechanisms that lead to degenerative disc disease (DDD) are not well understood, a significant genetic influence has been found. Focusing on DDD that occurs in young adults can be valuable in determining the exact role of genetic predisposition to DDD.

Methods

Patients (<40 years) with lumbar disc degeneration were evaluated with MRI imaging (1.5 Tesla) and genetic association analysis for 58 single nucleotide polymorphism (SNP) of 35 candidate genes was performed. Disc degeneration of individual discs of lumbar spine from L1 to S1 was graded by Pfirrmann’s grading. The subjects were stratified into two groups based on Total Disc Degenerative Score (TDDS). Based on TDDS, the severity of DDD was classified as mild (Group A: TDDS <10) and severe (Group B: TDDS >10).

Results

695 Indian subjects including 308 with mild TDDS and 387 with severe TDDS were studied. The mean age of the patients was 29.6 ± 6.9 years in group A and 31.7 ± 6.1 in group B (p < 0.05). Five of the 35 candidate genes viz., rs1337185 of COL11A (p = 0.02), rs5275 (p = 0.03) and rs5277 (p = 0.05) of COX2, rs7575934 of IL1F5 (p = 0.04), rs3213718 of CALM1 (p = 0.04) and rs162509 of ADAMTS5 (p = 0.04) were found to be significantly associated with severe TDDS.

Conclusion

The study identifies specific SNP associations of five genes in young adults with severe lumbar disc degeneration. These five genes (COL11A1, ADAMTS5, CALM1, IL1F5and COX2) have different functions in the matrix metabolism, intracellular signalling and inflammatory cascade. This shows that disc degeneration is a complex disease with an intricate interplay of multiple genetic polymorphisms.

Adams MA, Roughley PJ (2006) What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976) 31:2151–2161. doi:10.1097/01.brs.0000231761.73859.2c CrossRef

Salminen JJ, Erkintalo MO, Pentti J, Oksanen A, Kormano MJ (1999) Recurrent low back pain and early disc degeneration in the young. Spine (Phila Pa 1976) 24:1316–1321CrossRef

Seki S, Kawaguchi Y, Mori M, Mio F, Chiba K, Mikami Y, Tsunoda T, Kubo T, Toyama Y, Kimura T, Ikegawa S (2006) Association study of COL9A2 with lumbar disc disease in the Japanese population. J Hum Genet 51:1063–1067. doi:10.1007/s10038-006-0062-9 CrossRefPubMed

Solovieva S, Lohiniva J, Leino-Arjas P, Raininko R, Luoma K, Ala-Kokko L, Riihimaki H (2006) Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms. Eur Spine J 15:613–619. doi:10.1007/s00586-005-0988-1 PubMedCentralCrossRefPubMed

Videman T, Saarela J, Kaprio J, Nakki A, Levalahti E, Gill K, Peltonen L, Battie MC (2009) Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing. Arthritis Rheum 60:470–481. doi:10.1002/art.24268 CrossRefPubMed

Videman T, Leppavuori J, Kaprio J, Battie MC, Gibbons LE, Peltonen L, Koskenvuo M (1998) Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine (Phila Pa 1976) 23:2477–2485CrossRef

Jim JJ, Noponen-Hietala N, Cheung KM, Ott J, Karppinen J, Sahraravand A, Luk KD, Yip SP, Sham PC, Song YQ, Leong JC, Cheah KS, Ala-Kokko L, Chan D (2005) The TRP2 allele of COL9A2 is an age-dependent risk factor for the development and severity of intervertebral disc degeneration. Spine (Phila Pa 1976) 30:2735–2742CrossRef

Cheung KM, Chan D, Karppinen J, Chen Y, Jim JJ, Yip SP, Ott J, Wong KK, Sham P, Luk KD, Cheah KS, Leong JC, Song YQ (2006) Association of the Taq I allele in vitamin D receptor with degenerative disc disease and disc bulge in a Chinese population. Spine (Phila Pa 1976) 31:1143–1148. doi:10.1097/01.brs.0000216530.41838.d3 CrossRef

Solovieva S, Kouhia S, Leino-Arjas P, Ala-Kokko L, Luoma K, Raininko R, Saarela J, Riihimaki H (2004) Interleukin 1 polymorphisms and intervertebral disc degeneration. Epidemiology 15:626–633CrossRefPubMed

10.

Karppinen J, Daavittila I, Solovieva S, Kuisma M, Taimela S, Natri A, Haapea M, Korpelainen R, Niinimaki J, Tervonen O, Ala-Kokko L, Mannikko M (2008) Genetic factors are associated with modic changes in endplates of lumbar vertebral bodies. Spine (Phila Pa 1976) 33:1236–1241. doi:10.1097/BRS.0b013e318170fd0e CrossRef

11.

Mio F, Chiba K, Hirose Y, Kawaguchi Y, Mikami Y, Oya T, Mori M, Kamata M, Matsumoto M, Ozaki K, Tanaka T, Takahashi A, Kubo T, Kimura T, Toyama Y, Ikegawa S (2007) A functional polymorphism in COL11A1, which encodes the alpha 1 chain of type XI collagen, is associated with susceptibility to lumbar disc herniation. Am J Hum Genet 81:1271–1277. doi:10.1086/522377 PubMedCentralCrossRefPubMed

12.

Kawaguchi Y, Kanamori M, Ishihara H, Ohmori K, Matsui H, Kimura T (2002) The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Joint Surg Am 84-A:2022–2028PubMed

13.

Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N (2001) Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976) 26:1873–1878CrossRef

14.

Rajasekaran S, Kanna RM, Senthil N, Raveendran M, Cheung KM, Chan D, Subramaniam S, Shetty AP (2013) Phenotype variations affect genetic association studies of degenerative disc disease: conclusions of analysis of genetic association of 58 single nucleotide polymorphisms with highly specific phenotypes for disc degeneration in 332 subjects. Spine J 13:1309–1320. doi:10.1016/j.spinee.2013.05.019 CrossRefPubMed

15.

Boos N, Weissbach S, Rohrbach H, Weiler C, Spratt KF, Nerlich AG (2002) Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science. Spine (Phila Pa 1976) 27:2631–2644. doi:10.1097/01.BRS.0000035304.27153.5B CrossRef

16.

Miller JA, Schmatz C, Schultz AB (1988) Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens. Spine (Phila Pa 1976) 13:173–178CrossRef

17.

Kelempisioti A, Eskola PJ, Okuloff A, Karjalainen U, Takatalo J, Daavittila I, Niinimaki J, Sequeiros RB, Tervonen O, Solovieva S, Kao PY, Song YQ, Cheung KM, Chan D, Ala-Kokko L, Jarvelin MR, Karppinen J, Mannikko M (2011) Genetic susceptibility of intervertebral disc degeneration among young Finnish adults. BMC Med Genet 12:153. doi:10.1186/1471-2350-12-153 PubMedCentralCrossRefPubMed

18.

Mototani H, Mabuchi A, Saito S, Fujioka M, Iida A, Takatori Y, Kotani A, Kubo T, Nakamura K, Sekine A, Murakami Y, Tsunoda T, Notoya K, Nakamura Y, Ikegawa S (2005) A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese. Hum Mol Genet 14:1009–1017. doi:10.1093/hmg/ddi093 CrossRefPubMed

19.

Loughlin J, Sinsheimer JS, Carr A, Chapman K (2006) The CALM1 core promoter polymorphism is not associated with hip osteoarthritis in a United Kingdom Caucasian population. Osteoarthritis Cartilage 14:295–298. doi:10.1016/j.joca.2005.11.001 CrossRefPubMed

20.

Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, Little CB, Last K, Farmer PJ, Campbell IK, Fourie AM, Fosang AJ (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434:648–652. doi:10.1038/nature03417 CrossRefPubMed

21.

Le Maitre CL, Freemont AJ, Hoyland JA (2006) Human disc degeneration is associated with increased MMP 7 expression. Biotech Histochem 81:125–131. doi:10.1080/10520290601005298 CrossRefPubMed

22.

Miyamoto H, Saura R, Doita M, Kurosaka M, Mizuno K (2002) The role of cyclooxygenase-2 in lumbar disc herniation. Spine (Phila Pa 1976) 27:2477–2483. doi:10.1097/01.BRS.0000031273.25826.C8 CrossRef

23.

Takahashi M, Haro H, Wakabayashi Y, Kawa-uchi T, Komori H, Shinomiya K (2001) The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene. J Bone Joint Surg Br 83:491–495CrossRefPubMed

24.

Yuan HY, Tang Y, Liang YX, Lei L, Xiao GB, Wang S, Xia ZL (2010) Matrix metalloproteinase-3 and vitamin d receptor genetic polymorphisms, and their interactions with occupational exposure in lumbar disc degeneration. J Occup Health 52:23–30CrossRefPubMed

25.

Cipollone F, Toniato E, Martinotti S, Fazia M, Iezzi A, Cuccurullo C, Pini B, Ursi S, Vitullo G, Averna M, Arca M, Montali A, Campagna F, Ucchino S, Spigonardo F, Taddei S, Virdis A, Ciabattoni G, Notarbartolo A, Cuccurullo F, Mezzetti A (2004) A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA 291:2221–2228. doi:10.1001/jama.291.18.2221 CrossRefPubMed

26.

Hoyland JA, Le Maitre C, Freemont AJ (2008) Investigation of the role of IL-1 and TNF in matrix degradation in the intervertebral disc. Rheumatology (Oxford) 47:809–814. doi:10.1093/rheumatology/ken056 CrossRef

27.

Le Maitre CL, Freemont AJ, Hoyland JA (2005) The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther 7:R732–R745. doi:10.1186/ar1732 PubMedCentralCrossRefPubMed

28.

Annunen S, Paassilta P, Lohiniva J, Perala M, Pihlajamaa T, Karppinen J, Tervonen O, Kroger H, Lahde S, Vanharanta H, Ryhanen L, Goring HH, Ott J, Prockop DJ, Ala-Kokko L (1999) An allele of COL9A2 associated with intervertebral disc disease. Science 285:409–412CrossRefPubMed

29.

Paassilta P, Lohiniva J, Goring HH, Perala M, Raina SS, Karppinen J, Hakala M, Palm T, Kroger H, Kaitila I, Vanharanta H, Ott J, Ala-Kokko L (2001) Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 285:1843–1849CrossRefPubMed

Title: Genetic susceptibility of lumbar degenerative disc disease in young Indian adults
Authors: S. Rajasekaran
Rishi Mugesh Kanna
Natesan Senthil
Muthuraja Raveendran
Veera Ranjani
Kenneth M. C. Cheung
Danny Chan
Patrick Y. P. Kao
Anita Yee
Ajoy Prasad Shetty
Publication date: 01-09-2015
Publisher: Springer Berlin Heidelberg
Published in: European Spine Journal / Issue 9/2015
Print ISSN: 0940-6719
Electronic ISSN: 1432-0932
DOI: https://doi.org/10.1007/s00586-014-3687-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genetic susceptibility of lumbar degenerative disc disease in young Indian adults

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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