Lumbar disc herniation (LDH) is a common and frequent orthopedic disease with strong genetic determinants. The disruption of the intervertebral disc extracellular matrix has been found to play a key role in the development of LDH, suggesting that abnormal matrix metalloproteinases (MMPs) may promote the degradation of the disc matrix. MMP-9, an important member of the MMP family, is a good candidate for the LDH susceptibility gene. The present study aimed to investigate the association of common variants in the MMP-9 gene with the risk, severity, and clinical characteristic variables of LDH.
Materials and Methods:
Fourteen tag single nucleotide polymorphisms (SNPs) entirely covering the region of the MMP-9 gene were analyzed in a sample of 845 patients and 1751 healthy controls.
Results:
The SNP rs17576 was found to be significantly associated with susceptibility to LDH (OR = 0.77, p = 0.0002), which was also confirmed by haplotype-based analyses (rs79845319-rs17576-rs45437897, global p < 0.001). Our results indicated that the A allele of rs17576 reduced the risk of LDH by ∼23% on average. Furthermore, the G allele of rs17576 was found to correlate with more severe grades of disc degeneration.
Conclusion:
Our results provide additional evidence supporting an important role of the MMP-9 gene in the pathogenesis of LDH.
Get full access to this article
View all access options for this article.
References
1.
Ala-KokkoL (2002) Genetic risk factors for lumbar disc disease. Ann Med, 34:42-47.
2.
AndersonDG, IzzoMW, HallDJ, et al. (2002) Comparative gene expression profiling of normal and degenerative discs—analysis of a rabbit annular laceration model. Spine, 27:1291-1296.
AnnunenS, PaassiltaP, LohinivaJ, et al. (1999) An allele of COL9A2 associated with intervertebral disc disease. Science, 285:409-412.
5.
ArasAB, GuvenM, BalakN, et al. (2016) Evaluation of the association between matrix metalloproteinase 11 and intervertebral disc disease. Turk Neurosurg, 26:274-279.
6.
BarrettJC, FryB, MallerJ, DalyMJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics, 21:263-265.
7.
BattieMC, VidemanT (2006) Lumbar disc degeneration: epidemiology and genetics. J Bone Joint Surg Am 88 Suppl, 2:3-9.
8.
ChangCC, ChowCC, TellierLCAM, et al. (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience, 4:7.
9.
ChenG, GuanF, LinH, et al. (2015) Genetic analysis of common variants in the HDAC2 gene with schizophrenia susceptibility in Han Chinese. J Hum Genet, 60:479-484.
10.
CreanJKG, RobertsS, JaffrayDC, et al. (1997) Matrix metalloproteinases in the human intervertebral disc: role in disc degeneration and scoliosis. Spine, 22:2877-2884.
11.
CurtisD, KnightJ, ShamPC (2006) Program report: GENECOUNTING support programs. Ann Hum Genet, 70:277-279.
12.
de CamposMF, de OliveiraCP, NeffCB, et al. (2016) Studies of molecular changes in intervertebral disc degeneration in animal model. Acta Ortop Bras, 24:16-21.
13.
EserB, EserO, YukselY, et al. (2016) Effects of MMP-1 and MMP-3 gene polymorphisms on gene expression and protein level in lumbar disc herniation. Genet Mol Res. 15.
14.
GoupilleP, JaysonMIV, ValatJP, FreemontAJ (1998) Matrix metalloproteinases: the clue to intervertebral disc degeneration?. Spine, 23:1612-1626.
15.
GuanF, LiL, QiaoC, et al. (2015) Evaluation of genetic susceptibility of common variants in CACNA1D with schizophrenia in Han Chinese. Sci Rep, 5:12935.
16.
GuanF, LinH, ChenG, et al. (2016a) Evaluation of association of common variants in HTR1A and HTR5A with schizophrenia and executive function. Sci Rep, 6:38048.
17.
GuanF, NiuY, ZhangT, et al. (2016b) Two-stage association study to identify the genetic susceptibility of a novel common variant of rs2075290 in ZPR1 to type 2 diabetes. Sci Rep, 6:29586.
18.
GuanF, WeiS, FengJ, et al. (2012a) Association study of a new schizophrenia susceptibility locus of 10q24.32-33 in a Han Chinese population. Schizophr Res, 138:63-68.
19.
GuanF, WeiS, ZhangC, et al. (2013) A population-based association study of 2q32.3 and 8q21.3 loci with schizophrenia in Han Chinese. J Psychiatr Res, 47:712-717.
20.
GuanF, ZhangB, YanT, et al. (2014) MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese. Schizophr Res, 152:97-104.
21.
GuanF, ZhangC, WeiS, et al. (2012b) Association of PDE4B polymorphisms and schizophrenia in Northwestern Han Chinese. Hum Genet, 131:1047-1056.
22.
GuanF, ZhangT, LiL, et al. (2016c) Two-stage replication of previous genome-wide association studies of AS3MT-CNNM2-NT5C2 gene cluster region in a large schizophrenia case-control sample from Han Chinese population. Schizophr Res, 176:125-130.
23.
GuanF, ZhangT, LiuX, et al. (2016d) Evaluation of voltage-dependent calcium channel gamma gene families identified several novel potential susceptible genes to schizophrenia. Sci Rep, 6:24914.
24.
HangaiM, KaneokaK, KunoS, et al. (2008) Factors associated with lumbar intervertebral disc degeneration in the elderly. Spine J, 8:732-740.
25.
HiroseY, ChibaK, KarasugiT, et al. (2008) A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation. Am J Hum Genet, 82:1122-1129.
26.
HuangX, ChenF, ZhaoJ, et al. (2017) Interleukin 6 (IL-6) and IL-10 promoter region polymorphisms are associated with risk of lumbar disc herniation in a Northern Chinese Han population. Genet Test Mol Biomarkers, 21:17-23.
JiaX, ZhangT, LiL, et al. (2016) Two-stage additional evidence support association of common variants in the HDAC3 with the increasing risk of schizophrenia susceptibility. Am J Med Genet B Neuropsychiatr Genet, 171:1105-1111.
29.
KaoPYP, ChanD, SamartzisD, et al. (2011) Genetics of lumbar disk degeneration: technology, study designs, and risk factors. Orthop Clin North Am, 42:479-486.
30.
KawaguchiY, KanamoriM, IshiharaH, et al. (2002) The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Joint Surg Am, 84-A:2022-2028.
31.
LonsdaleJ, ThomasJ, SalvatoreM, et al. (2013) The genotype-tissue expression (GTEx) project. Nat Genet, 45:580-585.
32.
MartirosyanNL, PatelAA, CarotenutoA, et al. (2016) Genetic Alterations in intervertebral disc disease. Front Surg, 3:59.
33.
MatrisianLM (1990) Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet, 6:121-125.
34.
MoenA, SchistadEI, RyghLJ, et al. (2014) Role of IL1A rs1800587, IL1B rs1143627 and IL1RN rs2234677 genotype regarding development of chronic lumbar radicular pain; a prospective one-year study. PLoS One, 9:e107301.
35.
Paz AparicioJ, Fernández BancesI, López-Anglada FernándezE, et al. (2011) The IL-1B (+3953 T/C) gene polymorphism associates to symptomatic lumbar disc herniation. Eur Spine J 20 Suppl, 3:383-389.
36.
PereraRS, DissanayakePH, SenarathU, et al. (2017) Single nucleotide variants of candidate genes in aggrecan metabolic pathway are associated with lumbar disc degeneration and modic changes. PLoS One, 12:e0169835.
37.
PerteaM, PerteaGM, SalzbergSL (2011) Detection of lineage-specific evolutionary changes among primate species. BMC Bioinformatics, 12:274.
38.
PonzerS, SkoogA, BergstromG (2003) The Short Musculoskeletal Function Assessment Questionnaire (SMFA): cross-cultural adaptation, validity, reliability and responsiveness of the Swedish SMFA (SMFA-Swe). Acta Orthop Scand, 74:756-763.
39.
PritchardJK (2001) Are rare variants responsible for susceptibility to complex diseases?. Am J Hum Genet, 69:124-137.
40.
Ricard-BlumS. (2011) The collagen family. Cold Spring Harb Perspect Biol, 3:a004978.
41.
RobertsS, CatersonB, MenageJ, et al. (2000) Matrix metalloproteinases and aggrecanase—their role in disorders of the human intervertebral disc. Spine, 25:3005-3013.
42.
RutM, Machoy-MokrzynskaA, ReclawowiczD, et al. (2014) Influence of variation in the catechol-O-methyltransferase gene on the clinical outcome after lumbar spine surgery for one-level symptomatic disc disease: a report on 176 cases. Acta Neurochir, 156:245-252.
43.
SchneidermanG, FlanniganB, KingstonS, et al. (1987) Magnetic resonance imaging in the diagnosis of disc degeneration: correlation with discography. Spine, 12:276-281.
44.
SekiS, KawaguchiY, ChibaK, et al. (2005) A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nat Genet, 37:607-612.
45.
SkoczynskaA, WojakowskaA, TurczynB, et al. (2016) Serum CETP and PLTP activity in middle-aged men living in urban or rural area of the Lower Silesia region. PURE Poland sub-study. Arch Med Sci, 12:704-714.
46.
SongYQ, HoDWH, KarppinenJ, et al. (2008) Association between promoter-1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese. BMC Med Genet, 9:38.
47.
SunZM, MiaoL, ZhangYG, MingL (2009) Association between the-1562 C/T polymorphism of matrix metalloproteinase-9 gene and lumbar disc disease in the young adult population in North China. Connect Tissue Res, 50:181-185.
48.
SuzukiS, FujitaN, HosoganeN, et al. (2015) Excessive reactive oxygen species are therapeutic targets for intervertebral disc degeneration. Arthritis Res Ther, 17:316.
49.
SzklarczykD, FranceschiniA, WyderS, et al. (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res, 43:D447-D452.
50.
Tzotza Desrumaux, Lagrost (2009) Plasma phospholipid transfer protein (PLTP): review of an emerging cardiometabolic risk factor. Obes Rev, 10:403-411.
51.
VidemanT, BattieMC, RipattiS, et al. (2006) Determinants of the progression in lumbar degeneration—a 5-year follow-up study of adult male monozygotic twins. Spine, 31:671-678.
52.
WahlstromJ, BurstromL, NilssonT, JarvholmB (2012) Risk factors for hospitalization due to lumbar disc disease. Spine, 37:1334-1339.
53.
WeilerC, NerlichAG, ZippererJ, et al. (2002) 2002 SSE award competition in basic science: expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption. Eur Spine J, 11:308-320.
54.
WilliamsFMK, SambrookPN (2011) Neck and back pain and intervertebral disc degeneration: role of occupational factors. Best Pract Res Clin Rheumatol, 25:69-79.
55.
YangH, ZhangB, ZhuJ, et al. (2013) 4q22.1 contributes to bone mineral density and osteoporosis susceptibility in postmenopausal women of Chinese Han population. PLoS One, 8:e80165.
56.
YangXP, YanDG, QiaoCP, et al. (2003) Increased atherosclerotic lesions in ApoE mice with plasma phospholipid transfer protein overexpression. Arterioscler Thromb Vasc Biol, 23:1601-1607.
57.
ZhangB, GuanF, ChenG, et al. (2015) Common variants in SLC1A2 and schizophrenia: association and cognitive function in patients with schizophrenia and healthy individuals. Schizophr Res, 169:128-134.
58.
ZhangDW, JinL, ReamesDL, et al. (2013a) Intervertebral disc degeneration and ectopic bone formation in apolipoprotein E knockout mice. J Orthop Res, 31:210-217.
59.
ZhangY, GuZ, QiuG (2013b) Association of the polymorphism of MMP2 with the risk and severity of lumbar disc degeneration in the Chinese Han population. Eur Rev Med Pharmacol Sci, 17:1830-1834.
60.
ZigourisA, AlexiouGA, BatistatouA, et al. (2011) The role of matrix metalloproteinase 9 in intervertebral disc degeneration. J Clin Neurosci, 18:1424-1425.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
