Other entities represented in this entry:
SNOMEDCT: 36427004; ICD9CM: 722;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p21.1 | {Lumbar disc herniation, susceptibility to} | 603932 | 3 | COL11A1 | 120280 | |
| 6q27 | {Lumbar disc herniation, susceptibility to} | 603932 | 3 | THBS2 | 188061 | |
| 9q22.31 | {Lumbar disc degeneration} | 603932 | 3 | ASPN | 608135 | |
| 15q22.31 | {Lumbar disc disease, susceptibility to} | 603932 | 3 | CILP | 603489 | |
| 20q13.33 | {Intervertebral disc disease, susceptibility to} | 603932 | 3 | COL9A3 | 120270 |
A number sign (#) is used with this entry because of evidence that variations in many genes are involved in susceptibility to intervertebral disc disease. See MOLECULAR GENETICS section.
Lumbar disc disease is caused by degeneration of intervertebral discs of the lumbar spine. One of the most common musculoskeletal disorders, it has strong genetic determinants (Matsui et al., 1998; Battie et al., 1995; Sambrook et al., 1999).
Sambrook et al. (1999) compared MRI features of degenerative disc disease in the cervical and lumbar spine of 172 monozygotic and 154 dizygotic twins (mean age 51.7 and 54.4, respectively) who were unselected for back pain or disc disease. An overall score for disc degeneration was calculated as the sum of the grades for disc height, bulge, osteophytosis, and signal intensity at each level. A 'severe disease' score (excluding minor grades) and an 'extent of disease' score (number of levels affected) were also calculated. For the overall score, heritability was 74% at the lumbar spine and 73% at the cervical spine. For 'severe disease,' heritability was 64% and 79% at the lumbar and cervical spine, respectively, and for 'extent of disease,' heritability was 63% and 63%, respectively. These results were adjusted for age, weight, height, smoking, occupational manual work, and exercise. Examination of individual features showed that disc height and bulge were highly heritable at both sites, and osteophytes were heritable in the lumbar spine.
Association with the COL9A2 Gene on Chromosome 1p34
In a study that examined for allelic variation in the COL9A2 gene in Finnish individuals with sciatica and radiologically documented intervertebral disc disease, Annunen et al. (1999) found a substitution of tryptophan for glutamine at codon 326 (120260.0004). This change was found in 6 of 157 individuals with disc disease but in none of 174 controls. Further analysis of the families of 4 of the original patients revealed that all individuals heterozygous for the trp substitution demonstrated the disease phenotype. Many individuals within these families had IDD but not the trp allele. The authors invoked a high phenocopy rate to reconcile this observation with the conclusion that this sequence variant within COL9A2 contributes to the pathogenesis of disease. In the disease model chosen, this locus accounted for 10% of disease prevalence. Under these constraints, Annunen et al. (1999) demonstrated a lod score of 4.5 at a recombination fraction of 0.12. Subsequent linkage disequilibrium analysis conditional on linkage gave an additional lod score of 7.1. The authors did not exclude the possibility that a true disease locus may lie in close physical proximity to COL9A2.
Association with the COL11A1 Gene on Chromosome 1p21
Mio et al. (2007) identified an association between a polymorphism of the COL11A1 gene (120280.0007) and lumbar disc herniation in Japanese populations. Normally, the COL11A1 gene is highly expressed in the intervertebral disc; its expression was decreased in the intervertebral disc in patients with lumbar disc herniation, and the expression level was inversely correlated with the severity of disc degeneration. Mio et al. (2007) concluded that type XI collagen is critical for intervertebral disc metabolism and that its decrease is related to lumbar disc herniation.
Association with the THBS2 Gene on Chromosome 6q27
In an association study of 2 independent Japanese populations, involving a total of 847 patients with lumbar disc herniation (LDH) and 896 controls, Hirose et al. (2008) found a significant association between an intronic SNP in the THBS2 gene (rs9406328; 188061.0001) and LDH. A missense SNP in the MMP9 gene (rs17576) was also strongly associated with LDH in the Japanese population and showed a combinatorial effect with THBS2, with an odds ratio of 3.03 for the genotype that was homozygous for the susceptibility alleles of both SNPs.
Association with the ASPN Gene on Chromosome 9q21.3-q22
Song et al. (2008) found an association of the D14 allele of the ASPN gene (608135.0001) with lumbar disc degeneration in Chinese and Japanese individuals. The presence of this allele had previously been associated with susceptibility to knee osteoarthritis (165720).
Association with the CILP Gene on Chromosome 15q22
Using a case-control association study, Seki et al. (2005) identified a functional SNP in the CILP gene (I395T; 603489.0001), which encodes the cartilage intermediate layer protein, that acts as a modulator of susceptibility to lumbar disc disease.
Virtanen et al. (2007) analyzed the I395T SNP and flanking SNPs in the CILP gene in 243 Finnish patients with symptoms of lumbar disc disease and 259 controls, and in 348 Chinese individuals with MRI-defined lumbar disc disease and 343 controls. The authors found no evidence of association in the Finnish or Chinese samples and suggested that the CILP gene is not a major risk factor for symptoms of lumbar disc disease in Caucasians or in the general population.
Association with the AGC1 Gene on Chromosome 15q26
In a study of 64 young Japanese women with or without low back problems, Kawaguchi et al. (1999) demonstrated an association between lumbar disc degeneration and a shorter variable number of tandem repeat (VNTR) region in the chondroitin sulfate attachment domain of the AGC1 gene (155760).
Association with the COL9A3 Gene on Chromosome 20q13
Paassilta et al. (2001) demonstrated an association between a missense polymorphism in the COL9A3 gene (120270.0003) and lumbar disc disease in Finnish patients, with an approximately 3-fold increased risk of disease with the so-called 'trp3' allele.
Association with the MMP9 Gene on Chromosome 20q11.2-q13.1
In an association study of 2 independent Japanese populations involving a total of 847 patients with lumbar disc herniation and 896 controls, Hirose et al. (2008) found a significant association (corrected p = 0.0083) between LDH and a gln279-to-arg (Q279R) polymorphism (rs17576) in the MMP9 gene, located within the highly conserved gelatinase-specific fibronectin type II domains. Hirose et al. (2008) also found that an intronic SNP in the THBS2 gene (120361.0001) was strongly associated with LDH in the Japanese population and resulted in decreased THBS2 interaction with MMP2 (120360) and MMP9. They demonstrated a combinatorial effect of MMP9 and THBS2 for LDH, with an odds ratio of 3.03 for the genotype that was homozygous for the susceptibility alleles (G and T, respectively) of both SNPs.
Annunen, S., Paassilta, P., Lohinlva, J., Perala, M., Pihlajamaa, T., Karppinen, J., Tervonen, O., Kroger, H., Lahde, S., Vanharanta, H., Ryhanen, L., Goring, H. H. H., Ott, J., Prockop, D. J., Ala-Kokko, L. An allele of COL9A2 associated with intervertebral disc disease. Science 285: 409-411, 1999. [PubMed: 10411504] [Full Text: https://doi.org/10.1126/science.285.5426.409]
Battie, M. C., Haynor, D. R., Fisher, L. D., Gill, K., Gibbons, L. E., Videman, T. Similarities in degenerative findings on magnetic resonance images of the lumbar spines of identical twins. J. Bone Joint Surg. Am. 77: 1662-1670, 1995. [PubMed: 7593075] [Full Text: https://doi.org/10.2106/00004623-199511000-00004]
Hirose, Y., Chiba, K., Karasugi, T., Nakajima, M., Kawaguchi, Y., Mikami, Y., Furuichi, T., Mio, F., Miyake, A., Miyamoto, T., Ozaki, K., Takahashi, A., Mizuta, H., Kubo, T., Kimura, T., Tanaka, T., Toyama, Y., Ikegawa, S. 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, 2008. [PubMed: 18455130] [Full Text: https://doi.org/10.1016/j.ajhg.2008.03.013]
Kawaguchi, Y., Osada, R., Kanamori, M., Ishihara, H., Ohmori, K., Matsui, H., Kimura, T. Association between an aggrecan gene polymorphism and lumbar disc degeneration. Spine 24: 2456-2460, 1999. [PubMed: 10626307] [Full Text: https://doi.org/10.1097/00007632-199912010-00006]
Matsui, H., Kanamori, M., Ishihara, H., Yudoh, K., Naruse, Y., Tsuji, H. Familial predisposition for lumbar degenerative disc disease: a case-control study. Spine 23: 1029-1034, 1998. [PubMed: 9589542] [Full Text: https://doi.org/10.1097/00007632-199805010-00013]
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. 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, 2007. [PubMed: 17999364] [Full Text: https://doi.org/10.1086/522377]
Paassilta, P., Lohiniva, J., Goring, H. H. H., Perala, M., Raina, S. S., Karppinen, J., Hakala, M., Palm, T., Kroger, H., Kaitila, I., Vanharanta, H., Ott, J., Ala-Kokko, L. Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 285: 1843-1849, 2001. [PubMed: 11308397] [Full Text: https://doi.org/10.1001/jama.285.14.1843]
Sambrook, P. N., MacGregor, A. J., Spector, T. D. Genetic influences on cervical and lumbar disc degeneration: a magnetic resonance imaging study in twins. Arthritis Rheum. 42: 366-372, 1999. [PubMed: 10025932] [Full Text: https://doi.org/10.1002/1529-0131(199902)42:2<366::AID-ANR20>3.0.CO;2-6]
Seki, S., Kawaguchi, Y., Chiba, K., Mikami, Y., Kizawa, H., Oya, T., Mio, F., Mori, M., Miyamoto, Y., Masuda, I., Tsunoda, T., Kamata, M., Kubo, T., Toyama, Y., Kimura, T., Nakamura, Y., Ikegawa, S. A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nature Genet. 37: 607-612, 2005. [PubMed: 15864306] [Full Text: https://doi.org/10.1038/ng1557]
Song, Y.-Q., Cheung, K. M. C., Ho, D. W. H., Poon, S. C. S., Chiba, K., Kawaguchi, Y., Hirose, Y., Alini, M., Grad, S., Yee, A. F. Y., Leong, J. C. Y., Luk, K. D. K., Yip, S.-P., Karppinen, J., Cheah, K. S. E., Sham, P., Ikegawa, S., Chan, D. Association of the asporin D14 allele with lumbar-disc degeneration in Asians. Am. J. Hum. Genet. 82: 744-747, 2008. [PubMed: 18304494] [Full Text: https://doi.org/10.1016/j.ajhg.2007.12.017]
Virtanen, I. M., Song, Y. Q., Cheung, K. M. C., Ala-Kokko, L., Karppinen, J., Ho, D. W. H., Luk, K. D. K., Yip, S. P., Leong, J. C. Y., Cheah, K. S. E., Sham, P., Chan, D. Phenotypic and population differences in the association between CILP and lumbar disc disease. (Letter) J. Med. Genet. 44: 285-288, 2007. [PubMed: 17220213] [Full Text: https://doi.org/10.1136/jmg.2006.047076]