Low back pain and sciatica are the most common musculoskeletal complaints. Even though secondary factors such as environmental and anthropometric risk factors contribute to intervertebral disc disease, genetic factors may play a significant role in the pathogenesis of the disease. The role of genetic factors is supported by our recent findings: We showed that a tryptophan for glutamine substitution in the alpha2 chain of collagen IX co- segregated with sciatica and intervertebral disc disease in four families with a LOD score of 4.5. Subsequent linkage disequilibrium analysis conditional on linkage gave an additional LOD score of 7.1. Thus, the joint lod score is 11.6 (4.5 + 7.1). In addition, we identified another tryptophan mutation in collagen IX (alpha3 chain). The mutation is significantly associated with the disease (p value: 0.000013) and it increases the relative risk for the disease by a factor of 2.6 (95 percent confidence interval, 1.6 to 4.3).
The Specific Aims of the present proposal are: (1) To use the new sequence data from the genes and the new protocols we have developed to analyze DNA from 150 probands with sciatica and 100 probands that have had surgery for herniated discs for mutations in eight candidate genes: three genes for collagen IX (COL9A1, COL9A2 and COL9A3), three genes for collagen XI (COL11A1, COL11A2 and COL11A3 or COL2A1), the aggrecan gene, and the gene for link protein. (2) To evaluate the significance of the sequence variations as disease-causing mutations by analyzing the family members of the probands and non-symptomatic individuals for the presence of the sequence variations. (3) To distinguish neutral polymorphisms from mutations that cause or predispose to intervertebral disc disease, we will also synthesize the normal and mutated recombinant human proteins and determine whether the mutations alter the biological function of collagens IX and XI by assays that include (a) the thermostability of triple helices of the collagens; (b) binding to collagen II; and (c) potential of the collagen IX and XI to alter the self-assembly of collagen II into fibrils in vitro. (4) To do genome-wide screen on 100 affected sib pairs and/or families to identify additional loci for intervertebral disc disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045982-04
Application #
6375205
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Panagis, James S
Project Start
1999-09-27
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
4
Fiscal Year
2001
Total Cost
$281,321
Indirect Cost
Name
Tulane University
Department
Genetics
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Solovieva, Svetlana; Noponen, Noora; Mannikko, Minna et al. (2007) Association between the aggrecan gene variable number of tandem repeats polymorphism and intervertebral disc degeneration. Spine (Phila Pa 1976) 32:1700-5
Solovieva, Svetlana; Lohiniva, Jaana; Leino-Arjas, Paivi et al. (2006) Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms. Eur Spine J 15:613-9
Noponen-Hietala, Noora; Virtanen, Iita; Karttunen, Riitta et al. (2005) Genetic variations in IL6 associate with intervertebral disc disease characterized by sciatica. Pain 114:186-94
Jim, Jeffrey J T; Noponen-Hietala, Noora; Cheung, Kenneth M C et al. (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) 30:2735-42
Pihlajamaa, Tero; Lankinen, Hilkka; Ylostalo, Joni et al. (2004) Characterization of recombinant amino-terminal NC4 domain of human collagen IX: interaction with glycosaminoglycans and cartilage oligomeric matrix protein. J Biol Chem 279:24265-73
Solovieva, Svetlana; Kouhia, Sanna; Leino-Arjas, Paivi et al. (2004) Interleukin 1 polymorphisms and intervertebral disc degeneration. Epidemiology 15:626-33
Karppinen, Jaro; Paakko, Eija; Paassilta, Petteri et al. (2003) Radiologic phenotypes in lumbar MR imaging for a gene defect in the COL9A3 gene of type IX collagen. Radiology 227:143-8
Noponen-Hietala, N; Kyllonen, E; Mannikko, M et al. (2003) Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 62:1208-14
Paassilta, P; Lohiniva, J; Goring, H H et al. (2001) Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 285:1843-9