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Petteri Paassilta, MD,PhD; Jaana Lohiniva; Harald H. H. Göring, PhD; Merja Perälä, PhD; S. Susanna Räinä; Jaro Karppinen, MD; Markku Hakala, MD,PhD; Tiina Palm, MD; Heikki Kröger, MD,PhD; Ilkka Kaitila, MD,PhD; Heikki Vanharanta, MD,PhD; Jürg Ott, PhD; Leena Ala-Kokko, MD,PhD

JAMA. 2001;285:1843-1849.

Context  Lumbar disk disease (LDD) is one of the most common musculoskeletal diseases, with a prevalence of about 5%. A tryptophan (Trp) allele (Trp2) was recently discovered in the COL9A2 gene that is associated with dominantly inherited LDD but is only present in about 4% of Finnish patients with LDD.

Objective  To determine if other collagen IX gene sequence variations play a role in the pathogenesis of LDD.

Design and Setting  Case-control study conducted from February 1997 to May 1998 at university hospitals in Finland.

Participants  A total of 171 individuals with LDD (evaluated clinically and by magnetic resonance imaging or computed tomography) and 321 controls without LDD (186 healthy individuals, 83 patients with primary osteoarthritis, 31 with rheumatoid arthritis, and 21 with chondrodysplasias).

Main Outcome Measures  Frequencies of sequence variations covering the entire coding sequences and exon boundaries of the collagen IX genes, COL9A1, COL9A2, and COL9A3, which code for the 1, 2, and 3 chains of the protein, detected by conformation-sensitive gel electrophoresis and confirmed by sequencing, compared between individuals with and without LDD.

Results  Mutation analysis of all 3 collagen IX genes resulted in identification of an Arg103Trp (argininetryptophan) substitution in the 3 chain (Trp3 allele). The frequency of the Trp3 allele was 12.2% in LDD cases, excluding 7 individuals who were carriers of the previously identified Gln326Trp (glutaminetryptophan) substitution in the 2 chain (Trp2 allele), and was 4.7% among controls. The difference in the frequency was statistically significant (P = .000013). Presence of at least 1 Trp3 allele increases risk of LDD about 3-fold.

Conclusion  This study led to the identification of a novel common genetic risk factor for LDD, confirming that genetic risk factors likely play a significant role in LDD.

Author Affiliations: Collagen Research Unit, Biocenter, and Departments of Medical Biochemistry (Drs Paassilta, Perälä, and Ala-Kokko and Mss Lohiniva and Räinä), Physical Medicine and Rehabilitation (Drs Karppinen and Vanharanta), and Internal Medicine (Dr Hakala), University of Oulu, Oulu, Finland; Department of Genetics and Development, Columbia University, New York, NY (Drs Göring and Ott); Department of Surgery, University of Kuopio, Kuopio, Finland (Drs Palm and Kröger); Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland (Dr Kaitila); Laboratory of Statistical Genetics, Rockefeller University, New York, NY (Dr Ott); Center for Gene Therapy, Medical College of Pennsylvania/Hahnemann University, Philadelphia (Dr Ala-Kokko). Dr Göring is now with the Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Tex; Dr Ala-Kokko is now with the Center for Gene Therapy, Tulane University Health Sciences Center, New Orleans, La.

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