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Published online before print February 19, 2003, 10.1148/radiol.2271011821
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(Radiology 2003;227:143-148.)
© RSNA, 2003

Musculoskeletal Imaging

Radiologic Phenotypes in Lumbar MR Imaging for a Gene Defect in the COL9A3 Gene of Type IX Collagen1

Jaro Karppinen, MD, Eija Pääkkö, MD, PhD, Petteri Paassilta, MD, PhD, Jaana Lohiniva, MC, Mauno Kurunlahti, MD, Osmo Tervonen, MD, PhD, Pentti Nieminen, PhD, Harald H. H. Göring, PhD, Antti Malmivaara, MD, PhD, Heikki Vanharanta, MD, PhD and Leena Ala-Kokko, MD, PhD

1 From the Depts of Physical Medicine and Rehabilitation (J.K., H.V.) and Radiology (E.P., M.K., O.T.), Univ Hosp of Oulu, PL 25, FIN-90029 Oulu, Finland; Collagen Research Unit, Biocenter and Medical Biochemistry (P.P., J.L., L.A.K.) and Medical Informatics Group (P.N.), Univ of Oulu, Finland; Dept of Genetics, Southwest Foundation of Biomedical Research, San Antonio, Tex (H.H.H.G.); Dept of Occupational Medicine, Finnish Inst of Occupational Health, Helsinki (J.K., A.M.); Orton Hosp, Helsinki, Finland (J.K., A.M.); and Ctr for Gene Therapy and Dept of Medicine, Tulane Univ Health Sci Ctr, New Orleans, La (L.A.K.). Received Nov 13, 2001; revision requested Jan 23, 2002; final revision received Jul 15; accepted Aug 1. J.K. supported by Finnish Office for Health Technology Assessment and Finnish Work Environment Fund and by grants from the Yrjö Jahnsson Foundaton and the Finnish National Research and Development Ctr for Welfare and Health. L.A.K. supported by Acad of Finland, NIH (AR45982), Louisiana Gene Therapy Research Consortium (New Orleans), and HCA-The Health Care Company (Nashville, Tenn). Address correspondence to J.K. (e-mail: jaro.karppinen@ttl.fi).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate whether the COL9A3 tryptophan allele (Trp3 allele) is associated with a specific radiologic phenotype among patients with sciatica.

MATERIALS AND METHODS: One hundred fifty-three patients with sciatica were evaluated for the presence of Trp3 allele, Scheuermann disease, intervertebral disk degeneration, Schmorl nodules, dorsal anular tears, hyperintense lesions, and endplate degeneration on sagittal T2-weighted lumbar magnetic resonance images. The Trp3 genotype was determined by means of sequencing the COL9A3 gene. Radiologic phenotypes were evaluated while blinded to the genotype. Scheuermann disease was diagnosed if either endplate irregularities or Schmorl nodules and two of the other three criteria (disk space narrowing, disk dehydration, and wedging of anterior vertebral body margins) were present at three or more adjacent disk levels from T10–11 to L3–4. Disk degeneration was evaluated separately for each disk (T11–12 to L5–S1) and for all disks combined. Frequencies of radiologic phenotypes between individuals with or without Trp3 allele were compared.

RESULTS: Thirty-four patients had at least one Trp3 allele. When compared with the matched control subjects, they had an increased likelihood of Scheuermann disease (P = .035) and an increased number of degenerated disks from T11 to S1 (P = .021). Comparisons at individual disks showed a statistically significant increase in disk degeneration at T11–12 (analysis of all grades of degeneration [graded], P = .018; analysis of any degeneration vs none [dichotomous], P = .039) and L4–5 (graded, P = .011; dichotomous, P = .016). Prevalences of anular tears, endplate degeneration, Schmorl nodules, and hyperintense lesions were comparable.

CONCLUSION: The results of this study indicate that the presence of Trp3 allele is associated with Scheuermann disease and intervertebral disk degeneration. No associations were found for other radiologic phenotypes.

© RSNA, 2003

Index terms: Genes and genetics • Spine, diseases, 311.4963, 326.4963 • Spine, intervertebral disks, 326.4961, 326.4963, 336.4961, 336.4963 • Spine, MR, 326.12143, 336.12143


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Intervertebral lumbar disk disease, characterized by disk herniation and sciatica, is one of the most common musculoskeletal diseases (1). Determinants such as hard physical work, driving of motor vehicles, and patient sex and height are known to be associated with sciatica (2,3), but it has also been suggested that intervertebral disk disease involving disk herniations, sciatica, and disk degeneration may be largely explained by genetic factors (4–8).

In agreement with this hypothesis, a sequence variation in the COL9A2 gene that changes a codon for glutamine to a codon for tryptophan in the {alpha}2 chain of type IX collagen (known as the Trp2 allele) has been shown to be associated with dominantly inherited lumbar disk disease, which is characterized by sciatica in about 4% of Finnish patients (5). A similar sequence variation that changes a codon for arginine to a codon for tryptophan has recently been found in COL9A3 gene coding for the {alpha}3 chain of type IX collagen (Trp3 allele) (6). The latter allele was observed in 24.4% of a series of patients with sciatica but in only 9.3% of the control subjects and was found to increase the risk of lumbar disk disease almost threefold, representing the first common genetic risk factor for the disease (6).

The intervertebral disk is composed of a lamellar fibrous anulus encircling a central gelatinous nucleus pulposus, together with thin vertebral endplates. Collagens and proteoglycans are the primary structural components of the intervertebral disk macromolecular framework (9–11). Type IX collagen, which is found in the three main structures—nucleus, anulus, and endplates (10)—is a heterotrimeric protein consisting of three genetically distinct {alpha} chains—{alpha}1(IX), {alpha}2(IX), and {alpha}3(IX)—encoded by the COL9A1, COL9A2, and COL9A3 genes, respectively (12–14). The function of type IX collagen is not well understood, but it is believed to provide mechanical support for tissues by functioning as a bridging molecule.

The Trp3 allele is a common genetic risk factor for lumbar intervertebral disk disease. Since type IX collagen is found in the nucleus, anulus, and endplates, it is possible that the Trp3 alleles may cause distinct radiologically detectable changes in all three structures. The purpose of this study was to evaluate if the Trp3 allele is associated with specific radiologic phenotypes related to intervertebral lumbar disk disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Genetic Analysis
Patients who experienced unilateral sciatic pain below the knee for 1–6 months were included in the series. They had been recruited for a randomized controlled trial of transforaminal infiltration (15), and therefore, the exclusion criteria included previous back surgery and rare causes of sciatica visible with magnetic resonance (MR) imaging, such as synovial cysts (one patient) and nondegenerative spondylolisthesis (two patients). A total of 160 patients met the trial criteria, but because an anticoagulant therapy blood sample was not obtained from one patient, 159 patients remained for genetic analysis. Six carried a Trp2 allele and were excluded (5), leaving a population of 153 patients. Clinical symptoms and signs were assessed (16), and a complete medical history of back complaints was compiled. Blood samples had been collected from the patients previously for genomic DNA extraction and analysis of sequence variations in the human COL9A1, COL9A2, and COL9A3 genes (5,6). The analysis consisted of polymerase chain reaction amplification of all the exons and exon boundaries in the genes. The polymerase chain reaction products were subjected to conformation-sensitive gel electrophoresis analysis (17), and the sequence variations observed as heteroduplexes in this analysis were identified with automated sequencing (ABI PRISM 377 Sequencer and dRhod Dye Terminator Cycle Sequencing Kit; Applied Biosystems, Foster City, Calif). Both protocols (randomized trial and genetic analysis) were approved by the ethics committee of Oulu University Hospital. Every patient provided informed written consent.

MR Imaging and Evaluation
MR images were obtained with a 1.5-T system (Signa; GE Medical Systems, Milwaukee, Wis) and consisted of sagittal T2-weighted 4,000/95 (repetition time msec/echo time msec) images and transverse T1-weighted 640/14 images obtained before and immediately after an intravenous injection of contrast material (0.1 mmol per kilogram of body weight of gadopentetate dimeglumine [Magnevist; Schering, Berlin, Germany]). Frequency-selected fat saturation was used for the contrast material–enhanced transverse images. The technical specifications included intersection gaps of 1.0 and 0.5 mm for sagittal and transverse images, respectively, a field of view of 30 x 20 cm, a section thickness of 4 mm, and a matrix of 192 x 256 with two signals acquired. All images were evaluated independently by two radiologists experienced in MR imaging (E.P. and M.K.) who were blinded to the genotype of the patients. All lumbar disks and the two lowest thoracic disks were evaluated. Any discrepancies between the radiologists were resolved by means of consensus. Additionally, in the evaluation of Scheuermann disease, one radiologist (M.K.) reevaluated randomly chosen parts of the images (n = 30) at least 2 weeks after the first reading.

Intervertebral disk and endplate degeneration.—Intervertebral disk degeneration was graded as normal (no signal intensity changes), grade 1 (slight decrease in signal intensity of the nucleus on sagittal T2-weighted MR images), grade 2 (hypointense nucleus pulposus on T2-weighted MR images with normal disk height), or grade 3 (hypointense nucleus with disk space narrowing) (18). The endplates and adjacent bone marrow were evaluated in terms of the criteria of Modic et al (19), and the endplates were graded for the statistical analyses as normal or degenerated.

Anular tears.—Tears in the posterior fibrous anulus were evaluated according to the criteria of Yu et al (20). Hyperintense lesions were bright spots in the dorsal anulus (brighter than the nucleus), surrounded by the hypointense (black) fibrous anulus on sagittal T2-weighted MR images (21).

Schmorl nodules and Scheuermann disease.—Schmorl nodules in the lumbar disks and the two lowest thoracic disks (22) and the presence or absence of Scheuermann disease were evaluated visually on the sagittal T2-weighted MR images. Patients had Scheuermann disease if either endplate irregularities or Schmorl nodules and two of the other three criteria (disk space narrowing, disk dehydration, or wedging of the anterior vertebral body margins in the thoracolumbar region) were present at three or more adjacent disk levels from T10-11 to L3-4 (23).

Statistical Analysis
The reliability of the MR image readings was evaluated with {kappa} statistics (24), which were calculated for the separate readings before the consensus reading. A matched pair approach was used to investigate the relationship between the frequency of Trp3 alleles and the radiologic phenotypes. Matching was warranted because disk degeneration has previously been shown to have determinants such as patient age, sex, and occupation (4,25). In the matched pair analysis, each patient with at least one Trp3 allele was matched with a control subject without a Trp3 allele with similar age, sex, and occupation. Scheuermann disease was evaluated as present or absent. Intervertebral disk degeneration was evaluated separately for each disk from T11-12 to L5-S1 and for all disks combined. In the statistical analysis, both graded (ie, analysis of all grades of degeneration) and dichotomous (ie, analysis of any degeneration vs none) classifications were used. Endplate degeneration, dorsal anular tears, hyperintense lesions, and Schmorl nodules were evaluated for all disks from T11 to S1 combined. The statistical significance of differences in MR imaging findings between both groups was investigated with a two-sided binomial test (exact analogue of the McNemar test) for the binary phenotypes (Scheuermann disease and dichotomous disk degeneration for each individual disk) and the Wilcoxon signed rank test for other radiologic phenotypes.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Intraobserver and interobserver MR imaging findings showed mostly moderate to substantial agreement (26). The intraobserver {kappa} value for the evaluation of Scheuermann disease from the MR images was 1.0 (perfect agreement). The interobserver {kappa} value was 0.71 (substantial agreement). A consensus had to be negotiated in 18 cases, in which the discrepancies pertained mostly to older patients. The negotiated consensus of the two readers was used for the final status (presence or absence) of Scheuermann disease.

Patients and Genetic Analysis
Mutation analysis showed that 32 of 153 (21%) patients had one Trp3 allele (heterozygous). Two of the 153 (1.3%) patients were homozygous for the allele. The patients who were homozygous or heterozygous for the Trp3 allele did not differ with respect to clinical symptoms or clinical findings (data not shown) and were thus grouped together in the analysis.

Radiologic Phenotypes
Radiologic phenotypes for each patient with at least one Trp3 allele and his or her matched control subject are presented in Table 1. Fifteen of 34 (44%) patients with at least one Trp3 allele had Scheuermann disease, compared with six of 34 (18%) matched control subjects without the allele (Tables 1, 2; P = .035). Part a of the Figure is a sagittal T2-weighted MR image in one homozygous patient who has multiple Schmorl nodules and typical Scheuermann disease. Part b of the Figure was obtained in a patient with one Trp3 allele and endplate irregularities, disk space narrowing, and thoracolumbar disk dehydration. The diagnosis was Scheuermann disease in this patient.


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  		TABLE 1. MR Imaging Findings among Pairs of Patients with the Trp3 Allele and Their Matched Control Subjects

 

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  		TABLE 2. Statistical Association of Phenotypes with the Trp3 Allele among Patients with Sciatica at MR Imaging

 


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  		Figure a. Sagittal T2-weighted MR images (4,000/95) in two patients who received a diagnosis of Scheuermann disease. (a) Image in a 50-year-old man (case 9 in Table 1) who experienced right-sided sciatica for 11/2 months. He had two Trp3 alleles. Note Schmorl nodules at L2-3, L3-4, and L4-5 (open arrowheads); endplate irregularities in the thoracolumbar region (solid arrowheads); and a contained herniation at L4-5 (arrow). (b) Image in a 47-year-old woman (case 33 in Table 1) who had left-sided sciatica for 6 months. Note Schmorl nodule at T11-12 (open arrowhead), endplate irregularities from T12-L1 to L2-3 (solid arrowheads), and a noncontained herniation at L5-S1 (arrow).

 


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  		Figure b. Sagittal T2-weighted MR images (4,000/95) in two patients who received a diagnosis of Scheuermann disease. (a) Image in a 50-year-old man (case 9 in Table 1) who experienced right-sided sciatica for 11/2 months. He had two Trp3 alleles. Note Schmorl nodules at L2-3, L3-4, and L4-5 (open arrowheads); endplate irregularities in the thoracolumbar region (solid arrowheads); and a contained herniation at L4-5 (arrow). (b) Image in a 47-year-old woman (case 33 in Table 1) who had left-sided sciatica for 6 months. Note Schmorl nodule at T11-12 (open arrowhead), endplate irregularities from T12-L1 to L2-3 (solid arrowheads), and a noncontained herniation at L5-S1 (arrow).

 
Patients with Trp3 alleles had an increase in average disk degeneration grade (P = .052) and proportion of degenerated disks (P = .021; Table 2) for disks from T11 to S1. Comparisons of individual disks showed that patients with Trp3 alleles had significantly more disk degeneration at T11-12 (graded, P = .018; dichotomous, P = .039) and L4-5 (graded, P = .011; dichotomous, P = .016; Table 2) but not at other disks.

Comparison of the patients with the Trp3 allele with their matched control subjects showed no significant differences in endplate degeneration, dorsal anular tears, hyperintense lesions, or Schmorl nodules (Table 2). However, the total number of Schmorl nodules from T11 to S1 tended to be higher for patients with at least one Trp3 allele (P = .08; Table 2).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
The results in this study suggest that patients with painful discogenic disease (ie, sciatica) and Trp3 allele are more likely to have Scheuermann disease than are those without the allele. The association between painful discogenic disease and Scheuermann disease has been reported earlier (23,27). Heithoff et al (23) reported that 120 (9%) of 1,419 patients had both lower lumbar disk disease and Scheuermann disease. Since 81% of the patients with both diseases were younger than 40 years, and 9% were younger than 21 years, they proposed the term "juvenile discogenic disease." In a Finnish long-term follow-up study, children and adolescents with intervertebral disk degeneration and changes related to Scheuermann disease were shown to have an increased risk of recurrent low back pain at this age and also a long-term risk of recurrent pain up to early adulthood (27–29). The association of Trp3 allele with Scheuermann disease among patients with sciatica is a clinically important finding because Scheuermann disease is associated with low back pain (30–32). The incidence of Scheuermann disease reportedly ranges from 4% to 8% among patients with low back pain, although it is probably underestimated through being missed or attributed to poor posture (30). Scheuermann disease is inherited in an autosomal dominant manner with incomplete penetrance and variable expression (30). Histologic findings suggest that an abnormal collagen matrix may be a causative factor for the disease (33); this theory is supported by results in the present study.

In addition, the patients with the Trp3 allele had a significant increase in proportion of degenerated disks from T11 to S1 on T2-weighted MR images. Comparisons of individual disks showed that patients had more disk degeneration at T11-12 and L4-5 but not at other levels. Intervertebral disk degeneration has a multifactorial cause, although investigators in studies of identical twins have suggested that genetic factors may also be important (4). This suggestion was strengthened by reports of an association between degenerative disk disease and both vitamin D receptor gene polymorphism (34) and aggrecan gene polymorphism (35). The Trp3 allele may also be associated with disk degeneration, although unlike the situation in other studies, all of the patients in the present study had sciatica. A larger population-based study involving both symptomatic and asymptomatic subjects would be needed to test this apparent association.

In summary, findings in the present study showed a significant association between Trp3 allele, Scheuermann disease, and intervertebral disk degeneration among patients with sciatica. The association between Trp3 allele and Scheuermann disease is the first confirmed genotype–radiologic phenotype association (apart from intervertebral disk degeneration) for a common musculoskeletal disease, to our knowledge.


   FOOTNOTES
 
Author contributions: Guarantors of integrity of entire study, J.K., L.A.K.; study concepts, J.K., L.A.K.; study design, J.K., O.T., A.M., H.V., L.A.K.; literature research, J.K., H.V., L.A.K.; clinical studies, J.K., E.P., M.K.; data acquisition, J.K., E.P., M.K., P.P., J.L., O.T.; data analysis/interpretation, J.K., P.N., H.H.H.G.; manuscript preparation, J.K., M.K., L.A.K.; manuscript definition of intellectual content, J.K., L.A.K.; manuscript editing, J.K., E.P., A.M., H.V., L.A.K.; manuscript revision/review, J.K., A.M., O.T., H.H.H.G., L.A.K.; manuscript final version approval, J.K., H.H.H.G., L.A.K., A.M.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

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