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Are DISH and OPLL genetically related?
  1. S HAVELKA,
  2. M VESELÁ,
  3. A PAVELKOVÁ,
  4. Š RUZICKOVÁ
  1. Institute of Rheumatology
  2. Prague, Czech Republic
  3. Department of Orthopaedic Surgery
  4. Faculty of Medicine
  5. Kagoshima University, Japan
  6. Laboratory of Genetic Diagnosis
  7. Institute for Medical Science
  8. University of Tokyo, Japan
  9. Department of Radiology
  10. 3rd Faculty of Medicine
  11. Prague, Czech Republic
  1. sekretariat{at}revma.cz
  1. H KOGA
  1. Institute of Rheumatology
  2. Prague, Czech Republic
  3. Department of Orthopaedic Surgery
  4. Faculty of Medicine
  5. Kagoshima University, Japan
  6. Laboratory of Genetic Diagnosis
  7. Institute for Medical Science
  8. University of Tokyo, Japan
  9. Department of Radiology
  10. 3rd Faculty of Medicine
  11. Prague, Czech Republic
  1. sekretariat{at}revma.cz
  1. S MAEDA,
  2. I INOUE
  1. Institute of Rheumatology
  2. Prague, Czech Republic
  3. Department of Orthopaedic Surgery
  4. Faculty of Medicine
  5. Kagoshima University, Japan
  6. Laboratory of Genetic Diagnosis
  7. Institute for Medical Science
  8. University of Tokyo, Japan
  9. Department of Radiology
  10. 3rd Faculty of Medicine
  11. Prague, Czech Republic
  1. sekretariat{at}revma.cz
  1. L HALMAN
  1. Institute of Rheumatology
  2. Prague, Czech Republic
  3. Department of Orthopaedic Surgery
  4. Faculty of Medicine
  5. Kagoshima University, Japan
  6. Laboratory of Genetic Diagnosis
  7. Institute for Medical Science
  8. University of Tokyo, Japan
  9. Department of Radiology
  10. 3rd Faculty of Medicine
  11. Prague, Czech Republic
  1. sekretariat{at}revma.cz

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Fifty years ago, Forestier and Rotés-Querol published their fundamental paper on, what they called, senile ankylosing hyperostosis of the spine1—according to today's nomenclature, diffuse idiopathic skeletal hyperostosis (DISH).2 DISH is a systemic non-inflammatory disorder which might be classified as ossifying diathesis of entheses and ligaments. Ossification starts and extends from insertions of skeletal muscles, ligaments, and joint capsules. The most prominent features of DISH appear on the spine as flowing appositions of newly formed ectopic bone along the anterolateral aspect of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL), on the other hand, involves the posterior aspect of vertebral bodies and discs, predominantly of the cervical spine.3Systematic studies of OPLL began in Japan 25 years ago. A varying proportion of patients with DISH have OPLL, and vice versa.3 4 However, recent observations indicate that cervical OPLL may be fairly frequent in ankylosing spondylitis.5

Despite a series of clinical, x ray, and laboratory investigations the cause and pathogenesis are still unsolved, both in DISH and in OPLL. Some relations have been established between DISH and diabetes mellitus, or diminished glucose tolerance, obesity, gout, hypertriglyceridaemia, and hyperretinolaemia. This suggests, together with an occasional familial incidence of DISH, a suspicion of genetic predisposition. Although several authors found an increased frequency of HLA-B27 among their patients with DISH, most papers did not confirm it.2This discrepancy might partly be accounted for either by coincidence of DISH and ankylosing spondylitis, or by difficulties in differentiating between these two disorders.6 7 OPLL, similarly to DISH, seems to have some associations with low glucose tolerance and obesity.4 Attention has also focused on the role of bone formation promoting factors in OPLL.8

Recently, Japanese authors discovered a predisposing locus for OPLL on chromosome 6p, close to the HLA locus. They provided evidence of genetic linkage and allelic association of the COL 11 A2 gene which would constitute an inherited predisposition for OPLL. Among 20 genetic variants in this gene, a strong allelic association (p=0.0003) with OPLL was observed with intron 6 variant, which is at position −4 from the 3' splice junction.9 However, as far as we know, no investigation of this type has been so far performed in patients with DISH.

As the common clinical and metabolic features of OPLL and DISH can suggest their common aetiopathogenesis, a genotyping study on the COL 11 A2 gene was done in a group of 60 Czech patients with DISH. Diagnosis of DISH was based on the x ray changes on the spine. Sixty healthy Czech blood donors were controls. Genotyping was performed in DNA samples, 200 ng each, extracted from peripheral blood leucocyte cells. Polymorphism at intron 6 (−4) in the COL 11 A2 gene was determined by mutagenically separated polymerase chain reaction (PCR).10 For detection of the intron 6 (−4) allele, 16T and 16A primers, together with the common complementary strand primer G72, were used. In each PCR reaction, control DNAs of three known distinct genotypes and water as negative control were included. Comparison of the genotypic frequencies of single variants was made by contingency χ2 test.

Table 1 shows that no significant differences were found between results in patients with DISH and in healthy controls, with allele A frequency 34% v 37%, respectively, χ2=0.296 (df=1), p=0.587.

Table 1

Intron 6 (−4) allele frequency

In conclusion, results of analysis of intron 6 (−4) polymorphisms in the COL 11 A2 gene in Czech patients with DISH do not agree with data from Japanese patients with OPLL. However, the principal question of possible genetic relations between DISH and OPLL warrants further study, using a broader spectrum of genotyping and larger cohorts of patients.

Acknowledgments

This study was supported by a grant from the Grant Agency of the Czech Republic (No 311/98/1585).

References

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