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J Med Genet 2002;39:900-905 doi:10.1136/jmg.39.12.900
  • Original article

Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination

  1. P L Roddam1,
  2. S Rollinson1,
  3. M O’Driscoll2,
  4. P A Jeggo2,
  5. A Jack1,
  6. G J Morgan1
  1. 1Academic Unit of Haematology and Oncology, University of Leeds, Algernon Firth Building, Leeds, West Yorkshire LS2 9JT, UK
  2. 2Genome Damage and Stability Unit, University of Sussex, Falmer, Brighton, East Sussex BN1 9RR, UK
  1. Correspondence to:
 Professor G J Morgan, Academic Unit of Haematology and Oncology, University of Leeds, Algernon Firth Building, Leeds, West Yorkshire LS2 9JT, UK;
 garethm{at}pathology.leeds.ac.uk
  • Accepted 20 August 2002
  • Revised 20 August 2002

Abstract

The DNA double stranded break (DSB) repair mechanism, non-homologous end joining (NHEJ) represents an essential step in antigen receptor gene rearrangement mechanisms, processes believed to be intimately involved in the aetiology of lymphoproliferative disease. We investigated the potential impact that previously undescribed polymorphisms identified within NHEJ DNA ligase IV (LIG4) have upon predisposition to several lymphoproliferative disorders, including leukaemia, lymphoma, and multiple myeloma. Two LIG4 polymorphisms were examined, both C>T transitions, which result in the amino acid substitutions A3V and T9I. Inheritance of the LIG4 A3V CT genotype was found to be significantly associated with a two-fold reduction in risk of developing multiple myeloma (OR 0.49, 95% CI 0.27 to 0.89). Similarly, inheritance of the LIG4 T9I CT and the T9I TT genotypes were found to associate with a 1.5-fold reduction (OR 0.77, 95% CI 0.51 to 1.17) and a four-fold reduction (OR 0.22, 95% CI 0.07 to 0.70) in risk of developing multiple myeloma respectively, suggesting a gene dosage effect for this polymorphism. The LIG4 A3V and T9I variant alleles are in linkage disequilibrium (D‘=0.95, p<0.0001), and the protective effect associated with these polymorphisms was found to be the result of inheritance of the A3V-T9I CT and A3V-T9I TT haplotypes. These data suggest that genetic variants of NHEJ LIG4 may modulate predisposition to multiple myeloma, a tumour characterised by aberrant immunoglobulin (Ig) class switch recombination.

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