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  • Association of polymorphisms and allelic combinations in the tumour necrosis factor-α-complement MHC region with coronary artery disease

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Association of polymorphisms and allelic combinations in the tumour necrosis factor-α-complement MHC region with coronary artery disease
  1. C Szalai1,
  2. G Füst2,3,
  3. J Duba4,
  4. J Kramer5,
  5. L Romics2,3,
  6. Z Prohászka2,3,
  7. A Császár6
  1. 1Section of Molecular Immunology, Hungarian Academy of Sciences, Budapest, Hungary
  2. 23rd Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary
  3. 3Research Group on Metabolism, Genetics and Immunology, Hungarian Academy of Sciences, Budapest, Hungary
  4. 4National Institute of Cardiology, Budapest, Hungary
  5. 5St János Hospital, Budapest, Hungary
  6. 61st Department of Medicine, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
  1. Correspondence to:
 Dr C Szalai, Heim Pál Paediatric Hospital, PO Box 66, Budapest, Hungary;
 szalai{at}heim.sote.hu

https://doi.org/10.1136/jmg.39.1.46

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    It is a complicating factor in the search for disease associated genes in the human population that most diseases are very heterogeneous clinically and that certain genetic factors may not alone cause susceptibility to a disease, but in association with other genetic and environmental factors. It is especially true for coronary artery disease (CAD) and disease susceptibility genes in the human major histocompatibility complex (MHC). Given the conservation of whole haplotypes (polymorphic frozen blocks or extended haplotypes) and the cis acting genes within the MHC, it is highly likely that disease association is the result of a multiplicity of interactive genetic influences rather than a single gene.1 By tradition, a disease is said to be MHC associated if the frequency of one or more alleles is increased or decreased significantly when a patient group is compared with a relevant control group. This approach cannot uncover the possible interactions of different alleles and may result in both false positive and false negative association. In our study on patients with CAD, we make an attempt to investigate not only the impact of single allelic variations within the MHC, but also the impact of a combination of these allelic variations on susceptibility to the disease.

    The tumour necrosis factor-α (TNFα) gene is located on chromosome 6 between the class I and III clusters of the human MHC.2 It has been suggested that TNFα plays a role in cardiovascular pathophysiology as it may affect lipid metabolism3 and predispose to obesity related insulin resistance.4 Several TNFα variants with polymorphisms in their promoter regions have been described.5 Two of them (−308G-A and −238G-A) have been found to be associated with a variety of MHC linked diseases.5–7

    Complement factor genes are located just a few hundred kilobases (kb) from the …

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