IJE Advance Access originally published online on December 22, 2005
International Journal of Epidemiology 2006 35(2):490-491; doi:10.1093/ije/dyi297
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Letter to the Editor |
Genes underlying common complex diseases
Department of Pharmacology, Christian Medical College, Vellore 632 002, India. E-mail: jpeedi{at}cmcvellore.ac.in
I read with interest the article by Yang et al.1 on the number of genes underlying the occurrence of common complex diseases in the population. They rightly stated that most common diseases are the result of complex interactions between multiple genes and environmental factors and that the identification of genes underlying these diseases represents a high public health priority since these diseases greatly contribute to the total public health burden.
The authors estimated the number of disease susceptibility genes needed to account for varying population attributable fractions (the proportions of disease cases in a population that would be prevented if an exposure was eliminated, assuming the exposure to be causal; PAF) of complex diseases. For simplicity of illustration the authors considered N independent biallelic disease susceptibility loci and that each genetic allele was assumed to have the same prevalence and risk ratio. They also assumed that there is only one at-risk genotype for each disease susceptibility locus. They used two models of interaction of the underlying genes: a purely additive model and a purely multiplicative model and assumed that these interactive effects are of the same magnitude for all genotypes involved.
I would like to make two comments on this article: First, a complexity involving common diseases unmentioned by the authors is epigenetics, which refers to heritable changes in gene expression that occur without any change in DNA sequence.2 Epigenetics is known to involve three interacting molecular mechanisms: DNA methylation, modification of histones (DNA packaging proteins), and RNA-mediated gene silencing.3 These mechanisms are known to be markedly influenced by the environment and are thought to play an important role in the pathogenesis of common diseases.4 Epigenetic variants of a genetic allele have been referred to as epialleles.5
Second, the authors suggested (p 1130 and p 1134) that since genetic risk factors cannot be eliminated, the importance of PAF in genetic predisposition to disease is undermined. However, this assumption may no longer be tenable because of the advent of a new therapeutic option, epigenetic therapy, which attempts to correct epigenetic defects.3 An epigenetic drug, 5-azacytidine, has recently been approved by the Food and Drug Administration for the treatment of myelodysplastic syndrome6 and many other epigenetic drugs are undergoing development.3
References
1 Yang Q, Khoury MJ, Friedman JM, Little J, Flanders WD. How many genes underlie the occurrence of common complex diseases in the population? Int J Epidemiol 2005;34:1129–37.
2 Wolffe AP, Matzke MA. Epigenetics: regulation through repression. Science 1999;286:481–86.
3 Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004;429:457–63.[CrossRef][Medline]
4 Bjornsson HT, Fallin MD, Feinberg AP. An integrated epigenetic and genetic approach to common human disease. Trends Genet 2004;20:350–58.[CrossRef][Web of Science][Medline]
5 Peedicayil J. Epialleles and common disease. Med Hypotheses 2005;64:215.[Medline]
6 Laird PW. Cancer epigenetics. Hum Mol Genet 2005;14:R65–76.
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