Abstract
Genomic imprinting refers to a class of transmissible genetic effects in which the expression of the phenotype in the offspring depends on the parental origin of the transmitted allele. The DNA from one parent may be epigenetically modified so that only a single allele of the imprinted gene is expressed in the offspring. Although imprinting has an important role in the regulation of growth and development through its role in regulating gene expression, its contribution to susceptibility to common complex disorders is not well understood. We summarize current views on the role of imprinting in diabetes and in particular chromosome 6q24-related transient neonatal diabetes mellitus, the best known example of an imprinted genetic disorder that leads to diabetes.
Highlights
Introduction e past 2 years have been marked by the discovery of some 30 new genes associated with type 2 diabetes mellitus (T2DM) and 40 associated with type 1 diabetes mellitus (T1DM) [1,2]. ese have been discovered by association studies using very large sample sizes, and the susceptibility alleles discovered are associated with modest increases in diabetes risk of 10 to 20%
Expression of these risk alleles is probably influenced by the presence of other diabetes risk factors, such as lifestyle, viral exposures and perhaps other genetic variants
In addition to the susceptibility genes identified through conventional association studies, a small number of diabetes-associated genes has been discovered whose effects are mediated through imprinting
Summary
Efforts to identify imprinted genes have been enhanced greatly by the development of new genome-scale technologies for epigenomic profiling (for example, [50]) and by the cataloguing of known im printed genes [12,51]. As demonstrated by the case of 6q24-related TNDM, knowledge of the role of imprinting in disease has profound implications for recurrence risks in relatives. Using known SNPs to predict risk for polygenic T1DM or T2DM has not yet proven useful in a clinical setting. As the genetic architecture of these diseases continues to be revealed, such prediction may become feasible, and knowledge of the imprinting status of the relevant loci is likely to be an important component of building accurate risk models. Regardless of future clinical usage, paying careful attention to imprinting status clearly enhances the ability to accurately detect associations that will provide information important for continuing to elucidate the etiology of these complex diseases. Abbreviations DMR, differentially methylated region; HIL, hypomethylation at imprinted loci; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TNDM, transient neonatal diabetes mellitus; UPD, uniparental disomy. Competing interests The authors declare that they have no competing interests
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