For effective reduction of the effect of diabetes and its complications and numerous public and personal health consequences, every effort must be made to minimize the development of diabetes and early progression to diabetic complications. A current limitation of progress in this regard is uncertainty on who is "at risk." Although there are no recognized preventive measures for type 1 diabetes, numerous studies have demonstrated the relative efficacy of weight loss, diet, and exercise on normalization of glucose homeostasis, even in individuals with no clinical manifestations of type 2 diabetes (48,49). Unfortunately, despite significant relative risk reduction of these procedures, the absolute risk reduction remains low, resulting in the need to treat several hundred "healthy" (without diabetes) individuals to prevent a single person from progressing to overt disease event. The low absolute risk reduction in any single individual may also contribute to the underutilization of these procedures by patients and would require substantial increases in health care cost if it were administered to all patients who are at risk. It is also clear that many people develop diabetes and (ultimately) diabetic complications despite the absence of these risk factors. These facts underscore the need to develop more effective means to identify individuals who are most likely to develop diabetes and complications for targeted intervention and to continue to explore underlying mechanisms that contribute to their greater risk for disease. Genetic characterization is one important facet of an individual's risk profile that has yet to be proved as an efficacious strategy, yet it has the potential to allow a targeted and effective approach to identify a smaller subset of patients for whom specific interventions/treatments should be most effective. It is apparent from genetic studies of DN and studies of other diseases such as type 1 diabetes and type 2 diabetes that confirmation of results in different populations are of great value in trying to assess the validity of individual findings. Evidence of confirmation from multiple studies is the most widely used metric for accepting evidence of the importance of a gene in contribution to variation to risk for diabetes and its complications. Although this outcome would be comforting, there are (at least) two situations that limit the utility of population replication as a means for determining success of susceptibility gene identification. One limitation is if the "truth" in the genetics of diabetes or complications is in a series of population-specific private mutations within a common susceptibility framework. In this case, each population would be consistent with evidence for linkage at multiple sites, but the specific pattern of mutations could be different. A second limitation is that the same constellation of genetic factors contributes to susceptibility in all populations, but the subset of factors and effect sizes may differ. Thus, simple comparison of results across populations may provide erroneous "failure to replicate." The technology for carrying out large-scale molecular genetic studies is rapidly improving. In the near future, it will be possible to combine the power and the ease of association studies with comprehensive examination of the genome (whole genome association). One intriguing study that used elements of this approach has been reported (50) with 55,000 gene-based SNP loci. A single gene encoding solute carrier family 12 member 3 (SLC12A3), the gene associated with Gitelman's syndrome, exhibited consistent evidence for association with DN susceptibility with a single SNP in intron 24 having statistically significant association. The results suggested that the Arg913Gln substitution in the SLC12A3 gene provided protection from development of DN. With increasing coverage of the genome (approximately 500,000 SNP), these studies may become a valuable tool in identification of common variants that enhance the search for diabetes and complication susceptibility genes. Copyright © 2006 by the American Society of Nephrology.
CITATION STYLE
Rich, S. S. (2006). Genetics of diabetes and its complications. Journal of the American Society of Nephrology. American Society of Nephrology. https://doi.org/10.1681/ASN.2005070770
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