Monday, August 25, 2008

Genetics of T2D among Ashkenazi Jews: Replication and predictive value of genetic information

Last year 10 loci associated with type-2 Diabetes (T2D) were identified in a WGAS (whole genome association study) and replicated in various large samples (Scott et al. 2007). Here, they assess the association between these 10 loci and T2D among Ashkenazi Jews in Israel (all four grandparents are Ashkenazi Jews). They find that most markers show similar ORs as the Scott et al. meta-analysis, and p-values lower than 0.1 for 7 out of the 10 loci. They then look at the predictive power of information on these 10 loci on the risk of developing T2D, and find that it is rather limited (at least among Ashkenazi Jews):
"Consistent with the previous findings showing that such set of SNPs may explain only a small fraction (2–3%) ofthe trait variation (Saxena et al. 2007), we have also found that the predictive value of these findings is relatively limited.
For most individuals, the genotypic information will only modestly alter their baseline risk to develop T2D. Only for a small fraction of the population (about 3%), the genetic information may indicate a decrease or increase of the baseline risk by twofold (upwards or downwards). Consequently, at present, the use of genetic information by clinicians for the identification of patients at risk to develop T2D does not seem too relevant. Nevertheless, it is important to emphasize that the value of gene discovery lies primarily in the understanding of the disease as a means to develop efficient therapies."
Type 2 diabetes susceptibility loci in the Ashkenazi Jewish population.
Bronstein M, Pisanté A, Yakir B, Darvasi A.
Human Genetics
2008 Aug;124(1):101-4.
Abstract: Until last year, type 2 diabetes (T2D) susceptibility loci have hardly been identified, despite great effort. Recently, however, several whole-genome association (WGA) studies jointly uncovered 10 robustly replicated loci. Here, we examine these loci in the Ashkenazi Jewish (AJ) population in a sample of 1,131 cases versus 1,147 controls. Genetic predisposition to T2D in the AJ population was found similar to that established in the previous studies. One SNP, rs7754840 in the CDKAL1 gene, presented a significantly stronger effect in the AJ population as compared to the general Caucasian population. This may possibly be due to the increased homogeneity of the AJ population. The use of the SNPs considered in this study, to identify individuals at high (or low) risk to develop T2D, was found of limited value. Our study, however, strongly supports the robustness of WGA studies for the identification of genes affecting complex traits in general and T2D in particular.

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