Post Genome-Wide Association Studies of Novel Genes Associated with Type 2 Diabetes Show Gene-Gene Interaction and High Predictive Value

Abstract

BackgroundRecently, several Genome Wide Association (GWA) studies in populations of European descent have identified and validated novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D). Our aims were to validate these markers in other European and non-European populations, then to assess their combined effect in a large French study comparing T2D and normal glucose tolerant (NGT) individuals.Methodology/Principal FindingsIn the same French population analyzed in our previous GWA study (3,295 T2D and 3,595 NGT), strong associations with T2D were found for CDKAL1 (ORrs7756992 = 1.30[1.19–1.42], P = 2.3×10−9), CDKN2A/2B (ORrs10811661 = 0.74[0.66–0.82], P = 3.5×10−8) and more modestly for IGFBP2 (ORrs1470579 = 1.17[1.07–1.27], P = 0.0003) SNPs. These results were replicated in both Israeli Ashkenazi (577 T2D and 552 NGT) and Austrian (504 T2D and 753 NGT) populations (except for CDKAL1) but not in the Moroccan population (521 T2D and 423 NGT). In the overall group of French subjects (4,232 T2D and 4,595 NGT), IGFBP2 and CXCR4 synergistically interacted with (LOC38776, SLC30A8, HHEX) and (NGN3, CDKN2A/2B), respectively, encoding for proteins presumably regulating pancreatic endocrine cell development and function. The T2D risk increased strongly when risk alleles, including the previously discovered T2D-associated TCF7L2 rs7903146 SNP, were combined (8.68-fold for the 14% of French individuals carrying 18 to 30 risk alleles with an allelic OR of 1.24). With an area under the ROC curve of 0.86, only 15 novel loci were necessary to discriminate French individuals susceptible to develop T2D.Conclusions/SignificanceIn addition to TCF7L2, SLC30A8 and HHEX, initially identified by the French GWA scan, CDKAL1, IGFBP2 and CDKN2A/2B strongly associate with T2D in French individuals, and mostly in populations of Central European descent but not in Moroccan subjects. Genes expressed in the pancreas interact together and their combined effect dramatically increases the risk for T2D, opening avenues for the development of genetic prediction tests.

Construction of a prediction model for type 2 diabetes mellitus in the Japanese population based on 11 genes with strong evidence of the association

“…17 Two earlier cumulative risk assessments for type 2 diabetes in Asian populations with relatively small numbers of associated loci yielded values of 1.17 and 1.24 for the fold increase in risk for each additional risk allele. 11,34 In our prediction model for type 2 diabetes, the AUC for the ROC curve was lower than that in the earlier study 17 based on 15 loci in Caucasians (0.72 and 0.86, respectively). However, the number of loci in our study (11 loci) was lower than that in the study for Caucasians.…”

“…6 Follow-up of GWASs includes analysis of second-tier genes, metaanalysis for specific populations, as well as analysis of gene-gene or gene-environment interactions. A large-scale meta-analysis 16 and an analysis of gene-gene interaction for susceptibility genes 17 have been performed for type 2 diabetes in populations of European ancestry.…”

CDKAL1 and type 2 diabetes: a global meta-analysis

“…Replication studies reported significant associations between type 2 diabetes and rs10946398, rs7754840 and rs7756992 in the Han Chinese population (Liu et al, 2008), and rs10946398 and rs7754840 in the African American population (Lewis et al, 2008). However, the only trend found for association in the Morrocan population was for rs7754840 and rs10946398 (Cauchi et al, 2008a). Significant associations between rs7756992 and type 2 diabetes in Han Chinese individuals from Hong Kong (Steinthorsdottir et al, 2007), French individuals first set (Cauchi et al, 2008a) and Japanese (Horikoshi et al, 2007;Omori et al, 2008) were observed.…”

Predicting Type 2 Diabetes Based on Polymorphisms From Genome-Wide Association Studies

“…However, because of smaller numbers of cases in the subgroups, these results should be interpreted with caution. Cauchi et al (25) reported gene-gene interactions of recently discovered loci but did not report on the effects of these interactions on the AUC. Earlier studies found no evidence for strong gene-gene interactions (15,16).…”