In the present genetic association analysis performed on a Caucasian sample, we investigated the HIF-1α gene rs11549465 SNP, a C→T non synonymous SNP (g.C45035T) resulting in a substitution of proline to serine (P582S) in exon 12. Our result demonstrated a statistically significant decrease in frequencies of T allele containing genotypes (CT + TT), as well as in the T allele frequencies among individuals with diabetes (see Table 2). Of note, allele and genotype distribution was very similar between subjects with T1DM and those with T2DM. On the other hand both the T2DM and T1DM groups showed a statistically significant difference in allele and genotype distribution when compared to the control. In summary, a protective effect of the rare HIF-1α gene variant was proven against both, type 1 and type 2 diabetes, in a Caucasian sample.
As it was pointed out by earlier studies, it is highly relevant to replicate genetic association studies, because it is well known that there are significant differences in the frequencies of certain genetic variations among different ethnic groups. Our results regarding T2DM patients are in line with the first demonstration of association between the T allele in exon 12 of the HIF-1α gene and T2DM by Yamada and his colleagues. The frequency of the rare T allele in our control sample (13.3%) was comparable to previous reports on the European population , and indicated that the T allele is almost twice as frequent among Caucasians, than observed in Yamada's Japanese study group.
Due to the substantially different pathophysiological features of T1 and T2DM, candidate genes of T2DM have rarely been examined as candidate genes modifying the risk of T1DM [31, 32]. However recently an overlap has been proposed by Wilkin and coworkers . Their "accelerator hypothesis" suggests that T1 and T2 diabetes are the same disease of hyperglycemia-induced beta cell damage in which T1DM has the added effect of autoimmunity. Other findings have also strengthened this hypothesis from a genetic point of view by demonstrating familiar clustering of type 1 and type 2 diabetes mellitus [34–36]. There is also evidence that for selected susceptibility gene variants, there might be a shared genetic contribution to the pathogenesis of T1DM and T2DM. For example, the common variant of the peroxisome proliferator activated receptor γ gene isoform 2 (PPARγ2) Pro12Ala that has been consistently reported to associate with T2DM was recently shown to be associated with T1DM, as well . Moreover, Galanakis and coworkers just recently have shown that the intron 4 a/b polymorphism of the endothelial nitric oxide synthase gene (eNOS) is associated with both type 1 and type 2 diabetes . Our new finding that indicates a decreased number of the minor allele in the T1DM sample is another example for the possible shared genetic background of T2 and T1 diabetes.
The polymorphism investigated in our study causes a proline to serine change in the 582 position which is within the N-TAD near the ODD domain of the HIF-1α protein . Proline 582 has not been proven to be a HIF-1α hydroxylation site, and it is not known whether it mediates VHL binding. Moreover, the serine-proline substitution in this position does not appear to alter VHL binding in vitro to a fragment of HIF-1α after hydroxylation at proline 564 .
Previous in vitro functional analysis of this HIF-1α mutation gave conflicting results. First Yamada and his colleagues  indicated that the mutant variant has a consistently higher level of HIF-1α transcriptional activity than the wild-type. Since the enhanced transactivation capacity of the mutant was observed with statistical significance only under hypoxic condition, the authors suggested that this genetic variant, by enhancing the transcriptional activity of target genes, could be a protective factor against the onset of type 2 diabetes by its activities in the pancreatic developmental stage. Hlatky and coworkers  could not replicate these findings. We also attempted to demonstrate the functional importance of HIF-1α variants, however, we did not find any significant differences in the transcriptional activity of the HIF-1α variants using a luciferase reporter system (see Figure 1). One possible reason of this contradiction might be a relatively high endogenous HIF-1α activity in our cell line as measured in the presence of the luciferase vector with hypoxia responsive elements (Figure 1, pHRE) in the absence of any HIF-1α expression vector.
Tanimoto and colleagues suggested that the conformational changes caused by the amino acid substitution either might alter protein stability, or could enhance recruitment of transcriptional cofactors that interact with HIF-1α. Since, the authors could not detect any differences in degradation, the altered transactivational properties was taken into consideration as a possible molecular effect of Pro582Ser change . Further investigations in the field of cancer research demonstrated the rs11549465 variant to have enhanced transcription activities in in-vitro studies under both normoxic and hypoxic conditions [40, 41] associated with increased tumor microvessel density in head and neck cancer, and in prostate cancer. In conclusion, changes in the transactivational properties of the studied genetic variants could be hypothesized, however, their effect probably depends on the specific coactivators of various cell types.
HIF-1 is a major determinant in the expression and secretion of vascular endothelial growth factor (VEGF) by cells [42–44]. It has been shown that VEGF increases the survival of pancreatic islets and thus β cell sparing after islet transplantation by stimulating angiogenesis and improving islet revascularization [45, 46]. Moreover, transgenic mice that over-express VEGF are characterized by islet hyperplasia, suggesting that VEGF modulates endocrine pancreatic differentiation . Recent findings suggest that VEGF protects also against the development of T1DM and may play a role as a specific "pancreatic protector" . Therefore, one might speculate that the studied genetic variant of the HIF-1α, by enhancing the transcriptional activity of target genes, could be a protective factor against the onset of not only type 2 diabetes  but also that of type 1 diabetes by its activities in the pancreatic developmental stage.