In diabetes-free individuals, plasma CRP levels were lower among the S319 allele carriers compared to non-carriers, although both group mean CRP levels were within the average risk range for cardiovascular events (1.0-3.0 mg/L) . Among individuals with type 2 diabetes, however, CRP levels were elevated to the high risk range for cardiovascular events (> 3 mg/L) in both S319 allele carriers and non-carriers. In addition, the difference in CRP levels between the S319 carrier statuses was not present in those with diabetes, who are likely under chronic inflammatory stress.
Genetic variations in the HNF1A gene encoding HNF-1α protein have been associated with plasma CRP concentrations in predominantly European Caucasian samples [3–5]. In a genome-wide association study, several loci including HNF1A which are involved in protein production related to insulin resistance, beta-cell function, weight gain, diabetes and/or early atherogenesis were associated with plasma CRP . Therefore, the authors argued that variation in genes including HNF1A may have subsequent impact on vascular disease and diabetes risk that is influenced or marked by circulating CRP concentrations. In another genome-wide study, however, it was reported that the HNF1A locus was not associated with CHD although the locus was associated with CRP levels , arguing against a causal association of CRP with CHD.
Although the association of CRP with increased risk of developing cardiovascular disease has been well documented [1, 2, 5], previous studies on the association of CRP with incident type 2 diabetes have been less consistent. Several studies associated increased baseline levels of CRP [18, 19]with incident type 2 diabetes, while others reported no association, including a report from the current study population [20–22]. We have previously reported a higher prevalence of type 2 diabetes among HNF1A S319 carriers compared to non-carriers in this population , which is paradoxical in the context of the current finding of S319 carriers having a low level of CRP. The higher prevalence of type 2 diabetes observed among S319 carriers is likely explained by the compromised ability of these subjects to mount an adequate insulin response, resulting in an earlier loss of glycemic control .
HNF-1α protein binding to promoter regions of the CRP gene, down stream of the IL-6 responsive site, is known to be involved in synergistic trans-activation of CRP promoter [23–25]. The HNF1A G319S genomic sequence was recently reported to give rise to two abnormal transcripts, with altered quantities of the normal splicing products and reduced total HNF1A transcript levels . Therefore, under the acute-phase signaling mechanism, abnormal HNF-1α produced by S319 carriers may have an impact on CRP production explaining the lower CRP level observed among non-diabetic individuals with the HNF1A G319S polymorphism. Among individuals with diabetes who are likely under chronic inflammatory stress, however, another mechanism may be modulating increased circulating CRP. Stimulation of the CRP promoter caused by increased circulating IL-6 and/or other signaling factors involved may be responsible for the increase in CRP levels in diabetic subjects , while the synergistic effects of HNF-1α contributing to CRP expression would be masked in this setting [23–25].
Since ethnic variation in polymorphisms within the coding regions of HNFs has been reported in non-European populations [28–30], it was important to confirm the association of the population-specific polymorphism, HNF1A G319S, with CRP. The current study provides evidence that variation in HNF1A is associated with variation in CRP in diabetes-free individuals (although not in those with diabetes) in populations other than European Caucasians.