2014-LB: Association between Variants in Genes Involved in the Metabolism of Uric Acid and the Risk of Type 2 Diabetes

Introduction & Objective: Epidemiological and experimental evidence suggests that hyperuricemia is involved in the pathophysiology of type 2 diabetes (T2D), inducing insulin resistance or beta cell failure. Therefore, our objective was to investigate a possible association between variants in genes related to uric acid metabolism and T2D in a case-control study design.

Methods: Our sample consisted of 624 T2D patients from Greece and 356 normoglycemic, ancestry-matched controls. In the control group, individuals over 65 years of age were included to minimize the probability that T2D will present at a later stage in their life. The samples were genotyped on Illumina Human PsychArray 24 v1.1. We focused our investigation on 30 genes involved in the metabolism of uric acid. We conducted allelic and genotypic tests using PLINK v1.9. The significance of the association was determined using permutation for each type of test. Furthermore, we performed haplotypic tests using BEAGLE v3.2.3. SNPs with association P-values <0.05 were selected for permutation analysis.

Results: In the allelic tests our top hit was a rare variant, rs35008345 residing on the SLC22A1 gene, which was detected only in the control group, suggesting a potential protective role against the development of T2D (p<0.001). Genotypic tests revealed significant associations in the REN and ABCG4 genes, with ABCG4 harboring four markers (rs4301800: OR 1.269; 95% CI 1.053-1.530, p=0.012, rs643423: OR 1.210; 95% CI 1.001-1.463, p=0.048, rs4245191: OR 1.213; 95% CI 1.004-1.467, p=0.045, rs7234: OR 0.801; 95% CI 0.666-0.963, p=0.018) and REN harboring one marker (rs6693954: OR 0.748; 95% CI 0.613-0.914, p<0.01).

Conclusion: Our results suggest a potential role for variants in uric acid genes in the pathogenesis of T2D. Further studies are needed to validate these findings and clarify whether the detected associations are causal.