No association of multiple type 2 diabetes loci with type 1 diabetes
Raj SM., Howson JMM., Walker NM., Cooper JD., Smyth DJ., Field SF., Stevens HE., Todd JA.
Aims/hypothesis: We used recently confirmed type 2 diabetes gene regions to investigate the genetic relationship between type 1 and type 2 diabetes, in an average of 7,606 type 1 diabetic individuals and 8,218 controls, providing >80% power to detect effects as small as an OR of 1.11 at a false-positive rate of 0.003. Methods: The single nucleotide polymorphisms (SNPs) with the most convincing evidence of association in 12 type 2 diabetes-associated gene regions, PPARG, CDKAL1, HNF1B, WFS1, SLC30A8, CDKN2A-CDKN2B, IGF2BP2, KCNJ11, TCF7L2, FTO, HHEX-IDE and THADA, were analysed in type 1 diabetes cases and controls. PPARG and HHEX-IDE were additionally tested for association in 3,851 type 1 diabetes families. Tests for interaction with HLA class II genotypes, autoantibody status, sex, and age-at-diagnosis of type 1 diabetes were performed with all 12 gene regions. Results: Only PPARG and HHEX-IDE showed any evidence of association with type 1 diabetes cases and controls (p=0.004 and p=0.003, respectively; p>0.05 for other SNPs). The potential association of PPARG was supported by family analyses (p=0.003; p combined=1.0×10 -4). No SNPs showed evidence of interaction with any covariate (p>0.05). Conclusions/interpretation: We found no convincing genetic link between type 1 and type 2 diabetes. An association of PPARG (rs1801282/Pro12Ala) could be consistent with its known function in inflammation. Hence, our results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance.