As shown by our analysis (), none of the 13 SNPs from the 10 type 2 diabetes loci show statistically significant association. These 13 SNPs have a minor allele frequency range from 0.116 to 0.397. The statistical power of this study to detect an association from each SNP is shown in . Our study had sufficient power to detect an association with OR ≥1.20 for each SNP with different allele frequency. To further increase statistical power, we performed a combined analysis using the publicly available Wellcome Trust Case-Control Consortium (WTCCC) data (supplementary Table 1 [available in an online appendix at http://dx.doi.org/10,2337/db08-0270
]). The WTCCC tested 2,000 type 1 diabetic case and 3,000 control subjects for 500 k SNPs (Affymetrix
). As shown by the association analysis (), 12 of the 13 SNPs did not show statistical significance in either the WTCCC data alone or the combined analysis with our dataset. SNP rs1412829 in the CDKN2A/B
locus met the significance threshold of α = 0.00385 in the WTCCC data (P
= 0.002) (OR 0.879 [95% CI 0.810–0.954]) but not in the combined analysis (P
= 0.039) (0.929 [0.867–0.995]). CDKN2A
encode two specific inhibitors of cyclin-dependent kinase 4 (CDK4), i.e., p16INK4a
, respectively. CDK5 and CDK4 play important roles in β-cell function and proliferation (10
), and, as such, the locus is a reasonable functional candidate. Study of much larger cohorts will be needed to evaluate the possibility of a very weak effect in type 1 diabetes.
Type 1 diabetes association analysis
FIG. 1. The statistical power of this study to detect genetic associations with different minor allele frequencies (MAFs) at α = 0.05 level. The PPARG SNP rs2197423 has an MAF = 0.116; the CDKN2A/B SNP rs2383208 has an MAF = 0.176; (more ...)
Combined analysis of the WTCCC data and our data
Our study suggests that the type 2 diabetes loci do not play any obvious role in type 1 diabetes genetic susceptibility. These known type 2 diabetes genes are mainly involved in two mechanisms, i.e., pancreatic β-cell function and peripheral insulin sensitivity. To explore whether these genes may promote the early onset of type 1 diabetes by impairing insulin secretion or insulin sensitivity, we also investigated the age-at-onset difference of different genotypes for each type 2 diabetes SNP marker. As shown by the one-way ANOVA test of age at onset of three genotypes for each SNP (), no SNP has an obvious effect on the type 1 diabetes age at onset. Unlike type 2 diabetes, type 1 diabetes typically has an acute onset that can be reliably defined.
Both type 1 and type 2 diabetes are complex diseases. With the rapid technological development of functional genomics, distinct molecular mechanisms of the two diseases are being recognized, establishing the basis of different approaches for developing novel preventive or therapeutic strategies for type 1 and type 2 diabetes. In addition, this study highlights the importance of differentiation diagnosis of adult-onset type 1 diabetes from type 2 diabetes. Because type 1 diabetes does not share common genetic susceptibility with type 2 diabetes, it is important to manage different treatment for adult type 1 diabetic patients. Some issues remain for further studies on genetic mechanisms of type 1 and type 2 diabetes. The type 1 diabetes association of CDKN2A/B
needs to be confirmed by an independent study with a large sample size. Assuming a multiplicative effects model, an OR of 0.929, and a minor allele frequency of 0.452, a study with 5,790 case and 5,790 control subjects has 80% statistical power to replicate the association at α = 0.05. Both our study and the WTCCC study focused on pediatric-onset type 1 diabetes, and the possibility remains that type 2 diabetes loci may have some effect in adult-onset cases. Finally, the involvement of type 1 diabetes loci in type 2 diabetes genetics needs further investigation, the testing of which will require accurate phenotyping within the clinical spectrum of type 2 diabetes. For example, it will be interesting to study all type 1 diabetes loci in the subset of insulin-resistant, non–insulin-treated, adult-onset cases that are positive for islet autoantibodies (21