It is often difficult to distinguish between type 1 (T1D) and type 2 diabetes (T2D), particularly in young adulthood. Both T1D and T2D have significant genetic contributions to risk and understanding their genetic overlap may offer clinical insight. We examined whether a T1D genetic risk score (GRS) is associated with clinical features and diagnosis of T2D in the Framingham Heart Study (FHS).
We constructed a T1D GRS based on 79 SNPs from fine mapping results, with SNPs weighted by published effect sizes. The GRS included both HLA (27 SNPs) and non-HLA (52 SNPs) regions, and was applied to 1503 participants with T2D. Multivariable regression models assessed the association of the GRS with age of T2D onset, BMI, HbA1C, HOMA-β and HOMA-IR at the exam of diagnosis. Case-control analysis of 1503 cases and 5649 controls was done using multivariate generalized estimating equations (GEE) logistic models to determine the association between the T1D GRS and T2D risk with age and sex as covariates.
In FHS participants, the mean age was 57.2 y, BMI was 30 kg/m2, and HbA1c 6.05%. The T1D GRS was not associated with T2D age of onset, or BMI, HbA1c, HOMA-β and HOMA-IR after excluding participants on medications for T2D. There was a trend towards lower HOMA-β and HOMA-IR values in the top quintile of the GRS (n=244, mean=2.47, SD= 0.7 for ln(HOMA-β) and mean=2.88, SD=0.8 for ln(HOMA-IR)) when compared to the lowest quintile of the GRS (n=260, mean= 2.53, SD=0.8 for ln(HOMA-β) and mean=2.92, SD=0.8 for ln(HOMA-IR)). The T1D GRS was associated with T2D (β = 0.per SD increase in GRS, SE= 0.03, OR =1.1, P = 0.04). When the non-HLA and HLA components of the GRS were tested separately, the results remained significant only for the non-HLA T1D GRS (β = 0.per SD increase in GRS, SE= 0.03, OR=1.1, P= 0.02).
A T1D GRS of non-HLA SNPs is associated with T2D in the FHS participants. Our further analysis with increased sample size in multi-ethnic populations may refine the impact of the T1D GRS to characterize individuals with T2D.
S. Srinivasan: None. A. Leong: None. M. Udler: None. B.C. Porneala: None. J.B. Meigs: None. S.S. Rich: None. J. Dupuis: None.