In univariate analyses, UBASH3A
(rs11203203) was the only non-HLA SNP that predicted significantly both IA (hazard ratio [HR] 1.52 [95% CI 1.16–2.00], P
= 0.0024) and type 1 diabetes (2.02 [1.40–2.91], P
= 0.0002). The PTPN22
polymorphisms were both associated with IA (1.82 [1.27–2.61], P
= 0.001, and 1.46 [1.05–2.02], P
= 0.03, respectively), whereas the INS
polymorphism was significantly associated with diabetes (1.75 [1.09–2.83], P
= 0.02) (data not shown). There were no significant interactions between any of the SNPs and HLA-DR3/4-DQB1*0302. Multivariate analyses adjusting for family history of type 1 diabetes and HLA high-risk genotype are shown in . PTPN22
were significantly associated with both IA and type 1 diabetes. INS
remained significantly associated with diabetes outcome, whereas PTPN2
remained associated with IA. Stratified analyses by cohort are shown in Supplementary Table 1
. Overall, results are similar, although some of the SNPs do not reach statistical significance, which is likely due to smaller numbers. GAB3 shows a borderline significant association with diabetes in only FDRs; the rs2664170 G allele, previously associated with diabetes, is negatively associated with diabetes. These results should be interpreted with caution because of small sample size.
Association of non-HLA genes with IA and type 1 diabetes in DAISY NHW population (N = 1,743)*
Multivariate regression analyses including all SNPs with P value <0.05 were performed for both IA () and type 1 diabetes (). Genes that remained significantly associated with IA, adjusting for family history of type 1 diabetes and HLA-DR3/4-DQB1*0302, included PTPN22, UBASH3A, and INS. The final model for diabetes included the same five variables as for IA (PTPN22, UBASH3, INS, family history of type 1 diabetes, and HLA-DR3/4-DQB1*0302).
HRs and 95% CIs for predictors in multivariate model for IA. Model including all variables with an α level of <0.05. GP, general population.
HRs and 95% CIs for predictors in multivariate model for type 1 diabetes. Model including all variables with an α level of <0.05. GP, general population.
The most frequent combinations of the above five significant variables are shown in . Hazard ratios for the development of IA ranged from 1.6 to 13 for general population children and from 3.8 to 16 for FDRs, for those combinations that were present in >2% of the DAISY NHW population (). For the same combinations, HRs for type 1 diabetes ranged from 2.4 and 6.7 for general population and FDRs, respectively, to >40 for both (). These 15 combinations included 67% of the population studied but only half of the cases. Only 82 subjects (4.7%) of the DAISY NHW population were FDRs with the HLA-DR3/4-DQB1*0302 genotype. When adding the three non-HLA genes (PTPN22, UBASH3, and INS), none of the specific combinations in this high-risk group were present in >2% of the population.
FIG. 3. HR estimates for the most frequent combinations for IA (A) and type 1 diabetes (B). The height of the bars indicates the magnitude of the HR for the group of patients described by the predictor variables displayed in the table below the bars. The x-axis (more ...)
Antibody levels for insulin, GAD65, and IA-2 were analyzed for correlation with INS
, and UBASH3A
polymorphisms. Children with the INS
AA genotype had higher mean insulin autoantibody (IAA) levels compared with those carrying the AT/TT genotype (P
= 0.02), whereas children with the UBASH3A
AA genotype had higher mean IA-2 levels (P
= 0.03) (Supplementary Fig. 1