Of 2,256 relatives positive for at least one BAA on the first screening test, 486 (22%) did not return for follow-up. There were differences between this group and relatives who provided follow-up in age (mean = 22.4 vs. 20.4 years, respectively, P = 0.004) and multiple (greater than two) BAA positivity (21 vs. 27%, P = 0.02) but not in sex (female 57 vs. 59%, P = 0.43). Among the 1,770 relatives who were followed up, 142 developed diabetes after a mean of 1.3 years (range 0.02–4.9 years).
shows the prevalence of autoantibodies on the first screening test among BAA+ relatives. ZnT8A were found in 548 of 2,256 (24.3%) relatives positive for at least one BAA but were much less prevalent in BAA− relatives (8 of 911 [0.9%], P < 0.001 vs. BAA+ relatives). ZnT8A were strongly associated with the number of positive BAA, being present in 177 of 1,683 (10.5%) single BAA+, 221 of 384 (57.6%) double BAA+, and 150 of 189 (79.4%) triple BAA+ relatives (P < 0.001). ZnT8A were also associated with autoantibody type among single BAA+ relatives: ZnT8A were detected in 19 of 177 relatives (11%) with IAA, 109 of 177 (62%) with GAD65A, and 49 of 177 (28%) with IA-2A (P < 0.001). ZnT8A were more common in younger participants (454 of 1,316 [34.5%] aged <20 years vs. 94 of 940 [10.0%] relatives aged >20 years, P < 0.0001).
Prevalence of autoantibodies at screening
Samples for HLA typing were obtained in 723 BAA+ relatives. The prevalence of ZnT8A was strongly associated with high and moderate HLA risk genotypes compared with low risk genotypes (168 of 424 [39.6%] vs. 69 of 299 [23.1%], respectively, P < 0.0001). Among relatives with high and moderate risk genotypes, the respective ZnT8A+ rates were 60 of 126 (47.6%) and 108 of 298 (36.2%) (P = 0.03).
shows the cumulative incidence of diabetes in single standard BAA+
relatives subdivided by ZnT8A. ZnT8A were strongly associated with onset of diabetes, with an estimated 4-year risk (95% confidence limit) of 31% (19–46) compared with 7% (4–11) (P
< 0.001) among ZnT8A−
relatives. In relatives positive for ZnT8A and one other BAA, the 3-year cumulative diabetes incidence varied with the antibodies detected (GAD65A, 9%; IAA, 41%; and IA-2A, 45%; P
= 0.0002) (Supplementary Fig. 1
Figure 1 Cumulative incidences of diabetes in relatives positive for one standard BAA (IAA, GAD65A, or IA-2A) with or without ZnT8A. ICA+ relatives are excluded. The 95% confidence limits are indicated by the shaded areas. Diabetes risk was higher among ZnT8A (more ...)
shows diabetes risks in relatives positive for at least two standard BAA, subdivided by ZnT8A. The risk for diabetes was significantly higher (P
= 0.0001) among multiple BAA+
relatives who were also ZnT8A+
compared with those who were ZnT8A−
. The increased risk in ZnT8A+
relatives was concentrated in the subgroup with two BAA (P
= 0.0013) (Supplementary Fig. 2
). In relatives positive for all three standard BAA, diabetes risk was higher if they were also positive for ZnT8A, but this difference was not statistically significant compared with ZnT8A−
= 0.067) (Supplementary Fig. 3
). The risk for diabetes increased incrementally according to the number of positive tests for the standard BAA, ZnT8A, and ICA. Thus, the 3-year cumulative diabetes incidences (95% confidence limits) in relatives positive for two, three, four, and five autoantibodies were, respectively, 10 (6–15), 28 (21–36), 35 (18–62), and 52% (40–65).
Figure 2 Cumulative incidences of diabetes in multiple autoantibody (at least two standard BAA) positive relatives with or without ZnT8A. ICA+ relatives are excluded. The 95% confidence limits are indicated by the shaded areas. Diabetes risk was higher among ZnT8A (more ...)
The added impact of ICA positivity on diabetes risks in relatives positive for one or more of the standard BAA and ZnT8A is shown in and Supplementary Figs. 4–6
. The point estimates for diabetes risks by the 2nd year of follow-up were higher among ICA+
compared with ICA−
relatives irrespective of the number of other positive autoantibodies. The difference was statistically significant among ICA+
relatives with two other antibodies (P
< 0.0001) () and with one of the standard BAA (P
= 0.05) (Supplementary Fig. 4
) but not in relatives positive for three (P
= 0.07) and four (P
= 0.56) other autoantibodies (Supplementary Figs. 5 and 6
Figure 3 The cumulative incidence of diabetes in relatives positive for two BAA (any two of GAD65A, IAA, IA-2A, and ZnT8A) with or without ICA. The 95% confidence limits are indicated by the shaded area. Diabetes risk was higher among ICA+ relatives (P < (more ...)
In the proportional hazards regression that included HLA type (n = 723 subjects, n = 95 diabetic case subjects), age ≤20 years (hazard ratio 2.13, P = 0.03) and positive tests for IA-2A (2.15, P = 0.005), IAA (1.73, P = 0.01), ICA (2.37, P = 0.002), and ZnT8A (1.87, P = 0.03) were independently predictive of diabetes, whereas HLA type (high vs. low; moderate vs. low) and GAD65A positivity were not (adjusted P values = 0.81 and 0.86, respectively). In the model limited to age and autoantibodies (n = 1,767 subjects, n = 142 diabetic case subjects), age ≤20 years (1.77, P = 0.03) and positivity for IA-2A (2.17, P = 0.004), IAA (1.46, P = 0.03), ICA (2.33, P < 0.0001), and ZnT8A (2.65, P < 0.0001) independently predicted diabetes, but GAD65A were again not retained (adjusted P value = 0.55). These findings were similar in proportional hazards regressions using forward stepwise selection and that included sex as an additional variable.