Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study

Objective To test the hypothesis that non-diabetic dizygotic and monozygoti c twin siblings of patients with type 1 diabetes have a similar high preval ence of islet cell autoantibodies, thus suggesting that islet cell autoimmu nity is mainly environmentally determined. Design Prospective twin study. Setting Two specialist centres for diabetes in the United States. Participants Non-diabetic monozygotic twin (n = 53). dizygotic twin (n = 90 ), and non-twin (n = 149) siblings of patients with type 1 diabetes; 101 co ntrols. Main outcome measures Analysis of progression to diabetes and expression of anti-islet autoantibodies. Results Monozygotic twin siblings had a higher risk of progression to diabe tes (12/53) than dizygotic twin siblings (0/30; P < 0.005). At the last fol low up 22 (41.5%) monozygotic twin siblings expressed autoantibodies compar ed with 6 (20%) dizygotic twin siblings (P < 0.05), 16 (10.7%) non-twin sib lings (P < 0.0001), and 6 (5.9%) controls (P < 0.0001). Monozygotic twin si blings expressed multiple (greater than or equal to 2) antibodies more ofte n than dizygotic twin siblings (10/38 v 1/23; P < 0.05). By life table anal ysis the probability of developing positive autoantibodies was higher among the monozygotic twin siblings bearing the diabetes associated HLA DQ8/DQ2 genotype than in those without this genotype (64.2% (95% confidence interva l 32.5% to 96%) v 23.5% (7% to 40%) at 10 years of discordance; P < 0.05). Conclusion Monozygotic and dizygotic twins differ in progression to diabete s and expression of islet cell autoantibodies. Dizygotic twin siblings are similar to non-twin siblings. These two observations suggest that genetic f actors play an important part in determination of islet cell autoimmunity, thus rejecting the hypothesis. In addition, there is a high penetrance of i slet cell autoimmunity on DQ8/DQ2 monozygotic twin siblings.