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

BMJ 1999;318:698-702 ( 13 March )

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

Maria J Redondo, postdoctoral fellow, ^a Marian Rewers, associate professor, ^a Liping Yu, research associate, ^a Satish Garg, associate professor, ^a Colleen C Pilcher, technical officer, ^b Robert B Elliott, professor, ^b George S Eisenbarth, professor. ^a

^a Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Box B 140, Denver, CL 80262, USA, ^b Department of Paediatrics, University of Auckland School of Medicine, New Zealand

Correspondence to: Professor Eisenbarth george.eisenbarth{at}UCHSC.edu

Objective: To test the hypothesis that non-diabetic dizygoticand monozygotic twin siblings of patients with type 1 diabeteshave a similar high prevalence of islet cell autoantibodies, thussuggesting that islet cell autoimmunity is mainly environmentallydetermined.
Design: Prospective twinstudy.
Setting: Two specialist centres for diabetes in theUnitedStates.
Participants: Non-diabetic monozygotic twin (n=53), dizygotictwin (n=30), and non-twin (n=149) siblings of patients with type1 diabetes; 101controls.
Main outcome measures: Analysis of progression to diabetes and expressionof anti-isletautoantibodies.
Results: Monozygotic twin siblings had a higher riskof progression to diabetes (12/53) than dizygotic twin siblings(0/30; P<0.005). At the last follow up 22 (41.5%) monozygotictwin siblings expressed autoantibodies compared with 6 (20%) dizygotictwin siblings (P<0.05), 16 (10.7%) non-twin siblings (P<0.0001),and 6 (5.9%) controls (P<0.0001). Monozygotic twin siblings expressedmultiple ( $>=$ 2) antibodies more often than dizygotic twin siblings(10/38 v 1/23; P<0.05). By life table analysis the probabilityof developing positive autoantibodies was higher among the monozygotictwin siblings bearing the diabetes associated HLA DQ8/DQ2 genotypethan in those without this genotype (64.2% (95% confidence interval32.5% to 96%) v 23.5% (7% to 40%) at 10 years of discordance;P<0.05).
Conclusion: Monozygotic and dizygotic twins differ inprogression to diabetes and expression of islet cell autoantibodies.Dizygotic twin siblings are similar to non-twin siblings. Thesetwo observations suggest that genetic factors play an importantpart in determination of islet cell autoimmunity, thus rejectingthe hypothesis. In addition, there is a high penetrance of isletcell autoimmunity in DQ8/DQ2 monozygotic twinsiblings.

Key messages

Monozygotic twin siblings of patients with type 1 diabetes have a higher risk of progression to diabetes and of expressing islet cell antibodies than dizygotic twin and non-twin siblings
Monozygotic twins with the HLA genotype DQ8/DQ2 have a high risk of expression of islet cell autoimmunity and progression to diabetes
Islet cell autoimmunity seems to be predominantly genetically determined

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