Concordance for Type 1 Diabetes in Identical Twins Is Affected by Insulin Genotype
- Karl A. Metcalfe, MRCP1,
- Graham A. Hitman, MD1,
- Rachel E. Rowe, MD1,
- Mohammed Hawa, BSC1,
- Xiaojian Huang, PHD2,
- Timothy Stewart, PHD2 and
- R. David G. Leslie, MD1
- 1Department of Diabetes and Metabolic Medicine, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, University of London, London, U.K.
- 2Genentech, South San Francisco, California
Abstract
OBJECTIVE—Monozygotic twins are usually discordant (only one twin affected) for type 1 diabetes. Discordance for disease between such twins implies a role for nongenetically determined factors but could also be influenced by a decreased load of diabetes susceptibility genes. The aim of this study was to determine whether two susceptibility genes were less prevalent in discordant twins compared with concordant twins.
RESEARCH DESIGN AND METHODS—We studied 77 monozygotic twin pairs (INS), 40 concordant and 37 discordant, for type 1 diabetes at polymorphism of the insulin gene region on chromosome 11p and HLA-DQBI.
RESULTS—The disease-associated INS genotype (Hph I) was identified in 87.5% of the concordant twins but only in 59.5% (P = 0.005) of the discordant twins. Neither DQB1*0201 nor DQB1*0302 was seen in 2 of 40 (5%) concordant twins compared with 8 of 37 (22%) discordant twins (P = 0.04). No statistical differences were seen between concordant and discordant twins at individual alleles of DQB1. Combining insulin and DQ data, 5% of concordant twins compared with 32.4% of discordant twins had neither DQB1*0201/DQB1*0302 nor the high-risk Hph I INS “++” genotype (P = 0.002).
CONCLUSIONS—We conclude that the possession of the high-risk Hph I insulin genotype increases the likelihood of identical twins being concordant for type 1 diabetes and that the “load” of both major histocompatibility complex (MHC) and non-MHC susceptibility genes has an impact on the disease penetrance of type 1 diabetes.
Footnotes
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Address correspondence and reprint requests to Graham A. Hitman, MD, Department of Diabetes and Metabolic Medicine, Medical Unit, The Royal London Hospital, Whitechapel, London E1 1BB, U.K. E-mail: G.A.Hitman{at}mds.qmw.ac.uk.
Received for publication 8 May 2000 and accepted in revised form 21 December 2000.
X.H. and T.S. are employed by and hold stock in Genentech. Genentech is engaged in the development of pharmaceuticals for the treatment of diabetes and its complications.
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