Concordance for type 1 diabetes in identical twins is affected by insulin genotype.
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.


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 11 p 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.
Metcalfe
K A
KA
Department 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, UK.
Hitman
G A
GA
Rowe
R E
RE
Hawa
M
M
Huang
X
X
Stewart
T
T
Leslie
R D
RD
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000097:blood; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D004200:Diseases in Twins / Q000453:epidemiology* / Q000235:genetics*; D006580:Genetic Carrier Screening; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006801:Humans; D007223:Infant; D007328:Insulin / Q000235:genetics*; D007527:Isoenzymes / Q000276:immunology; D011110:Polymorphism, Genetic; D015995:Prevalence; D012307:Risk Factors; D014430:Twins, Monozygotic; D006113:United Kingdom / Q000453:epidemiology; D044465:White People
D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C096322:ICA512 autoantibody; D007328:Insulin; D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2