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Genetic susceptibility for insulin-dependent diabetes mellitus in Caucasians revisited: the importance of diabetes registries in disclosing interactions between HLA-DQ- and insulin gene-linked risk. Belgian Diabetes Registry

Genetic susceptibility for insulin-dependent diabetes mellitus in Caucasians revisited: the... Abstract Whether genetic susceptibility for insulin-dependent diabetes mellitus (IDDM) at the 5' insulin gene polymorphic region (5' INS) interacts with human leukocyte antigen (HLA)-DQ-linked disease risk and whether it is associated with autoantibody formation is presently controversial. Diabetes registries allow more systematic reassessment of these questions. Two hundred and ninety-six Caucasian IDDM patients were recruited by the Belgian Diabetes Registry and sampled at disease onset, together with 195 ethnically matched control subjects. 5'INS genotypes were determined by Southern blotting, HLA-DQ by allele-specific oligotyping, and autoantibodies by validated immunoassays. The 5' INS 1/1 genotype was more prevalent in patients than in controls [relative risk (RR) = 2.3; P < 10(-4)]. Regardless of age at onset, the 5' INS 1/1 genotype occurred less frequently in patients with the high-risk genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 than in patients without it (P < 0.04). The RR associated with this high-risk HLA-DQ genotype (24.9; P < 10(-6)) was not affected by the presence or absence of the 5' INS 1/1 genotype. Combined positivity for the 5' INS 1/1 genotype and for one of three other HLA-DQ genotypes associated with an intermediate risk for IDDM conferred an age-independent RR of 12.1 (P < 10(-4)). In the absence of the 5' INS 1/1 genotype, intermediate-risk HLA-DQ genotypes no longer conferred a significant risk (2.9; not significantly different from 1). In subjects carrying neutral, protective, or infrequent HLA-DQ genotypes, the overall RR for IDDM was significantly lower than 1 (0.2; P < 10(-6)) in the absence of the 5' INS 1/1 genotype but not in its presence (0.8; not significantly different from 1). The 5' INS 1/1 genotype was not preferentially associated with immune markers for IDDM. In conclusion, regardless of age at onset and the presence of autoantibodies, 5' INS polymorphisms contribute preferentially to IDDM susceptibility in subjects without the highest HLA-DQ-associated risk. This content is only available as a PDF. Copyright © 1995 by The Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Genetic susceptibility for insulin-dependent diabetes mellitus in Caucasians revisited: the importance of diabetes registries in disclosing interactions between HLA-DQ- and insulin gene-linked risk. Belgian Diabetes Registry

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References (29)

Publisher
Oxford University Press
Copyright
Copyright © 1995 by The Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
DOI
10.1210/jcem.80.9.7673396
Publisher site
See Article on Publisher Site

Abstract

Abstract Whether genetic susceptibility for insulin-dependent diabetes mellitus (IDDM) at the 5' insulin gene polymorphic region (5' INS) interacts with human leukocyte antigen (HLA)-DQ-linked disease risk and whether it is associated with autoantibody formation is presently controversial. Diabetes registries allow more systematic reassessment of these questions. Two hundred and ninety-six Caucasian IDDM patients were recruited by the Belgian Diabetes Registry and sampled at disease onset, together with 195 ethnically matched control subjects. 5'INS genotypes were determined by Southern blotting, HLA-DQ by allele-specific oligotyping, and autoantibodies by validated immunoassays. The 5' INS 1/1 genotype was more prevalent in patients than in controls [relative risk (RR) = 2.3; P < 10(-4)]. Regardless of age at onset, the 5' INS 1/1 genotype occurred less frequently in patients with the high-risk genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 than in patients without it (P < 0.04). The RR associated with this high-risk HLA-DQ genotype (24.9; P < 10(-6)) was not affected by the presence or absence of the 5' INS 1/1 genotype. Combined positivity for the 5' INS 1/1 genotype and for one of three other HLA-DQ genotypes associated with an intermediate risk for IDDM conferred an age-independent RR of 12.1 (P < 10(-4)). In the absence of the 5' INS 1/1 genotype, intermediate-risk HLA-DQ genotypes no longer conferred a significant risk (2.9; not significantly different from 1). In subjects carrying neutral, protective, or infrequent HLA-DQ genotypes, the overall RR for IDDM was significantly lower than 1 (0.2; P < 10(-6)) in the absence of the 5' INS 1/1 genotype but not in its presence (0.8; not significantly different from 1). The 5' INS 1/1 genotype was not preferentially associated with immune markers for IDDM. In conclusion, regardless of age at onset and the presence of autoantibodies, 5' INS polymorphisms contribute preferentially to IDDM susceptibility in subjects without the highest HLA-DQ-associated risk. This content is only available as a PDF. Copyright © 1995 by The Endocrine Society

Journal

Journal of Clinical Endocrinology and Metabolism – Oxford University Press

Published: Sep 1, 1995

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