GENETIC SUSCEPTIBILITY FOR INSULIN-DEPENDENT DIABETES-MELLITUS IN CAUCASIANS REVISITED - THE IMPORTANCE OF DIABETES REGISTRIES IN DISCLOSING INTERACTIONS BETWEEN HLA-DQ-LINKED AND INSULIN GENE-LINKED RISK

Citation
B. Vanderauwera et al., GENETIC SUSCEPTIBILITY FOR INSULIN-DEPENDENT DIABETES-MELLITUS IN CAUCASIANS REVISITED - THE IMPORTANCE OF DIABETES REGISTRIES IN DISCLOSING INTERACTIONS BETWEEN HLA-DQ-LINKED AND INSULIN GENE-LINKED RISK, The Journal of clinical endocrinology and metabolism, 80(9), 1995, pp. 2567-2573
Citations number
45
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Endocrynology & Metabolism
ISSN journal
0021-972X
Volume
80
Issue
9
Year of publication
1995
Pages
2567 - 2573
Database
ISI
SICI code
0021-972X(1995)80:9<2567:GSFIDI>2.0.ZU;2-I
Abstract
Whether genetic susceptibility for insulin-dependent diabetes mellitus (IDDM) at the 5' insulin gene polymorphic region (5' INS) interacts w ith human leukocyte antigen (HLA)-DQ-linked disease risk and whether i t is associated with autoantibody formation is presently controversial . Diabetes registries allow more systematic reassessment of these ques tions. Two hundred and ninety-six Caucasian IDDM patients were recruit ed by the Belgian Diabetes Registry and sampled at disease onset, toge ther with 195 ethnically matched control subjects. 5' INS genotypes we re determined by Southern blotting, HLA-DQ by allele-specific oligotyp ing, and autoantibodies by validated immunoassays. The 5' INS 1/1 geno type was more prevalent in patients than in controls [relative risk (R R) = 2.3; P < 10(-4)]. Regardless of age at onset, the 5' INS 1/1 geno type occurred less frequently in patients with the high-risk genotype DQA10301-DQB1*0302/DQA1*0501-DQB1*0201 than in patients without it (P < 0.04). The RR associated with this high-risk HLA-DQ genotype 124.9; 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 r isk 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 genot ypes no longer conferred a significant risk (2.9; not significantly di fferent from 1). In subjects carrying neutral, protective, or infreque nt HLA DQ genotypes, the overall RR for IDDM was significantly lower t han 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 I DDM susceptibility in subjects without the highest HLA-DQ-associated r isk.