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
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
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.