Genetic susceptibility markers in Danish patients with type 1 (insulin-dependent) diabetes--evidence for polygenicity in man. Danish Study Group of Diabetes in Childhood.
Fifty-five Danish families with two offspring concordant for type 1 diabetes--identified through a nationwide population-based survey, and 57 "true sporadic" cases--matched with familial cases for age at onset, but with no IDDM-affected first-degree relatives and long disease duration, and 110 control subjects were typed for putative genetic susceptibility markers for type 1 diabetes identified from a pathogenetic model. The markers included MHC class I, II and III loci, the manganese superoxide dismutase (MnSOD) locus (chr. 6q), interleukin-1 beta (IL1B), the IL-1 receptor antagonist (IL1RN), and the IL-1 type 1 receptor (IL1RI) loci (each chr. 2q). No significant differences between familial and sporadic cases were found within the MHC region (including the following loci: HLA-DQ, -DR, heat shock protein (HSP) 70, tumour necrosis factor (TNF), HLA-B and -A). In both groups of patients 11% were negative for both DQA1*0301-DQB1*0302 and DQA1*0501-DQB1*0201 genotypes, and 7% of the type 1 diabetics had genotypes unable to encode a susceptibility DQ alpha beta heterodimer. Disease association was found for the IL1RN (p = 0.04) and for the IL1RI (p = 0.03). When comparing controls and only familial cases with type 1 diabetes for the IL1RN polymorphism a difference was observed (p = 0.003). For the IL1B RFLP a trend for difference was observed between familial cases and control subjects (p = 0.046), whereas no differences between sporadic cases and control subjects could be demonstrated neither at the IL1B nor at the IL1RN loci. A difference in the MnSOD pattern was observed between sporadic cases and controls (p = 0.04).
Pociot
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F
Steno Diabetes Center, Gentofte, Denmark.
Rønningen
K S
KS
Bergholdt
R
R
Lorenzen
T
T
Johannesen
J
J
Ye
K
K
Dinarello
C A
CA
Nerup
J
J
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002889:Chromosomes, Human, Pair 2; D004276:DNA, Satellite / Q000235:genetics; D003718:Denmark / Q000453:epidemiology; D003922:Diabetes Mellitus, Type 1 / Q000208:ethnology / Q000235:genetics*; D004198:Disease Susceptibility / Q000208:ethnology; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D012795:Sialoglycoproteins / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics
D015415:Biomarkers; D004276:DNA, Satellite; D005819:Genetic Markers; D006680:HLA Antigens; D018840:HSP70 Heat-Shock Proteins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008233:Lymphotoxin-alpha; D012795:Sialoglycoproteins; D013482:Superoxide Dismutase