Genetic Susceptibility Markers in Danish Patients with Type 1 (Insulin-Dependent) Diabetes-Evidence for Polygenecity in Man

Abstract

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).

Genetics of type 1 diabetes mellitus

“…128,129 Furthermore, polymorphisms of the SOD2 gene have been associated with T1D susceptibility. 130 Structural variants of the MnSOD protein with reduced activity have been reported, 131 and such variants might be hypothesised to increase predisposition to T1D.…”

“…142,143 A number of genes have been proposed and investigated as candidate genes for the IDDM7 region. These include genes of the interleukin-1 gene cluster (ie IL1R1, [144][145][146] IL1B, 130,147,148 and IL1RN 130,149 ) HOXD8, 150 GAD1, 151 GALNT3, 141 and NEUROD. [152][153][154] However, linkage or association has not been convincingly demonstrated for any of these candidate genes.…”

High‐throughput single‐nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry

“…Two case-control studies from Scotland and The Netherlands have shown a disease association with allele 2 of a variable-number tandem repeat (VNTR) in intron 2 of the IL1RN gene (9,10). This same allele has been associated with insulin-dependent diabetes mellitus, lichen sclerosus, psoriasis, ulcerative colitis, systemic lupus erythematosus, diabetic nephropathy, multiple sclerosis, essential hypertension, attention deficit hyperactivity disorder, and alopecia areata, as well as survival following severe sepsis (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). An increase in the frequency of allele 2 was also noted in juvenile arthritis, particularly in patients with oligoarticular disease and enthesitis (25).…”

IL-1β induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis

“…Described strain differences in rat islet sensitivity to IL-1β and nitric oxide might be due to different capacities to mount a free radical defence [14]. Hereditary catalase deficiencies and polymorphisms in the MnSOD gene are reported to increase the risk for Type I diabetes [79,80,81].…”