Characterization of new polymorphisms in the 5′UTR of the human interleukin-1 receptor type 1 (IL1R1) gene: linkage to type 1 diabetes and correlation to IL-1RI plasma level

Abstract

The human interleukin-1 type I receptor (IL-1RI) is the signal transducing receptor for IL-1, a principal proinflammatory cytokine, which is cytotoxic to pancreatic islet beta cells. The IL-1RI gene, IL1R1, maps to chromosome 2q12. We have previously examined part of the IL1R1 promoter region and in the present study we further characterized the promoter region demarcating exon 1B and 1C by sequencing and mutation scanning. New sequence was obtained 1762 bp upstream and 1609 bp downstream the known region. Within this sequence, we identified four frequent single nucleotide polymorphisms (SNPs). PCR-based RFLP assays were established and three of the polymorphisms were typed in a Danish Type 1 (insulin-dependent) diabetes mellitus (T1DM) family collection comprising 103 simplex and 150 sib-pair affected families. Linkage was evaluated by the sib-TDT (transmission disequilibrium test). One of the polymorphisms, defined by a HinfI RFLP assay, demonstrated linkage to T1DM, P(sTDT) = 0.026. Random transmission was observed to unaffected offspring from heterozygous parents, P = 0.87. No evidence for positive linkage was seen for the other tested polymorphisms, P = 0.14 and P = 0.21, respectively. To evaluate the possible functional significance of the HinfI polymorphism, we measured circulating IL-1RI plasma level in 30 T1DM patients and in 30 control subjects -10 with each genotype in both groups. Significant differences in plasma levels in relation to genotype -independent of disease status -were found (P = 0.04). In both diabetic and non-diabetic subjects, the wt/wt genotype correlated with the highest IL-1RI plasma level, whereas the plasma levels were lowest for the mt/mt genotype. Genes and Immunity (2000) 1, 495-500.

Extended haplotypes and linkage disequilibrium in the IL1R1–IL1A–IL1B–IL1RN gene cluster: association with knee osteoarthritis

“…Indeed, we, and others, have previously reported nucleotide sequence polymorphism in the promoter region spanning introns 1A-1C. [27][28][29][30][31] In the present report, we describe the identification and characterisation of a further eight novel polymorphisms in the IL1R1 promoter. Recently, a number of reports have indicated that polymorphic IL-1 haplotypes or extended haplotypes, as opposed to single locus polymorphisms, may provide better genetic markers of transcriptional activity and disease association, 32 in particular with the complex nature of the IL-1 agonist/antagonist relationship and the two IL-1 receptors.…”

Genetics of type 1 diabetes mellitus

“…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.…”

Genetic control of autoimmunity in Type I diabetes and associated disorders

“…A SNP allele in the interleukine1-type 1 receptor (IL1R1) apparently leads to low plasma concentrations of IL-1-R1 and was reported to be associated with type 1A diabetes [129]. In Japanese patients, but not in Italian patients, an Arg140Trp mutation has been identified in the CD38 gene, which is a non-lineage pleiotropic cell surface receptor.…”