title: 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 Hinfl 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 Hinfl 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.
authors.affiliation: Steno Diabetes Center, DK-2820 Gentofte, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Bergholdt
authors.forename: Z M
authors.initials: ZM
authors.lastname: Larsen
authors.forename: N A
authors.initials: NA
authors.lastname: Andersen
authors.forename: J
authors.initials: J
authors.lastname: Johannesen
authors.forename: O P
authors.initials: OP
authors.lastname: Kristiansen
authors.forename: T
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.forename: J
authors.initials: J
authors.lastname: Nerup
authors.forename: F
authors.initials: F
authors.lastname: Pociot
mesh_terms: D020121:5' Untranslated Regions; D001483:Base Sequence; D018076:DNA, Complementary; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology; D008040:Genetic Linkage; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017472:Receptors, Interleukin-1 / Q000097:blood / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D018076:DNA, Complementary; D017472:Receptors, Interleukin-1; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1