Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist

Mansfield, John C.; Holden, Hazel M.; Tarlow, Joanna K.; Giovine, F. S. Di; McDowell, Tarra L.; Wilson, Anthony G.; Holdsworth, C D; Duff, Gordon W.

doi:10.1016/0016-5085(94)90696-3

Cited by 388 publications

(244 citation statements)

References 29 publications

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“…Other possibilities include genuine locus or allele heterogeneity among different populations and differences in risk-allele frequencies among studies (46)(47)(48). Substantial differences in IL1RN VNTR frequencies have been reported among different ethnic groups (9,10,25,41,49). Samples of similar size may have very different power to detect associations, depending on the frequency of the risk allele.…”

Section: Discussionmentioning

confidence: 99%

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

Maksymowych¹,

Reeve²,

Reveille³

et al. 2003

Arthritis & Rheumatism

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Objective. To examine single-nucleotide polymorphisms (SNPs) in the 3 region of the IL1RN gene in a large Caucasoid case-control series and in ankylosing spondylitis (AS) families from Western Canada by use of high-throughput MassArray matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry SNP typing.Methods. An association analysis was performed in a case-control cohort of 394 AS cases and 500 controls. Family-based association analysis was performed in 58 simplex and 13 multiplex families. Three SNPs located in the 3 region of the IL1RN gene (T/C at position 27810 in exon 4, T/C at position 30735 in exon 6, and G/C at position 31017 in exon 6) were examined by high-throughput MassArray MALDI-TOF mass spectrometry. Haplotype inference software programs were used to infer the most likely haplotypes and to compare haplotype frequencies, which were then further analyzed in family-based association studies by transmission disequilibrium tests.Results. The frequency of allele C at SNP position 30735 in exon 6 was significantly increased in AS cases (35.1%) versus controls (27.8%), as was the phenotype frequency (61.7% versus 48.6%). A significantly increased frequency of SNP allele G at position 31017 in exon 6 in cases (32.9%) versus controls (28.3%) was also noted. A highly significant difference in the overall distribution of haplotype frequencies was evident between cases and controls, with significant increases in the frequencies of the 27810C/30735C/31017C and 27810C/30735T/31017G haplotypes, but a significant reduction in the estimated frequency of the 27810C/ 30735T/31017C haplotype, in the AS cases. Estimation of haplotype frequencies based on 2 SNP markers indicated a highly significant increase in the 30735C/ 31017C haplotype and a highly significant decrease in the 30735T/31017C haplotype in cases compared with controls. Preliminary evidence for reduced transmission of the 27810C/30735T/31017C 3-marker haplotype was also found in family-based association analyses. Conclusion. Our data establish a highly significant disease association with markers in the IL1RN gene. In the absence of nonsynonymous coding sequence substitutions, it is possible that the primary diseaseassociated locus regulates gene expression. Association with specific haplotypes raises the possibility that the primary disease locus is in linkage disequilibrium with a specific combination(s) of markers in the IL1RN gene.Genetic modeling studies in twins have suggested that 97% of the population variance for developing ankylosing spondylitis (AS) can be explained by additive genetic effects, while comparison of disease concordance in identical twins (75%) versus HLA-B27-concordant dizygotic twins (27%) points to an important Dr. Maksymowych is a Senior Scholar with the Alberta

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Section: Discussionmentioning

confidence: 99%

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

Maksymowych¹,

Reeve²,

Reveille³

et al. 2003

Arthritis & Rheumatism

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“…The IL1B-31T/C biallelic polymorphism was genotyped by PCR-CTPP (PCR with confronting 2-pair primers) according to Hamajima et al 29 The PCR-restriction fragment length polymorphism (RFLP) method was used for the IL1B-511C/T biallelic polymorphism genotyping by using the primers and the PCR conditions described by Mansfield et al 30 The PCR products were digested with AvaI (Promega, Madison, WI) overnight at 378C and resolved in 2% agarose gel that was stained with ethidium bromide. The genotypes were designated as follows: C/C, 2 bands of 114 and 190 bp; C/T, 3 bands of 114, 190 and 304 bp; and T/T, a single band of 304 bp.…”

Section: Pcr Analysismentioning

confidence: 99%

“…IL1RN pentaallelic variable-number tandem repeats (VNTR) was genotyped according to Mansfield et al 30 The polymorphism was based on the number of repeats of an 86 bp and the alleles were coded conventionally as follows: allele 1, 4 repeats (410 bp); allele 2, 2 repeats (210 bp); allele 3, 5 repeats (500 bp); allele 4, 3 repeats (325 bp); and allele 5, 6 repeats (595 bp). For statistical analysis and due to the rarity of alleles 3, 4 and 5, this polymorphism was treated as biallelic by classifying the alleles in short (allele 2) and long (alleles 1, 3, 4 and 5) categories.…”

Section: Pcr Analysismentioning

confidence: 99%

“…For statistical analysis and due to the rarity of alleles 3, 4 and 5, this polymorphism was treated as biallelic by classifying the alleles in short (allele 2) and long (alleles 1, 3, 4 and 5) categories. 10 For investigating the G/A substitution at À307 position of TNFA, a 107 bp fragment of this region was amplified by PCR-RFLP using the primers and conditions described by Mansfield et al 30 …”

Section: Pcr Analysismentioning

confidence: 99%

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IL1RN polymorphic gene and cagA‐positive status independently increase the risk of noncardia gastric carcinoma

Rocha

Guerra

Rocha

et al. 2005

Intl Journal of Cancer

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Helicobacter pylori cagA-positive strains and host cytokine proinflammatory polymorphisms have been associated with gastric carcinoma. However, the individual role of each factor has not been evaluated yet. Our aim was to evaluate whether IL-1 gene cluster and tumor necrosis factor-a (TNFA)-307 polymorphisms, as well as cagA-positive status, are associated with gastric carcinoma in a non-Caucasian population by analyzing the data in logistic regression models. We evaluated 166 patients with noncardia gastric carcinoma and 541 blood donors. Among them, 702 were successfully genotyped for all cytokine studied: 166 with gastric carcinoma and 536 controls. The carcinoma patients were considered to be H. pylori-positive if culture alone or 2 among preformed urease test, stained smear or histologic section, serology, polymerase chain reaction (PCR) for ureA and urea breath test were positive. In blood donors, H. pylori status was based on enzyme-linked immunosorbent assay. The cagA status was determined by PCR or serology. IL1B-511/-31, IL1RN (interleukin-1 receptor antagonist) and TNFA-307 polymorphisms were genotyped by PCR, PCR with restriction fragment length polymorphism, or PCR with confronting 2-pair primers. We found that the IL1RN2 polymorphic allele (OR 5 1.93) was associated with noncardia gastric carcinoma, even after inclusion of age, gender and cagA status in the logistic models. However, the cagA-positive status was the strongest independent factor associated with gastric carcinoma (OR 5 11.89). The other polymorphisms were not significantly associated with the disease when they were evaluated in logistic models. This study provides evidence supporting the independent associations of cagA-positive H. pylori status and IL1RN polymorphisms with noncardia gastric carcinoma. ' 2005 Wiley-Liss, Inc.

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“…The 4-repeat (ILlRN*l) and 2-repeat (ILlRN*2) alleles are relatively common, while 3-repeat and 5-repeat alleles occur at much lower frequencies, and the 6-repeat allele is so rare as not to be represented in this study. We have found associations of ILIRN*2 with several diseases, including psoriasis (43), ulcerative colitis (44), and diabetes mellitus (45). In the present study, we compared allele and genotype frequencies in the normal population with those in a cohort of patients with SLE, in order to test the association with ILIRN*2.…”

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confidence: 94%

Interleukin–1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus

Blakemore

Tarlow

Cork

et al. 1994

Arthritis & Rheumatism

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262

133

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Objective. We have previously described associations between an allele of the interleukin-1 receptor antagonist gene (ILlRN) and several inflammatory diseases. In this study we tested the ILlRN gene as a possible marker in patients with systemic lupus erythematosus (SLE).Methods. Eighty-one SLE patients and 261 ethnically matched control subjects were genotyped by polymerase chain reaction.Results. We found an increase in both frequency and carriage rate of ILlRN*2 in the SLE group. This association strengthened with extensive disease and particularly with the presence of photosensitivity and discoid skin lesions.Conclusion. We describe a novel association between ILlRN*2 and SLE. Carriage of the allele seems to influence severity rather than susceptibility to SLE. We postulate that the association of this polymorphism with disease severity is a widespread feature of common inflammatory and autoimmune diseases.

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Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist

Cited by 388 publications

References 29 publications

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

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

IL1RN polymorphic gene and cagA‐positive status independently increase the risk of noncardia gastric carcinoma

Interleukin–1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus

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