Five Novel Intragenic Dimorphisms in the Human Interleukin–1 Genes Combine to High Informativity

Guasch, Joan Francesc; Bertina, Rogier M.; Reitsma, Pieter H.

doi:10.1006/cyto.1996.0080

Cited by 86 publications

(54 citation statements)

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“…In addition, rather low linkage disequilibrium between markers in the 5Ј and 3Ј regions of the IL1RN gene was shown in earlier studies (43,45), which could explain why our data demonstrated significant associations with SNPs in the 3Ј region. Other possibilities include genuine locus or allele heterogeneity among different populations and differences in risk-allele frequencies among studies (46)(47)(48).…”

Section: Discussionsupporting

confidence: 62%

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: Discussionsupporting

confidence: 62%

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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“…Campbell, unpublished observations). A single base change in IL-1 (Ϫ31) that changes the TATA box and is associated with differential binding of transcription factors and enhanced susceptibility to Helicobacter pylori infection and gastric cancer (36,37). Likewise, in a study of scleroderma, IL-4 VNTR polymorphism has been hypothesized to affect transcriptional activity, inducing IL-4 overexpression and leading to a shift in the Th1/Th2 balance towards Th2 (23).…”

Section: Discussionmentioning

confidence: 99%

Association of interleukin‐4 and interleukin‐1B gene variants with Larsen score progression in rheumatoid arthritis

Genevay¹,

Giovine²,

Perneger³

et al. 2002

Arthritis & Rheumatism

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Objective. To perform a genetic association study using markers in the interleukin-1 (IL-1) gene cluster and the IL-4/IL-4 receptor system genes, seeking evidence for involvement in the onset or the erosive outcome of rheumatoid arthritis (RA). Methods. We tested the allelic distribution of IL-1A (؉4845), IL-1B (؊511), IL-1B (؉3954), IL-1RN (؉2018), IL-4 variable number of tandem repeat (VNTR), and IL-4R (؉1902) in 233 patients with RA, 99 with polymyalgia rheumatica, and 148 ethnically matched controls. We analyzed the frequency of these gene variants in respect to presence of disease, but also to the degree of radiologic erosions (Larsen score) as a function of disease duration in 157 patients who had available radiographs of both hands. Results. None of the 6 genetic polymorphisms was significantly different in frequency between RA patients and healthy controls or patients with polymyalgia rheumatica. Among RA patients, the rarer (#2) alleles of IL-4 VNTR and IL-1B (؊511) were both associated with a milder Larsen score progression: The slope of Larsen progression in the rare allele groups diverged significantly from those of the frequent allele groups after approximately 20 years of disease duration (P < 0.001). Conclusion. None of the markers tested were shown to be associated with increased or decreased risk of RA. The rarer alleles of IL-4 VNTR and IL-1B (؊511) appear to be associated with a less severe course in RA of long duration.

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“…Alleles at the loci of IL1B were typed using polymerase chain reaction (PCR)-RFLP methods as described elsewhere. 25,26,35 Tandem repeat polymorphism in the second intron of IL1RN was analyzed by PCR-gel electrophoresis as described. 13 a Number of alleles.…”

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confidence: 99%

T helper 1-type immunity to trophoblast antigens in women with a history of recurrent pregnancy loss is associated with polymorphism of the IL1B promoter region

et al. 2002

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Recurrent pregnancy loss (RPL) is a common disorder during early gestation. Recent evidence suggests that T helper 1 (Th1)-type immunity is associated with unsuccessful pregnancy especially in women with RPL of otherwise unknown etiology, while Th2-type immunity is associated with pregnancy success. Interleukin (IL)-1 may influence Th1/Th2 immune responsiveness and has been implicated in the establishment of successful pregnancy. In the present study, we investigated polymorphism of the IL-1␤ gene (IL1B) in women with a history of RPL. Significant increases in the frequencies of IL1B promoter region variants IL1-511C and IL1B-31T were found in women with a history of RPL. Increased frequencies of these two variants and their homozygotes were found only in cases having evidence of Th1 immunity to trophoblast as determined by IFN-␥ production of peripheral blood mononuclear cells (PBMCs) stimulated with a trophoblast cell-line extract. Significantly higher IFN-␥ production by PBMCs in response to trophoblast correlated with variant IL1B-511C and its homozygocity in women with RPL. These results suggest that variants −511C and −31T in the IL1B promoter region confer risk for RPL associated with Th1 immunity to trophoblast antigens.

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Five Novel Intragenic Dimorphisms in the Human Interleukin–1 Genes Combine to High Informativity

Cited by 86 publications

References 0 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

Association of interleukin‐4 and interleukin‐1B gene variants with Larsen score progression in rheumatoid arthritis

T helper 1-type immunity to trophoblast antigens in women with a history of recurrent pregnancy loss is associated with polymorphism of the IL1B promoter region

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