Molecular Cloning of the Interleukin-1 Gene Cluster: Construction of an Integrated YAC/PAC Contig and a Partial Transcriptional Map in the Region of Chromosome 2q13

doi:10.1006/geno.1997.4654

Genomics

Volume 41, Issue 3, 1 May 1997, Pages 370-378

https://doi.org/10.1006/geno.1997.4654 Get rights and content

Abstract

Genes of the interleukin-1 (IL-1) gene cluster localized on chromosome 2q13 are implicated in many physiological and pathophysiological processes. We present here a high-resolution physical map of this region between markers D2S2008 and D2S43/PAX8. An integrated YAC/PAC contig and a partial transcriptional map were constructed by STS-content mapping using the CEPH YAC library and three PAC libraries. A total of 3 YACs, 34 PACs, and 56 STSs were integrated: 33 newly generated probes to PAC end sequences, 9 polymorphic and 4 nonpolymorphic markers, 5 known genes, 4 expressed sequence tags, and 1 pseudogene. Within the map, a complete PAC contig of >1 Mb encompasses the IL-1 gene cluster and PAX8, a paired-box-containing gene. This allowed us to define the transcriptional orientation of GLVR1, IL1B, and IL1RN and to show that PAX8 is localized outside the IL-1 gene cluster. FISH analysis localized PAC clones containing the IL-1 gene cluster to 2q12–q13. The data provide the basis for further characterization of the IL-1 gene cluster and for the construction of a sequence-ready PAC contig of this region.

References (46)

J.C. Gingrich et al.
Construction and characterization of human chromosome 2-specific cosmid, fosmid, and PAC clone libraries
Genomics
(1996)
F. Hildebrandt et al.
Refined genetic mapping of a gene for familial juvenile nephronophthisis (NPH1) and physical mapping of linked markers
Genomics
(1995)
M. Konrad et al.
An 11-Mb YAC-based contig spanning the familial juvenile nephronophthisis region (NPH1) located on chromosome 2q
Genomics
(1995)
C. Lengauer et al.
Fluorescencein situAlu
Genomics
(1992)
P. Li et al.
Mice deficient in IL-1b-converting enzyme are defective in production of mature IL-1b and resistant to endotoxic shock
Cell
(1995)
M. Medhioub et al.
Refined mapping of a gene (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity
Genomics
(1994)
M.J.H. Nicklin et al.
A physical map of the region encompassing the human interleukin-1α, interleukin-1β and interleukin-1 receptor antagonist genes
Genomics
(1994)
K. Osoegawa et al.
An integrated map with cosmid/PAC contigs of a 4-Mb Down syndrome critical region
Genomics
(1996)
D.L. Rossi et al.
Function of the homeo and paired domain proteins TTF-1 and PAX-8 in thyroid cell proliferation
J. Biol. Chem.
(1995)
N.L. Sternberg
Cloning high molecular weight DNA fragments by the bacteriophage P1 system
Trends Genet.
(1992)

L.K. Ashworth et al.

An integrated metric physical map of human chromosome 19

Nature Genet.

(1995)

J.F. Bazan et al.

A newly defined interleukin-1?

Nature

(1996)

R. Berry et al.

Gene-based sequence tagged sites (STSs) as the basis for a human gene map

Nature Genet.

(1995)

A.J. Buckler et al.

Exon amplification: A strategy to isolate mammalian genes based on RNA splicing

Proc. Natl. Acad. Sci. USA

(1991)

H. Cheng et al.

Isolation and mapping of human chromosome 21 cDNA: Progress in constructing a chromosome 21 expression map

Genomics

(1994)

I.M. Chumakov et al.

A YAC contig map of the human genome

Nature

(1995)

K. Chowdhury

One step “miniprep” method for the isolation of plasmid DNA

Nucleic Acids Res.

(1991)

D.M. Church et al.

Isolation of genes from complex sources of mammalian genomic DNA using exon amplification

Nature Genet.

(1994)

S. Cox et al.

Integrated genetic map of human chromosome 2

Ann. Hum. Genet.

(1995)

D.R. Cox et al.

A map to the future

Nature Genet.

(1996)

C. Dib et al.

A comprehensive genetic map of the human genome based on 5264 microsatellites

Nature

(1996)

C.A. Dinarello et al.

The role of interleukin-1 in disease

N. Engl. J. Med.

(1993)

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Citation Excerpt :
However, the association of NLRP3 (rs4612666) SNP with CP has not been described. In addition to the former, the production of IL-1β might be also synchronously modulated by the presence of a functional SNP at the position +3954 of the IL-1B gene (rs1143634) located in the exon 5 of the chromosome 2q13, where a transition between C and T occurs (Pociot, Mølvig, Wogensen, Worsaae, & Nerup, 1992; Nothwang et al., 1997). Nevertheless, the results of association of IL-1B +3954 SNP regarding chronic periodontitis have been conflictive, because while some researchers have found no evidence for association between IL-1B +3954 SNP and CP (Trevilatto, de Souza Pardo, Scarel-Caminaga, Alvim-Pereira, & Alvim-Pereira, 2011; Boukortt et al., 2015; Yücel et al., 2013), others authors have showed a strong association of the CT genotype with disease status in different populations (Shete, Joseph, Vijayan, Srinivas, & Banerjee, 2010; Masamatti, Kumar, Baron, Mehta, & Bhat, 2012; Amirisetty et al., 2015).
The focus of the current study was to identify if a possible association between NLRP3 (rs4612666) and IL-1B (rs1143634) single-nucleotide polymorphisms (SNPs) may be implicated in the etiopathogenesis of chronic periodontitis (CP) in a Colombian population.
One hundred and twenty-four CP subjects and 81 periodontally healthy controls (HC) were recruited. Periodontal status was assessed by criteria based on probing depth, clinical attachment level, extent, and severity of periodontal breakdown. Human genomic DNA was obtained from saliva samples of the study subjects. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to identify the NLRP3 (rs4612666) and IL-1B (rs1143634) SNPs. The association of polymorphisms with CP was assessed individually and adjusted for confounding using a multivariate binary logistic regression model.
Bivariate analysis showed a weak association between CT genotype of NLRP3 (rs4612666) SNP and CP, however after logistic regression analysis, neither NLRP3 (rs4612666) nor IL-1B (rs1143634) polymorphisms were strongly/independently associated with disease status. Even so, an interaction effect was significantly detected not only among CT/CC genotypes of NLRP3 gene regarding to the age stratum ≥48 years, but also between CC genotype of the same gene and smoking habit.
Although the present results do not support that IL-1B (rs1143634) SNP could be identified as a risk predictor for CP in the present population, the synergistic interaction of the CT/CC genotypes of NLRP3 (rs4612666) SNP with ageing and/or smoking habit potentially might play a significant role in the pathogenic pathways of periodontal disease.
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Proinflammatory genotype of interleukin-1 and interleukin-1 receptor antagonist is associated with ESRD in proteinase 3-ANCA vasculitis patients
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Small-vessel vasculitides are associated with antineutrophil cytoplasmic antibodies (ANCAs). Cytoplasmic ANCAs are targeted mainly against proteinase 3 (PR3), whereas myeloperoxidase (MPO) is the major antigen of perinuclear ANCAs. These relapsing vasculitides show heterogeneous clinical pictures, and disease severity may vary broadly from mild local organ manifestation to acute organ failure (eg, renal failure). We tested whether two cytokine polymorphisms in the interleukin-1β (IL-1β) and IL-1 receptor antagonist (IL-1ra) genes, known to determine cytokine secretion, are associated with clinical manifestations and outcome of ANCA-associated vasculitides.
Polymerase chain reaction and restriction fragment length polymorphism analyses were performed to determine polymorphisms in the IL-1β and IL-1ra genes in 79 patients with PR3-ANCA, 30 patients with MPO-ANCA vasculitis, and 196 healthy controls.
The frequency of the so-called proinflammatory genotype, characterized by high secretion of IL-1β and low secretion of its antagonist IL-1ra, was increased significantly in patients with PR3-ANCA with end-stage renal disease.
Patients with a renal manifestation of PR3-ANCA vasculitis have an increased risk for developing end-stage renal disease when carrying the proinflammatory IL-1β/IL-1ra genotype. Anti-inflammatory therapy specifically antagonizing the proinflammatory effect of IL-1β may be a promising treatment for patients with Wegener′s granulomatosis with renal manifestations.
A sequence-based map of the nine genes of the human interleukin-1 cluster
2002, Genomics
Six novel genes encoding proteins with the interleukin (IL)-1 fold have been identified recently. The classical family members are involved in inflammatory signaling. Previous work has placed the novel genes close to or within the same cluster as IL1A, IL1B, and IL1RN, which occupy an ∼400-kb interval on chromosome 2. We have combined the incomplete public database sequence with our own sequence to generate a reference sequence and map that encompass all of the novel genes, allowing determination of the gene structures, precise localization of exons, and determination of distances between conventional SNP and microsatellite markers. Gene order from centromere to telomere is IL1A-IL1B-IL1F7-IL1F9-IL1F6-IL1F8-IL1F5-IL1F10-IL1RN, of which only IL1A, IL1B, and IL1F8 are transcribed towards the centromere. The gene order relates to the volutionary relationship between the genes. Key features of exon boundaries are conserved. There is no evidence for other IL-1 family members within the cluster.
Genome studies and linkage in primary osteoarthritis
2002, Rheumatic Disease Clinics of North America
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2000, Biochemical and Biophysical Research Communications
Genes of the IL-1 family encode three different peptides, IL-1α, IL-1β, and IL-1Ra, respectively. IL-1 operates through IL-1RI, and is involved in airway inflammation in asthmatic subjects, whereas IL-1Ra appears to be a specific competitive inhibitor of IL-1. All genes are on chromosome 2q12-21 where genomewide searches have identified linkage for asthma. To test whether variants of IL-1 relate to asthma, we conducted a genetic association study in a Japanese population. We show that the A2 allele of IL1RN (encoding IL-1Ra) associates with nonatopic asthma [OR = 5.71, 95% CI: 1.63–19.8, Pc = 0.007]. Both atopic and nonatopic asthmatics with the A2 allele had significantly lower serum IL-1Ra levels in both types of asthmatics. Peripheral blood cells from asthmatics with A2 alleles, however, produced as much IL-1 as did those with A1 homozygotes. Since Th1 and Th2 cytokines differentially regulate the ratio between IL-1β and IL-1Ra, these findings suggest that dysregulation of IL-1β/IL-1Ra, probably due to interaction between epithelium and immuno-competent cells in the airway, is important in asthma inflammation.

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^☆: Sequence data from this article have been deposited with the GenBank Data Library under Accession Nos. U68351–U68379.

^☆☆: D. E. RooneyB. H. Czepulkowski, Eds.

¹: To whom correspondence should be addressed at the University Children's Hospital, Mathildenstrasse 1, D-79106 Freiburg, Germany. Telephone: +49 (761) 270 4301. Fax: +49 (761) 270 4481. E-mail: [email protected].

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Regular ArticleMolecular Cloning of the Interleukin-1 Gene Cluster: Construction of an Integrated YAC/PAC Contig and a Partial Transcriptional Map in the Region of Chromosome 2q13☆,☆☆

Abstract

Genomics

Genomics

Genomics

Genomics

Cell

Genomics

Genomics

Genomics

J. Biol. Chem.

Trends Genet.

An integrated metric physical map of human chromosome 19

Nature Genet.

A newly defined interleukin-1?

Nature

Gene-based sequence tagged sites (STSs) as the basis for a human gene map

Nature Genet.

Exon amplification: A strategy to isolate mammalian genes based on RNA splicing

Proc. Natl. Acad. Sci. USA

Isolation and mapping of human chromosome 21 cDNA: Progress in constructing a chromosome 21 expression map

Genomics

A YAC contig map of the human genome

Nature

One step “miniprep” method for the isolation of plasmid DNA

Nucleic Acids Res.

Isolation of genes from complex sources of mammalian genomic DNA using exon amplification

Nature Genet.

Integrated genetic map of human chromosome 2

Ann. Hum. Genet.

A map to the future

Nature Genet.

A comprehensive genetic map of the human genome based on 5264 microsatellites

Nature

The role of interleukin-1 in disease

N. Engl. J. Med.

Regular Article
Molecular Cloning of the Interleukin-1 Gene Cluster: Construction of an Integrated YAC/PAC Contig and a Partial Transcriptional Map in the Region of Chromosome 2q13☆,☆☆