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Variation within Genes Encoding Interleukin-1 and the Interleukin-1 Receptor Antagonist Influence the Severity of Meningococcal Disease[dhelix]

Robert C. Read, MD, FRCP; Chris Cannings, PhD; Simone C. Naylor, BSc; Janine M. Timms, BSc; Ravi Maheswaran, MD, MFPH; Raymond Borrow, PhD; Edward B. Kaczmarski, MD, MRCPath; and Gordon W. Duff, PhD, FRCP
[+] Article and Author Information

From University of Sheffield Medical School, Sheffield, and Meningococcal Reference Unit for England and Wales, Manchester Public Health Laboratory, Manchester, United Kingdom.


For definitions of terms, see Glossary.

Acknowledgments: The authors thank Dr. M.W. McKendrick for helpful discussions, Pauline A. Whitaker for administrative assistance, and all Consultants in Communicable Disease who helped obtain demographic information.

Grant Support: By the Meningitis Research Foundation (award 4/00), Thornbury, Bristol, United Kingdom.

Potential Financial Conflicts of Interest:Consultancies: C. Cannings (Interleukin Genetics, Myriad Genetics), G.W. Duff (Interleukin Genetics); Stock ownership or options (other than mutual funds): R.C. Read (Interleukin Genetics; University of Sheffield is a stockholder), C. Cannings (Myriad Genetics), G.W. Duff (Interleukin Genetics; University of Sheffield is a stockholder); Grants received: G.W. Duff (Interleukin Genetics); Patents received: G.W. Duff (Interleukin Genetics).

Requests for Single Reprints: Robert C. Read, MD, FRCP, Division of Genomic Medicine, F Floor, University of Sheffield School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, United Kingdom; e-mail, r.c.read@sheffield.ac.uk.

Current Author Addresses: Drs. Read, Cannings, Duff, Ms. Naylor, and Ms. Timms: Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, United Kingdom.

Dr. Maheswaran: School of Health and Related Research, University of Sheffield, Regent Court, 30 Regent Street, Sheffield S1 4DA, United Kingdom.

Drs. Borrow and Kaczmarski: Meningococcal Reference Unit, Manchester Public Health Laboratory, Withington Hospital, Manchester M20 8LR, United Kingdom.

Author Contributions: Conception and design: R.C. Read, R. Borrow, E.B. Kaczmarski, G.W. Duff.

Analysis and interpretation of the data: R.C. Read, C. Cannings, S.C. Naylor, J.M. Timms, R. Maheswaran, R. Borrow, E.B. Kaczmarski.

Drafting of the article: R.C. Read.

Critical revision of the article for important intellectual content: R.C. Read, C. Cannings, J.M. Timms, R. Maheswaran, R. Borrow, E.B. Kaczmarski, G.W. Duff.

Final approval of the article: R.C. Read, C. Cannings, S.C. Naylor, J.M. Timms, R. Maheswaran, R. Borrow, E.B. Kaczmarski, G.W. Duff.

Provision of study materials or patients: R. Borrow, E.B. Kaczmarski.

Statistical expertise: C. Cannings, R. Maheswaran.

Obtaining of funding: R.C. Read, E.B. Kaczmarski, G.W. Duff.

Administrative, technical, or logistic support: S.C. Naylor, J.M. Timms.

Collection and assembly of data: R.C. Read, S.C. Naylor, R. Maheswaran, R. Borrow, E.B. Kaczmarski.


Ann Intern Med. 2003;138(7):534-541. doi:10.7326/0003-4819-138-7-200304010-00009
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In this study of patients with confirmed meningococcal disease, we examined the frequency of well-described variants in the IL-1 gene cluster. We restricted our analysis to two polymorphic sites (IL1B[−511] and IL1RN[+2018]) because we previously found an effect of IL-1 genotype in meningococcal disease (which was confined to these two SNPs) in a separate and smaller sample for which genotyping was done at several sites in the IL-1 gene cluster (13). In the current study, we sought to exclude confounding effects of age, infecting serogroup, and socioeconomic status. With these variables included in a logistic regression model, we found that IL1B(−511) was associated with outcome; patients carrying the common allele at this site were more likely to survive. However, among the group carrying the common allele at IL1B(−511), we found an additional effect on likelihood of survival, which was conditional on genotype at IL1RN(+2018). Patients carrying the rare allele at IL1RN(+2018) were less likely to survive than those who did not carry the rare allele. In our previous, smaller study of 276 patients who were between 4 and 70 years of age, 39 died, and the association between death and genotype at IL1B(−511) was significant. The composite genotype consisting of heterozygosity of IL1B(−511), together with homozygosity of the common allele at IL1RN(+2018), was significantly associated with survival. Therefore, the current study confirms a relationship between allelic variation of the IL-1 gene cluster and meningococcal disease. The study sample is large enough to provide more detailed information about this relationship and includes patients of all ages.

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Figures

Grahic Jump Location
Figure 1.
The interleukin-1 (IL-1) gene cluster.kbIL1AIL1BIL1RNIL1BIL1BIL1RNVNTR

Within a 430-kilobase ( ) region of human chromosome 2q, three genes of the IL-1 cluster— , , and —encode IL-1α, IL-1β (two distinct proteins that perform the functions of IL-1), and the IL-1 receptor antagonist, respectively. Each of these genes contains several polymorphisms, but the figure shows only those investigated in this study. (−511) is located 511 nucleotides upstream of the transcriptional start-site of and is in near-total linkage disequilibrium with another polymorphism at −31 (the minus and plus signs denote the location of the polymorphism relative to the site where messenger RNA transcription begins). The gene contains a variable-number tandem repeat ( ) with which a polymorphism at (+2018) is also in linkage disequilibrium. The horizontal bars indicate the part of the gene that encodes the three proteins. The arrows indicate the direction of transcription of the DNA sequence into messenger RNA.

Grahic Jump Location
Grahic Jump Location
Figure 2.
The Meningococcal Reference Unit confirms the identity of allNeisseria meningitidisisolates recovered from blood and cerebrospinal fluid at hospitals throughout England and Wales and also receives blood samples for polymerase chain reaction (PCRN. meningitidis.N. meningitidis

) detection of Culture or PCR detection of in blood or cerebrospinal fluid samples was accepted as microbiological evidence of meningococcal disease.

Grahic Jump Location

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Summary for Patients

Gene Forms and Meningococcal Disease

The summary below is from the full report titled “Variation within Genes Encoding Interleukin-1 and the Interleukin-1 Receptor Antagonist Influence the Severity of Meningococcal Disease.” It is in the 1 April 2003 issue of Annals of Internal Medicine (volume 138, pages 534-541). The authors are R.C. Read, C. Cannings, S.C. Naylor, J.M. Timms, R. Maheswaran, R. Borrow, E.B. Kaczmarski, and G.W. Duff.

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